28617242	The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.
28617195	Circadian regulation of hepatic detoxification seems to be amongst the key roles of the biological clock. The liver is the major site for biotransformation, and in mammals, it contains several clock-controlled transcription factors such as proline and acidic amino acid-rich basic leucine zipper proteins (PAR bZIP) and basic-helix-loop-helix Per-Arnt-Sim (bHLH-PAS) family that act as circadian regulators of detoxification genes. This investigation explored the existence of daily and circadian expression of transcription factors involved in detoxification, as well as the temporal profile of a set of their target genes in zebrafish liver. In our study, zebrafish were able to synchronize to a light-dark (LD) cycle and displayed a diurnal pattern of activity. In addition, the expression of clock genes presented daily and circadian rhythmicity in liver. Apart from hlfa, the expression of PAR bZIP transcription factors also displayed daily rhythms, which appeared to be both light-dependent and clock-controlled, as circadian rhythms free-ran under constant conditions (continuous darkness, DD). Under LD, tefb, dbpa and dbpb expression peaked at the end of the darkness period whereas tefa showed peak levels of expression at the onset of the photophase. In addition, these four genes exhibited circadian expression under DD, with higher expression levels at the end of the subjective night. The expression of the bHLH-PAS transcription factor arh2 also showed circadian rhythmicity in zebrafish liver, peaking in the middle of the subjective night and approximately 3-4 h before peak expression of the PAR bZIP genes. Regarding the detoxification genes, the major target gene of AhR, cyp1a, showed daily and circadian expression with an acrophase 2 h after ahr2. Under LD, abcb4 also showed daily rhythmicity, with an acrophase 1-2 h after that of PAR bZIP factors during the transition between darkness and light phases, when zebrafish become active. However, the expression of six detoxification genes showed circadian rhythmicity under DD, including cyp1a and abcb4 as well as gstr1, mgst3a, abcg2 and sult2_st2. In all cases, the acrophases of these genes were found during the second half of the subjective night, in phase with the PAR bZIP transcription factors. This suggested that their expression is clock-controlled, either directly by core clock genes or through transcription factors. This study presents new data demonstrating that the process of detoxification is under circadian control in fish. Results showed that time of day should be considered when designing toxicological studies or administering drugs to fish.
28617043	Eveningness is associated with greater depressive symptoms in the general population. Depression and type 2 diabetes (T2D) commonly coexist. We aimed to explore the association between morningness-eveningness and depressive symptoms in T2D patients in the United States and in Thailand.T2D patients (n = 182) from an endocrinology clinic in Chicago, Illinois, and six hospitals in Thailand (n = 251) were enrolled.	Diabetes history was collected. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale (CES-D). The Chicago cohort completed the Morningness-Eveningness Questionnaire (MEQ) and the Thai cohort completed the Composite Scale of Morningness (CSM). Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI).	The mean (SD) CES-D score was 13.7 (9.1) in Chicago and 11.9 (6.4) in Thailand. In Chicago participants, after adjusting for age, sex, ethnicity, hemoglobin A1c, insulin use, and PSQI score, greater eveningness (lower MEQ scores) was associated with higher CESD scores (B = -0.117, p = 0.048). In Thai participants, after adjusting for age, sex, and PSQI score, eveningness (lower CSM score) was associated with higher CES-D score (B = -0.147, p = 0.016). In both cohorts, however, eveningness was not independently associated with the likelihood of being in the at-risk range for clinical depression (CES-D ≥ 16).	Eveningness is independently associated with greater depressive symptoms in T2D in two different ethnic cohorts. The results support the association between individual differences in circadian rhythms and psychological functioning in T2D.	
28616776	Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10-16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.
28616659	This is the first report to clone and functionally characterize a flowering time gene GbCO in perennial gymnosperm Ginkgo biloba. GbCO complements the co mutant of Arabidopsis, restoring normal early flowering. CONSTANS (CO) is a central regulator of photoperiod pathway, which channels inputs from light, day length, and circadian clock to promote the floral transition. In order to understand the role of CO in gymnosperm Ginkgo biloba, which has a long juvenile phase (15-20 years), a CO homolog (GbCO) was isolated and characterized from G. biloba. GbCO encodes a 1741-bp gene with a predicted protein of 400 amino acids with two zinc finger domains (B-box I and B-box II) and a CCT domain. Phylogenic analysis classified GbCO into the group 1a clade of CO families in accordance with the grouping scheme for Arabidopsis CO (AtCO). Southern blot analysis indicated that GbCO belongs to a multigene family in G. biloba. Real-time PCR analysis showed that GbCO was expressed in aerial parts of Ginkgo, with the highest transcript level of GbCO being observed in shoot apexes. GbCO transcript level exhibited a strong diurnal rhythm under flowering-inductive long days and peaked during early morning, suggesting that GbCO is tightly coupled to the floral inductive long-day signal. In addition, an increasing trend of GbCO transcript level was observed both in shoot tips and leaves as the shoot growth under long-day condition, whereas GbCO transcript level decreased in both tissues under short-day condition prior to growth cessation of shoot in G. biloba. GbCO complemented the Arabidopsis co-2 mutant, restoring normal early flowering. All the evidence being taken together, our findings suggested that GbCO served as a potential inducer of flowering in G. biloba.
28616534	In patients with Brugada syndrome (BS), VF occurred predominantly during the nocturnal period. Some patients also developed ESs. In addition to the circadian rhythm, patients showed weekly and seasonal patterns. The patients with ESs had peak episodes of VF on Saturday and in the winter and spring, while episodes of VF in patients with single VF events occurred most often on Monday with smaller seasonal variation. Except for age, there was no difference in the clinical or ECG characteristics between the patients with ESs and those with single VF episodes.

28615472	Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the-clock active animals in a constant physical environment.
28615380	Background: Amino acids, especially leucine, are particularly effective in promoting protein synthesis. Leucine is known to increase the rate of protein synthesis in skeletal muscle through the mechanistic target of rapamycin complex 1-dependent, as well as -independent, signaling pathways. However, the overall translation program is poorly defined, and it is unknown how the activation of these pathways differentially controls the translation of specific mRNAs.Objective: Ribosome profiling and RNA sequencing were used to precisely define the translational program activated by an acute oral dose of leucine.Methods: Adult male C57BL/6 mice were deprived of food overnight before the delivery of an acute dose of l-leucine (9.4 mg) (n = 6) or vehicle (n = 5) and tissues collected 30 min later. Ribosome footprints and total RNA were isolated and subjected to deep sequencing. Changes in gene-specific mRNA abundance and ribosome occupancy were determined between the leucine-treated and control groups by aligning sequence reads to Reference Sequence database mRNAs and applying statistical features of the Bioconductor package edgeR.Results: Our data revealed mRNA features that confer translational control of skeletal muscle mRNAs in response to an acute dose of leucine. The subset of skeletal muscle mRNAs that are activated consists largely of terminal oligopyrimidine mRNAs (false discovery rate: <0.05), whereas those with reduced translation had 5' untranslated regions with increased length. Only the small nuclear RNAs, which are required for ribosome biogenesis, were significantly altered in RNA abundance. The inferred functional translational program activated by dietary leucine includes increased protein synthesis capacity and energy metabolism, upregulation of sarcomere-binding proteins, modulation of circadian rhythm, and suppression of select immune components.Conclusions: These results clarify the translation program acutely stimulated by leucine in mouse skeletal muscle and establish new methodologies for use in future studies of skeletal muscle disease or aging and further examination of downstream effects of leucine on gene expression.
28615046	Despite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance-collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications. These INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the leptin-proopiomelanocortin pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters' metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity. A systemic proinflammatory state in combination with activation of the renin-angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity. Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity.In conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment.	
28614626	The global prevalence of childhood overweight and obesity has increased in the last years. Epigenetic dysregulation affecting gene expression could be a determinant in early-life obesity onset and accompanying complications.The aim of the present investigation was to analyse the putative association between DNA methylation and childhood obesity.	DNA was isolated from white blood cells of 24 children obtained from the GENOI study and was hybridized in a 450K methylation array. Two CpG sites associated with obesity were validated in 91 children by MassArray® EpiTyper™ technology.	Genome-wide analysis identified 734 CpGs (783 genes) differentially methylated between cases (n = 12) and controls (n = 12). Ingenuity Pathway Analysis showed that these genes were involved in oxidative stress and circadian rhythm signalling pathways. Moreover, the DNA methylation levels of VIPR2, GRIN2D, ADCYAP1R1, PER3 and PTPRS regions correlated with the obesity trait. EpiTyper™ validation also identified significant correlations between methylation levels of CpG sites on PTPRS and PER3 with BMI z-score.	This study identified several CpG sites and specifically several CpGs in the PTPRS and PER3 genes differentially methylated between obese and non-obese children, suggesting a role for DNA methylation concerning development of childhood obesity.	
28613957	Morningness/eveningness (M/E) preference is an important circadian rhythm indicator with strong individual variation. M/E chronotype has been found to be correlated with depression in adults, yet the relationship is less clear in children and adolescents. Additionally, poor sleep quality is another commonly studied risk factor for depression. The aims of the present study are to investigate the independent effects of M/E chronotype on youth depression using both self-report and parental-report questionnaires. We also evaluated how poor sleep quality may affect the relationship through a mediating or moderating effect. In total, 2,139 students attending grades 1 to 7 participated in this study. They completed questionnaires regarding M/E chronotype, depression, and sleep quality. A total of 1,708 parents also participated and filled out parental-reports of emotional and behavioral problems of their children. The prevalence of self- and parental-report depression was 16.8% and 12.8% among young students, respectively. Overall, 15.4% of the students were the eveningness type. Being an eveningness type was independently associated with self-report depression after adjustment for poor sleep quality (OR = 1.86, 95% CI = 1.07-3.24). We also observed that poor sleep quality mediated the influence of M/E chronotype on self-report depression among students aged 7-13 years (p < 0.001). On the other hand, being an eveningness type was associated with a number of parental-report emotional and behavioral problems in the students, in addition to depression, although these associations become non-significant after adjusted for poor sleep quality. Our results demonstrate the importance of M/E chronotype on youth depression and poor sleep quality partly mediates this effect.
28611667	Increasing evidence indicates the occurrence of cognitive impairment in astronauts under spaceflight compound conditions, but the underlying mechanisms and countermeasures need to be explored. In this study, we found that learning and memory abilities were significantly reduced in rats under a simulated long-duration spaceflight environment (SLSE), which includes microgravity, isolation confinement, noises, and altered circadian rhythms. Dammarane sapogenins (DS), alkaline hydrolyzed products of ginsenosides, can enhance cognition function by regulating brain neurotransmitter levels and inhibiting SLSE-induced neuronal injury. Bioinformatics combined with experimental verification identified that the PI3K-Akt-mTOR pathway was inhibited and the MAPK pathway was activated during SLSE-induced cognition dysfunction, whereas DS substantially ameliorated the changes in brain. These findings defined the characteristics of SLSE-induced cognitive decline and the mechanisms by which DS improves it. The results provide an effective candidate for improving cognitive function in spaceflight missions.
28611660	Despite varied etiologies and symptoms, several neurodegenerative diseases-specifically, Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HDs)-share the common feature of abnormal circadian rhythms, such as those in behavior (e.g., disrupted sleep/wake cycles), physiological processes (e.g., diminished hormone release) and biochemical activities (e.g., antioxidant production). Circadian disturbances are among the earliest symptoms of these diseases, and the molecular mechanisms of the circadian system are suspected to play a pivotal, and possibly causal, role in their natural histories. Here, we review the common circadian abnormalities observed in ADs, PDs and HDs, and summarize the evidence that the molecular circadian clockwork directly influences the course of these disease states. On the basis of this research, we explore several circadian-oriented interventions proposed as treatments for these neurological disorders.
28611079	The absolute sensitivity of vertebrate retinas is set by a background noise, called dark noise, which originates from several different cell types and is generated by different molecular mechanisms. The major share of dark noise is produced by photoreceptors and consists of two components, discrete and continuous. Discrete noise is generated by spontaneous thermal activations of visual pigment. These events are undistinguishable from real single-photon responses (SPRs) and might be considered an equivalent of the signal. Continuous noise is produced by spontaneous fluctuations of the catalytic activity of the cGMP phosphodiesterase. This masks both SPR and spontaneous SPR-like responses. Circadian rhythms affect photoreceptors, among other systems by periodically increasing intracellular cAMP levels ([cAMP]in), which increases the size and changes the shape of SPRs. Here, we show that forskolin, a tool that increases [cAMP]in, affects the magnitude and frequency spectrum of the continuous and discrete components of dark noise in photoreceptors. By changing both components of rod signaling, the signal and the noise, cAMP is able to increase the photoreceptor signal-to-noise ratio by twofold. We propose that this results in a substantial improvement of signal detection, without compromising noise rejection, at the rod bipolar cell synapse.
28609096	To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [3H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [3H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).
28608287	In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We, therefore, studied GABA in the SCN in relation to the changes in arginine vasopressin (AVP), which is one of the major SCN output systems. Postmortem hypothalamus specimens of 13 subjects suffering from depression and of 13 well-matched controls were collected. Quantitative immunocytochemistry was used to analyze the protein levels of glutamic acid decarboxylase (GAD)65/67 and AVP, and quantitative in situ hybridization was used to measure transcript levels of GAD67 in the SCN. There were a significant 58% increase of SCN GAD65/67-ir and a significant 169% increase of SCN GAD67-mRNA in the depression group. In addition, there were a significant 253% increase of AVP-ir in female depression subjects but not in male depression patients. This sex difference was supported by a re-analysis of SCN AVP-ir data of a previous study of our group. Moreover, SCN-AVP-ir showed a significant negative correlation with age in the control group and in the male, but not in the female depression group. Given the crucial role of GABA in mediating SCN function, our finding of increased SCN GABA expression may significantly contribute to the disordered circadian rhythms in depression. The increased SCN AVP-ir in female-but not in male-depression patients-may reflect the higher vulnerability for depression in women.
28608154	Bird migration is one of most salient annual events in nature. It involves predictable seasonal movements between breeding and non-breeding habitats. Both circadian and circannual clocks are entrained by photoperiodic cues and time daily and seasonal changes in migratory physiology and behavior. This mini-review provides an update on daily and seasonal rhythms of migratory behavior, and examines the neuroendocrine and molecular pathways involved in the timing of migration in songbirds. Recent findings have identified key neural substrates, and suggest the involvement of multiple neuroendocrine regulatory systems in controlling seasonal states in migrants. We propose that four distinct neural substrates are involved in the timing of migration and include (1) pineal gland and suprachiasmatic nucleus (mSCN); (2) a cluster of hypothalamic nuclei, the mediobasal hypothalamus (MBH); (3) dorsomedial hypothalamic nucleus (DMH); and (4) tanycytes along ependymal layer of the 3rd ventricle (3V). Cluster N, a nucleus in the telencephalon involved in the integration of geomagnetic cues, likely maintains functional connectivity with brain regions involved in timing songbird migration. These nuclei form an interconnected network that coordinates daily timing (pineal gland/mSCN), annual photoperiodic response (MBH, 3V), energetic state (MBH, DMH, 3V), and magnetic compass information (i.e., cluster N) for migration in songbirds.
28607746	Nearly 70% of individuals with multiple sclerosis (MS) experience sleep disturbances. Increasing physical activity in people with MS has been shown to produce a moderate improvement in sleep quality, and exercise has been shown to improve sleep quality in non-neurologically impaired adults.The purpose of this pilot randomized controlled trial study was to examine the effect of two exercise interventions on sleep quality and daytime sleepiness in individuals with MS.	Twenty-eight individuals with relapsing-remitting or secondary progressive MS were randomized into one of two 12-week exercise interventions: a supervised, moderate-intensity aerobic exercise (AE) program or an unsupervised, low-intensity walking and stretching (WS) program. Only individuals who were ≥ 70% compliant with the programs were included in analysis (n = 12 AE; n = 10 WS).	Both groups demonstrated a moderate improvement in sleep quality, although only the improvement by the WS group was statistically significant. Only the AE group demonstrated a significant improvement in daytime sleepiness. Change in sleep quality and daytime sleepiness was not correlated with disease severity or with change in cardiovascular fitness, depression, or fatigue.	The mechanisms for improvement in sleep quality and daytime sleepiness need further investigation, but may be due to introduction of zeitgebers to improve circadian rhythm.	
28607474	The association of irregular sleep schedules with circadian timing and academic performance has not been systematically examined. We studied 61 undergraduates for 30 days using sleep diaries, and quantified sleep regularity using a novel metric, the sleep regularity index (SRI). In the most and least regular quintiles, circadian phase and light exposure were assessed using salivary dim-light melatonin onset (DLMO) and wrist-worn photometry, respectively. DLMO occurred later (00:08 ± 1:54 vs. 21:32 ± 1:48; p < 0.003); the daily sleep propensity rhythm peaked later (06:33 ± 0:19 vs. 04:45 ± 0:11; p < 0.005); and light rhythms had lower amplitude (102 ± 19 lux vs. 179 ± 29 lux; p < 0.005) in Irregular compared to Regular sleepers. A mathematical model of the circadian pacemaker and its response to light was used to demonstrate that Irregular vs. Regular group differences in circadian timing were likely primarily due to their different patterns of light exposure. A positive correlation (r = 0.37; p < 0.004) between academic performance and SRI was observed. These findings show that irregular sleep and light exposure patterns in college students are associated with delayed circadian rhythms and lower academic performance. Moreover, the modeling results reveal that light-based interventions may be therapeutically effective in improving sleep regularity in this population.
28607147	Cell proliferation and release from the bone marrow have been demonstrated to be controlled by circadian rhythms in both humans and mice. However, it is unclear whether local circadian clocks in the bone marrow influence physiological functions and life span of erythrocytes. Here, we report that loss of the clock gene Per2 significantly decreased erythrocyte life span. Mice deficient in Per2 were more susceptible to acute stresses in the erythrocytes, becoming severely anemic upon phenylhydrazine, osmotic, and H2O2 challenges. 1H NMR-based metabolomics analysis revealed that the Per2 depletion causes significant changes in metabolic profiles of erythrocytes, including increased lactate and decreased ATP levels compared with wild-type mice. The lower ATP levels were associated with hyperfunction of Na+/K+-ATPase activity in Per2-null erythrocytes, and inhibition of Na+/K+-ATPase activity by ouabain efficiently rescued ATP levels. Per2-null mice displayed increased levels of Na+/K+-ATPase α1 (ATP1A1) in the erythrocyte membrane, and transfection of Per2 cDNA into the erythroleukemic cell line TF-1 inhibited Atp1a1 expression. Furthermore, we observed that PER2 regulates Atp1a1 transcription through interacting with trans-acting transcription factor 1 (SP1). Our findings reveal that Per2 function in the bone marrow is required for the regulation of life span in circulating erythrocytes.
28605351	In this short review, we discuss evidence supporting the modulation of peripheral circadian systems as a therapeutic strategy for rheumatoid arthritis (RA). We first review the role of proinflammatory cytokines and oxidative stress, two of the primary mediators of chronic inflammation in RA, and their regulation by circadian clock machinery. We further highlight the role of environmental and metabolic signals in regulating the central and peripheral circadian clocks, with an emphasis on seasonal variations in photoperiod and rhythmic metabolic input, respectively. Finally, we hypothesize that the entrainment and realignment of peripheral clock rhythms have the ability to modulate these mediators, improving clinical outcomes in RA patients. Our discussion emphasizes the use of light therapy and time-restricted feeding for entraining peripheral clocks either via the entrainment of the central circadian clock in suprachiasmatic nuclei (SCN) or directly by uncoupling the peripheral circadian clocks from SCN. In doing so, we highlight the use of nonpharmacologic interventions as a potential strategy for improving clinical outcomes in chronic inflammatory conditions such as RA.
28602615	Tissue integrity requires constant maintenance of a quiescent, yet responsive, population of stem cells. In the skin, hair follicle stem cells (HFSCs) that reside within the bulge maintain tissue homeostasis in response to activating cues that occur with each new hair cycle or upon injury. We found that PTEN, a major regulator of the PI3K-AKT pathway, controlled HFSC number and size in the bulge and maintained genomically stable pluripotent cells. This regulatory function is central for HFSC quiescence, where PTEN-deficiency phenotype is in part regulated by BMAL1. Furthermore, PTEN ablation led to downregulation of BMI-1, a critical regulator of adult stem cell self-renewal, and elevated senescence, suggesting the presence of a protective system that prevents transformation. We found that short- and long-term PTEN depletion followed by activated BMAL1, a core clock protein, contributed to accumulation of HFSC.
28600396	I worked almost exclusively on nucleic acids and gene expression from the age of 19 as an undergraduate until the age of 38 as an associate professor. Mentors featured prominently in my choice of paths. My friendship with influential Brandeis colleagues then persuaded me that genetics was an important tool for studying gene expression, and I switched my experimental organism to yeast for this reason. Several years later, friendship also played a prominent role in my beginning work on circadian rhythms. As luck would have it, gene expression as well as genetics turned out to be important for circadian timekeeping. As a consequence, background and training put my laboratory in an excellent position to contribute to this aspect of the circadian problem. The moral of the story is, as in real estate, "location, location, location."
28600326	Nonsense-mediated RNA decay (NMD) is a crucial post-transcriptional regulatory mechanism that recognizes and eliminates aberrantly processed transcripts, and mediates the expression of normal gene transcripts. In this study, we report that in the filamentous fungus Neurospora crassa, the NMD factors play a conserved role in regulating the surveillance of NMD targets including premature termination codon (PTC)-containing transcripts and normal transcripts. The circadian rhythms in all of the knockout strains of upf1-3 genes, which encode the Up-frameshift proteins, were aberrant. The upf1 knockout strain displays a shortened circadian period, which can be restored by constantly expressing exogenous Up-frameshift protein 1 (UPF1). UPF1 regulates the circadian clock by modulating the splicing of the core clock gene frequency (frq) through spliceosome and spliceosome-related arginine/serine-rich splicing factors, which partly account for the short periods in the upf1 knockout strain. We also demonstrated that the clock genes including White Collar (WC)-1, WC-2, and FRQ are involved in controlling the diurnal growth rhythm, and UPF1 may affect the growth rhythms by mediating the FRQ protein levels in the daytime. These findings suggest that the NMD factors play important roles in regulating the circadian clock and diurnal growth rhythms in Neurospora.
28599987	Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1±7.5 (12.6±9.2; mean±SD)mmHg for 20mg, 14.2±7.0 (15.1±9.3) mmHg for 60mg, and 15.9±6.8 (11.5±9.9)mmHg for 180mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23ng/mL fimasartan for diastolic and 12ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60mg oral fimasartan given once daily was predicted as optimal dose range.
28598825	Breast cancer is the most common type of cancer and the second leading cause of cancer death in females. Despite numerous studies in this field, the etiology and clinical behavior of breast tumors have not been understood yet. Retinoid orphan nuclear receptor alpha (RORA) is a member of the orphan nuclear factor family involved in the regulation of lipid and steroid metabolism, immune response and circadian rhythms. Recent evidences support its role as a tumor suppressor gene.To find the associations between RORA polymorphisms and breast cancer.	In the present study, we evaluated the association between two functional polymorphisms in RORA (rs11639084 and rs4774388) and breast cancer risk in a population of 122 Iranian breast cancer patients as well as 200 healthy subjects by means of tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method.	The rs4774388 has been shown to be associated with breast cancer risk in recessive inheritance model (OR (95% CI = 0.51 (0.26-0.97) and P = 0.041). However, the allele and genotype frequencies of rs11639084 were not different in patients and control (P > 0.05). Haplotype analysis revealed no significant association of any estimated block of rs11639084/rs4774388 in breast cancer patients versus healthy controls.	The results of this study support a putative role for RORA in breast cancer pathogenesis.	
28598695	Rhodopsin is the classical light sensor. Although rhodopsin has long been known to be important for image formation in the eye, the requirements for opsins in non-image formation and in extraocular light sensation were revealed much later. Most recent is the demonstration that an opsin in the fruit fly, Drosophila melanogaster, is expressed in pacemaker neurons in the brain and functions in light entrainment of circadian rhythms. However, the biggest surprise is that opsins have light-independent roles, countering more than a century of dogma that they function exclusively as light sensors. Through studies in Drosophila, light-independent roles of opsins have emerged in temperature sensation and hearing. Although these findings have been uncovered in the fruit fly, there are hints that opsins have light-independent roles in a wide array of animals, including mammals. Thus, despite the decades of focus on opsins as light detectors, they represent an important new class of polymodal sensory receptor. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 33 is October 6, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
28598202	In clinical practice, circadian rhythms play a prominent role in pharmacokinetics and cell responses to therapy, hence necessitating in designing a defined protocol for drug administration. Clinical evidence for chronopharmacological behavior of cardiovascular active drugs in human subjects has been limited for amlodipine. Hence, the present study was undertaken to study the chronopharmacokinetic and chronopharmacodynamic phenomena of amlodipine and evaluate the effect of time of dosage in hypertensive subjects. Single oral dose of amlodipine was administered to the hypertensive/normotensive subjects either morning or evening to assess the pharmacokinetic profile after morning dosing or evening dosing, respectively. PK parameters obtained revealed that Tmax was shorter and Cmax was greater after evening dosing than the morning dosing in both hypertensive and normotensive subjects. These observations were comparable with the hypothesis that amlodipine is absorbed rapidly when it is given during the night time. Also, the changes in systolicBP, DiastolicBP, and heart rate in comparison to the respective circadian baseline values were markedly different depending on the time and dosing. SBP and HR were significantly reduced after evening dosing with slight difference in measurement of DBP in hypertensive patients. Hence, it can be concluded that prescription of antihypertensive medications containing amlodipine, to be administered at night offers highly efficacious means to control BP without the need to increase either the dose or number of medications. The current treatment strategy method involves delivery of medications, so that they are synchronized in time to biological need that varies according to the chronobiology of the targeted tissues.
28597784	Objective The aim of this study was to investigate the correlation between non-dipper circadian rhythm of blood pressure (BP) and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). Methods and results All 257 patients with stage 1 to 5 CKD were enrolled in the study and classified into a CKD1-3 group and a CKD4-5 group according to renal function. The parameters and circadian rhythm of BP were measured by a GE Marquette Tonoport V Eng dynamic sphygmomanometer, and cardiac structure was examined by echocardiography. The incidence of abnormal circadian BP rhythm (non-dipper rhythm) was quite high (75.4% in all enrolled patients and 71.3% in the patients with normal BP levels) in CKD patients and increased with the deterioration of renal function. Changes of cardiac structure such as LVH in patients with non-dipper BP were more distinct than in patients with dipper BP. The development of left ventricular mass index (LVMI) correlated positively with the incidence of non-dipper BP rhythm. Multiple regression analysis showed that 24-h systolic BP (β = 0.417, P < 0.01), triglycerides (TG) (β = -0.132, P = 0.007), Hb (β = -0.394, P = 0.016) and gender (β = 0.158, P = 0.039) were independent risk factors of LVMI. Conclusions The incidence of non-dipper circadian rhythm of blood pressure was quite high in CKD patients and increased with the deterioration of renal function. Non-dipper circadian rhythm of BP is closely related with LVMI.
28597081	To assess which type of evening light exposure has the greatest effect on reaction time and maximum handgrip strength. These were pre-specified secondary outcomes in a trial which primarily investigated the influence of light on cycling performance.Seventy-four male athletes were allocated at random to either bright light (BRIGHT), monochromatic blue light (BLUE), or a control condition (CONTROL). Light exposure lasted for 60 min and started 17 h after the individual midpoint of sleep. Reaction time, handgrip strength, and melatonin levels were measured before and after the light exposure. We used analysis of covariance to compare the groups with respect to the investigated outcomes.	Two participants had to be excluded retrospectively. The remaining 72 participants had a median age of 23 years. The adjusted difference in reaction time was -1 ms [95% confidence interval (CI) -8, 6] for participants in BRIGHT and 2 ms (95% CI -5, 9) for participants in BLUE, both relative to participants in CONTROL. The adjusted difference in handgrip strength was 0.9 kg (95% CI -1.5, 3.3) for participants in BRIGHT and -0.3 kg (95% CI -2.7, 2.0) for participants in BLUE, both relative to participants in CONTROL. After the light exposure, 17% of participants in BRIGHT, 22% in BLUE, and 29% in CONTROL showed melatonin concentrations of 2 pg/ml or higher.	The results suggest that bright light might reduce melatonin levels but neither bright nor blue light exposure in the evening seem to improve reaction time or handgrip strength in athletes.	
28596466	The nerve center responsible for controlling our circadian rhythm is located in a cluster of cells known as the suprachiasmatic nucleus in the hypothalamus. Various physiological functions such as sleep, arousal, blood pressure, body temperature, and hormone secretion are regulated in a 24-hour rhythm by this circuit. Somatic cells of other organs have a peripheral clock gene and by synchronizing the rhythm of the central and peripheral clocks, it is possible to live a healthy life. Due to aging and degenerative disease, circadian rhythm gradually collapses. Factors that can contribute to this include reduced expression of the time gene associated with photo stimulation, a reduction in neurotransmitter levels, and reduced melatonin production. Biological clocks play an important role in our emotions, cognitive function, and behavior. Sleep disorders and metabolic disease related to the circadian rhythm affect metabolic and endocrine activities via the autonomic nervous system and the intestinal bacterial flora. Shift work disorder is associated with insomnia and excessive drowsiness as individuals often work during their sleeping hours. Now time management is placed at the center of our society, and it is important to evaluate the medical risk of engaging in shift work. In frontotemporal dementia (FTD), the stereotypical behaviors may be associated with time. In some patients, multiple timed behaviors occupy a considerable part of the patient's daily life. Stereotypical behaviors in FTD are often considered in contrast to obsessive-compulsive disease (OCD). Studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function.
28596085	It is generally accepted that myopic defocus is a more potent signal to the emmetropization system than hyperopic defocus: one hour per day of myopic defocus cancels out 11 h of hyperopic defocus. However, we have recently shown that the potency of brief episodes of myopic defocus at inhibiting eye growth depends on the time of day of exposure. We here ask if this will also be true of the responses to brief periods of hyperopic defocus: may integration of the signal depend on time of day? If so, are the rhythms in axial length and choroidal thickness altered? Hyperopic defocus: Birds had one eye exposed to hyperopic defocus by the wearing of -10D lenses for 2 or 6 h at one of 3 times of day for 5 days: Morning (7 am - 9 am: n = 13; 7 am - 1 pm: n = 6), Mid-day (12 pm - 2 pm: n = 20; 10 am - 4 pm: n = 8), or Evening (7 pm - 9 pm: n = 12; 2 pm - 8 pm: n = 11). A separate group wore monocular lenses continually as a control (n = 12). Form deprivation: Birds wore a diffuser over one eye for 2 h at one of 3 times of day for 5 days: Morning (n = 12); Mid-day (n = 19) or Evening (n = 6). For all groups, ocular dimensions were measured using high-frequency A-scan ultrasonography at noon on the first day, under inhalation anesthesia. On day 5, eye dimensions were re-measured at 12 pm, and refractive errors were measured using a Hartinger's refractometer. A subset of birds in the 2-h lens group (morning, n = 8; mid-day, n = 8; evening, n = 6), and the deprivation group (n = 6 per time point), were also measured at 6 pm, 12 am, 6 am and 12 pm on the last day of exposure, to obtain the parameters of the diurnal rhythms in axial length and choroidal thickness. The effects of 2 h of defocus depended on time of day of exposure: it stimulated eye growth when exposure was in the morning and inhibited it when it was at mid-day (change in vitreous chamber, X-C; ANOVA p < 0.0005; 120 μm vs -77 μm/5d, respectively; t-tests: p = 0.001; p = 0.01; post-hoc tests: p = 0.002). For mid-day, experimental eyes were more hyperopic (1.4 D; p < 0.0001). Similar to 2 h defocus, 6 h exposures at mid-day inhibited growth and produced hyperopia (X-C: -167 μm; t-test p = 0.005; RE: 1.8 D; p = 0.03). The effects of 2 h of FD were similar to those of hyperopic defocus in inhibiting growth for mid-day exposures, but FD inhibited growth for the morning exposures as well (Axial length: X-C: Morning: -122 μm; mid-day: -92 μm; ttests p = 0.006 and p = 0.016 respectively). Experimental eyes were more hyperopic (1.8 D; 1.0 D; p < 0.05). The rhythms in axial length were altered for the morning exposures in both conditions. Form deprivation in the morning, which caused inhibition, caused the phases of the two rhythms to shift toward one another (peaks at 6:00 am and 10:45 am for choroid and axial length respectively). Our findings imply that the retinal "integrator", and/or scleral growth regulator exhibit diurnal rhythms. Furthermore, they suggest that reading activities early in the day may be contraindicated in school children at risk of becoming myopic.
28595569	Cytoplasmic male sterility (CMS) conferred by the cytoplasm from Gossypium harknessii (D2) is an important system for hybrid seed production in Upland cotton (G. hirsutum). The male sterility of CMS-D2 (i.e., A line) can be restored to fertility by a restorer (i.e., R line) carrying the restorer gene Rf1 transferred from the D2 nuclear genome. However, the molecular mechanisms of CMS-D2 and its restoration are poorly understood.In this study, a genome-wide comparative transcriptome analysis was performed to identify differentially expressed genes (DEGs) in flower buds among the isogenic fertile R line and sterile A line derived from a backcross population (BC8F1) and the recurrent parent, i.e., the maintainer (B line). A total of 1464 DEGs were identified among the three isogenic lines, and the Rf1-carrying Chr_D05 and its homeologous Chr_A05 had more DEGs than other chromosomes. The results of GO and KEGG enrichment analysis showed differences in circadian rhythm between the fertile and sterile lines. Eleven DEGs were selected for validation using qRT-PCR, confirming the accuracy of the RNA-seq results.	Through genome-wide comparative transcriptome analysis, the differential expression profiles of CMS-D2 and its maintainer and restorer lines in Upland cotton were identified. Our results provide an important foundation for further studies into the molecular mechanisms of the interactions between the restorer gene Rf1 and the CMS-D2 cytoplasm.	
28595523	Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K  900 lux) were compared with four weeks of control white lighting (4000 K  200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue-enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants' rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people.
28595522	Disturbances of circadian rest-activity rhythms in demented patients often culminate in the clinical problem of evening and nighttime agitation. The aim of the current study was to test the impact of a dynamic lighting system on agitation and rest-activity cycles. From midwinter on, a ceiling mounted dynamic lighting system was installed in the common room of a nursing home and programmed to produce high illuminance with higher blue light proportions during the day and lower illuminance without blue light in the evening. Fifteen residents with dementia were regularly assessed with the Cohen Mansfield Agitation Index (CMAI) before and after the intervention. Additionally rest-activity cycles were continuously monitored for 6 months by a wrist worn activity watch. Analysis of CMAI data was performed by using the Wilcoxon-Test for matched pairs (before vs. after the lighting installation). Rest-activity data was compared with t-tests for dependent samples. The dynamic lighting significantly reduced the CMAI sum-scores from 30.2±5.1 to 27.9±2.6 (mean ± SD; N = 12; p<0.05). Analysis of the CMAI subscores revealed that under the dynamic lighting mainly non-physically aggressive behaviors were reduced. Results from the rest-activity analysis did not show differences of circadian amplitude and other circadian variables before and after the lighting installation. The dynamic lighting in the living room significantly reduced agitated behavior in demented patients, indicating short-term benefits from higher daily light exposures. Whether such lighting also impacts long-term (circadian) rest-activity cycles needs to be further investigated.
28595099	Circadian rhythm dysfunction is thought to play a key role in the pathogenesis of bipolar disorder (BD). We focused on circadian rhythm sleep-wake disorders (CRSWD) as possible predictors for bipolar disorder in patients with remitted mood disorders.One hundred four BD (41 type I and 63 type II) outpatients and 73 age- and sex-matched major depressive disorder (MDD) outpatients participated in this study. The subjects were asked to answer questionnaires including demographic variables, clinical course of the disorder, and family history of psychiatric disorders. Severity of mood status was evaluated by the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. CRSWD was diagnosed by clinical interview and sleep logs based on the International Classification of Sleep Disorders, third edition.	The rate of CRSWD in BD subjects was significantly higher than that in MDD subjects (33.7% vs 9.6%; P < 0.001). A multiple logistic regression analysis revealed that comorbid CRSWD (OR = 3.35, 95% CI = 1.24 - 9.07; P = 0.018), two or more previous mood episodes within the past year (OR = 3.57, 95% CI = 1.10 - 11.63; P = 0.035), and antidepressant-related switch to mania/hypomania (OR = 10.01, 95% CI = 1.20 - 83.52; P = 0.033) were significantly associated with BD in patients with remitted mood disorders.	CRSWD, as well as other factors, could be diagnostic predictors for BD in patients with remitted mood disorders. Combinations of these factors might be useful for predicting a BD diagnosis among the mood disorders in a clinical setting.	
28594845	Most biological processes accelerate with temperature, for example cell division. In contrast, the circadian rhythm period is robust to temperature fluctuation, termed temperature compensation. Temperature compensation is peculiar because a system-level property (i.e., the circadian period) is stable under varying temperature while individual components of the system (i.e., biochemical reactions) are usually temperature-sensitive. To understand the mechanism for period stability, we measured the time series of circadian clock transcripts in cultured C6 glioma cells. The amplitudes of Cry1 and Dbp circadian expression increased significantly with temperature. In contrast, other clock transcripts demonstrated no significant change in amplitude. To understand these experimental results, we analyzed mathematical models with different network topologies. It was found that the geometric mean amplitude of gene expression must increase to maintain a stable period with increasing temperatures and reaction speeds for all models studied. To investigate the generality of this temperature-amplitude coupling mechanism for period stability, we revisited data on the yeast metabolic cycle (YMC) period, which is also stable under temperature variation. We confirmed that the YMC amplitude increased at higher temperatures, suggesting temperature-amplitude coupling as a common mechanism shared by circadian and 4 h-metabolic rhythms.
28594248	Self-reported eveningness has been previously associated with depressed mood among adults and adolescents. Here, we study how circadian indicators based on actigraphic data differ between depressed and healthy adolescent boys. Our sample consisted of 17 medication-free adolescent boys, aged 14.5 to 17.5 years, of which eight had depressive disorder and were currently depressed and nine were healthy comparison participants. Psychiatric assessment was conducted by diagnostic interviews and complemented with observer-rating and self-rating scales. Actigraphic data were collected with wrist actigraphs for a minimum period of 25 consecutive days (range of 25 to 44 days). The behavioral trait of morningness-eveningness was measured with the 19-item Horne-Östberg Morningness-Eveningness Questionnaire. Based on the self-report, the depressed boys were more prone to eveningness than healthy controls, but based on the actigraphic data, they had earlier phases especially on school days and lower activity levels especially on weekends. On weekends, the depressed boys showed a greater shift toward later-timed phases than healthy controls. Our results confirm a mismatch of the subjective morningness-eveningness preference (late-preference) and the objective rest-activity rhythm (early-prone) during school days in depressed adolescent boys.
28593182	The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied.We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture.	The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway.	Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology.	
28592698	Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled (unf) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period (per) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837, which we termed R and B (Rnb), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit.SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics distinguishing the s-LNvs, the master pacemaker of the locomotor rhythms, from other clock neuron subtypes. We demonstrated that a newly identified gene Rnb is an s-LNv-specific regulator of the molecular clock and essential for the generation of circadian locomotor behavior. Our results provide additional evidence to the emerging view that the differential regulation of the molecular clocks underlies the functional differences among the pacemaker neuron subgroups.

28592477	The desire for families to be physically present to support their loved ones in the intensive care unit, and guidelines in favor of this open visitation approach, require that clinicians consider both patient and family sleep. This article reviews the causes of poor sleep for patients and their family members in the intensive care unit as well as the expected changes in cognition and emotion that can result from sleep deprivation. Measures are proposed to improve the intensive care unit environment to promote family sleep. A framework to educate family members and engage them in preservation of their and their loved one's circadian rhythm is also presented. Although further research is needed, the proposed framework has the potential to improve outcomes for patients and their families in the intensive care unit.
28592378	There is growing evidence of reciprocal interactions between the endogenous circadian clock and subcellular redox pathways. Recently, researchers at the University of California unearthed another possible link between redox metabolism and the mammalian circadian clock: the redox cofactor FAD stabilises the clock protein cryptochrome (CRY), modifying rhythmic clock gene expression.
28591634	Besides circadian rhythms, oscillations cycling with a 12 hr period exist. However, the prevalence, origin, regulation, and function of mammalian 12 hr rhythms remain elusive. Utilizing an unbiased mathematical approach identifying all superimposed oscillations, we uncovered prevalent 12 hr gene expression and metabolic rhythms in mouse liver, coupled with a physiological 12 hr unfolded protein response oscillation. The mammalian 12 hr rhythm is cell autonomous, driven by a dedicated 12 hr pacemaker distinct from the circadian clock, and can be entrained in vitro by metabolic and ER stress cues. Mechanistically, we identified XBP1s as a transcriptional regulator of the mammalian 12 hr clock. Downregulation of the 12 hr gene expression strongly correlates with human hepatic steatosis and steatohepatitis, implying its importance in maintaining metabolic homeostasis. The mammalian 12 hr rhythm of gene expression also is conserved in nematodes and crustaceans, indicating an ancient origin of the 12 hr clock. Our work sheds new light on how perturbed biological rhythms contribute to human disease.
28590406	Saussurea involucrata grows in high mountain areas covered by snow throughout the year. The temperature of this habitat can change drastically in one day. To gain a better understanding of the cold response signaling pathways and molecular metabolic reactions involved in cold stress tolerance, genome-wide transcriptional analyses were performed using RNA-Seq technologies. A total of 199,758 transcripts were assembled, producing 138,540 unigenes with 46.8 Gb clean data. Overall, 184,416 (92.32%) transcripts were successfully annotated. The 365 transcription factors identified (292 unigenes) belonged to 49 transcription factor families associated with cold stress responses. A total of 343 transcripts on the signal transduction (132 upregulated and 212 downregulated in at least any one of the conditions) were strongly affected by cold temperature, such as the CBL-interacting serine/threonine-protein kinase (CIPKs), receptor-like protein kinases, and protein kinases. The circadian rhythm pathway was activated by cold adaptation, which was necessary to endure the severe temperature changes within a day. There were 346 differentially expressed genes (DEGs) related to transport, of which 138 were upregulated and 22 were downregulated in at least any one of the conditions. Under cold stress conditions, transcriptional regulation, molecular transport, and signal transduction were involved in the adaptation to low temperature in S. involucrata. These findings contribute to our understanding of the adaptation of plants to harsh environments and the survival traits of S. involucrata. In addition, the present study provides insight into the molecular mechanisms of chilling and freezing tolerance.
28589993	Experiments were performed on the subtropical tree sparrow (Passer montanus) to investigate the involvement of an endogenous circadian rhythm in photoperiodic time measurement during the initiation of gonadal growth and functions and also to study the photic entrainment of the circadian activity rhythm. Groups of photosensitive birds of both sexes were exposed to different "night-interruption" light-dark regimes of 24 h duration viz., G1 - 6L/5D/1L/12D, G2 - 6L/6D/1L/11D, G3 - 6L/7D/1L/10D, G4 - 6L/8D/1L/9D, G5 - 6L/10D/1L/7D, G6 - 6L/12D/1L/5D, G7 - 6L/14D/1L/3D and G8 - 6L/16D/1L/1D for 30 days in which 17 h long nights were interrupted by 1 h light pulse falling at different ZTs (i.e., 11, 12, 13, 14, 16, 18, 20 and 22). A control group, for each sex, was maintained under 7L/17D. The birds of all groups behaved as though they had been exposed to a stimulatory photoperiod except those of G1, G8 and the control. Furthermore, the serum levels of testosterone in males and estradiol-17β in females ran almost parallel to changes in the gonadal size. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. However, various characteristics of the activity rhythm differed significantly upon transfer of birds to various night interruption regimes. These results suggest the involvement of the endogenous circadian rhythm in photoperiodic time measurement during the induction of gonadal growth and functions in the tree sparrow. Also, there is photic entrainment of the locomotor activity rhythm that shows variations in various circadian characteristics under different night interruption cycles suggesting that the photoinducible phase is differentially sensitive to light.
28588500	Circadian rhythms are essential for health and regulate various physiological functions. These rhythms are regulated by a negative-feedback loop involving clock genes in the suprachiasmatic nucleus (SCN) and peripheral tissues. The rate of secretion of salivary substances, ions, and water follows a circadian rhythm, however, the relationship between the molecular mechanism of salivary secretion and peripheral circadian rhythm is not yet clear. Anoctamin 1 (ANO1, also known as TMEM16A) and Aquaporin 5 (AQP5) play an important role in the transport of ions and water in the submandibular glands (SGs). We examined the interaction between the rhythmic expression pattern of the clock genes, Ano1 and Aqp5, in rat whole SGs as well as isolated acinar and ductal cells. Circadian rhythmic expression for Bmal1, Per1, Per2, Clock, Cry1, Cry2, Rorα, and Rev-erbα mRNAs, also called the clock genes, was observed in rat SGs by semi-quantitative RT-PCR analysis. We also observed rhythmic patterns in Ano1 and Aqp5 mRNA expression. The expression of ANO1 protein also showed circadian rhythm, as confirmed by western blot analysis. We could not observe any time delay between the peak expression of ANO1 protein and its mRNA. Expression levels of the clock gene mRNAs in the ductal cells was higher than that in acinar cells, however, rhythmic oscillations were observed in both. Our results suggest that SGs have peripheral clocks, and rhythmic expressions of Ano1 and Aqp5 along with the clock genes, may play an important role in the circadian regulation of salivary secretion.
28587229	RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases.
28586769	The importance of vasopressin and/or urine concentration in various kidney, cardiovascular, and metabolic diseases has been emphasized recently. Due to technical constraints, urine osmolality (Uosm), a direct reflect of urinary concentrating activity, is rarely measured in epidemiologic studies.We analyzed 2 possible surrogates of Uosm in 4 large population-based cohorts (total n = 4,247) and in patients with chronic kidney disease (CKD, n = 146). An estimated Uosm (eUosm) based on the concentrations of sodium, potassium, and urea, and a urine concentrating index (UCI) based on the ratio of creatinine concentrations in urine and plasma were compared to the measured Uosm (mUosm).	eUosm is an excellent surrogate of mUosm, with a highly significant linear relationship and values within 5% of mUosm (r = 0.99 or 0.98 in each population cohort). Bland-Altman plots show a good agreement between eUosm and mUosm with mean differences between the 2 variables within ±24 mmol/L. This was verified in men and women, in day and night urine samples, and in CKD patients. The relationship of UCI with mUosm is also significant but is not linear and exhibits more dispersed values. Moreover, the latter index is no longer representative of mUosm in patients with CKD as it declines much more quickly with declining glomerular filtration rate than mUosm.	The eUosm is a valid marker of urine concentration in population-based and CKD cohorts. The UCI can provide an estimate of urine concentration when no other measurement is available, but should be used only in subjects with normal renal function.	
28585704	During normal pregnancy, the mechanism by which the fetus escapes immunological rejection by the maternal womb remains elusive. Given the biological complexities, the immunological mechanism is unlikely to be simply an allograft response in acceptance or rejection of the early pregnancy. Circadian clock responsible for the mammalian circadian rhythm is an endogenously generated rhythm associated with almost all physiological processes including reproduction. There is now growing evidence to suggest that the circadian clocks are intricately linked to the immune system and pregnancy. When perturbed, the role of immune cells can be affected on maintaining the enriched vascular system needed for placentation. This alteration can be triggered by the irregular production of maternal and placental melatonin. Hence, the role of circadian rhythm modulators such as melatonin offers intriguing opportunities for therapy. In this review, we evaluate the complex interaction between the circadian clock and melatonin within the immune system and their roles in the circadian regulation and maintenance of normal pregnancy.
28585236	Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most prevalent joint diseases. A such, they are important causes of pain and disability in a substantial proportion of the human population. A common characteristic of these diseases is the erosion of articular cartilage and consequently joint dysfunction. Melatonin has been proposed as a link between circadian rhythms and joint diseases including RA and OA. This hormone exerts a diversity of regulatory actions through binding to specific receptors and intracellular targets as well as having receptor-independent actions as a free radical scavenger. Cytoprotective effects of melatonin involve a myriad of prominent receptor-mediated pathways/molecules associated with inflammation, of which the role of omnipresent NF-κB signalling is crucial. Likewise, disturbance of circadian timekeeping is closely involved in the aetiology of inflammatory arthritis. Melatonin is shown to stimulate cartilage destruction/regeneration through direct/indirect modulation of the expression of the main circadian clock genes, such as BMAL, CRY and/or DEC2. In the current article, we review the effects of melatonin on RA and OA, focusing on its ability to regulate inflammatory pathways and circadian rhythms. We also review the possible protective effects of melatonin on RA and OA pathogenesis.
28585194	The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronizes these with daily cycles, feeding patterns also regulates circadian clocks. The clock genes and adipocytokines show circadian rhythmicity. Dysfunction of these genes are involved in the alteration of these adipokines during the development of obesity. Food availability promotes the stimuli associated with food intake which is a circadian oscillator outside of the suprachiasmatic nucleus (SCN). Its circadian rhythm is arranged with the predictable daily mealtimes. Food anticipatory activity is mediated by a self-sustained circadian timing and its principal component is food entrained oscillator. However, the hypothalamus has a crucial role in the regulation of energy balance rather than food intake. Fatty acids or their metabolites can modulate neuronal activity by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. The timing of three-meal schedules indicates close association with the plasma levels of insulin and preceding food availability. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition can lead to uncoupling of peripheral clocks from the central pacemaker and to the development of metabolic disorders. Metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, eventual disruption of circadian clock functioning can lead to obesity. While CLOCK expression levels are increased with high fat diet-induced obesity, peroxisome proliferator-activated receptor (PPAR) alpha increases the transcriptional level of brain and muscle ARNT-like 1 (BMAL1) in obese subjects. Consequently, disruption of clock genes results in dyslipidemia, insulin resistance and obesity. Modifying the time of feeding alone can greatly affect body weight. Changes in the circadian clock are associated with temporal alterations in feeding behavior and increased weight gain. Thus, shift work is associated with increased risk for obesity, diabetes and cardio-vascular diseases as a result of unusual eating time and disruption of circadian rhythm.
28583847	This study investigated the expression, clinicopathological significance and mechanism of action of TIMELESS, a mammalian homolog of a Drosophila circadian rhythm gene, in nasopharyngeal carcinoma. Quantitative real-time PCR, western blotting and immunohistochemistry revealed TIMELESS was upregulated in NPC cell lines (n = 8 vs. NP69 cells), and freshly-frozen (n = 6) and paraffin-embedded human NPC specimens (n = 108 vs. normal samples/non-tumor cells). TIMELESS expression was associated with T category (P = 0.002), N category (P = 0.001), clinical stage (P < 0.001), metastasis (P = 0.047), vital status (P = 0.013) and serum Epstein-Barr DNA (P = 0.005). High TIMELESS expression was associated with poorer overall survival (80.7% vs. 95.9%; P = 0.004) and progression free survival (68.1% vs. 88.0%; P = 0.005). Univariate and multivariate analysis revealed TIMELESS was an independent prognostic factor for overall survival and progression free survival. Stable ectopic overexpression of TIMELESS in NPC cell lines conferred resistance to cisplatin-induced apoptosis in vitro and in vivo, promoted an epithelial-to-mesenchymal transition phenotype, and activated the Wnt/β-catenin pathway and downstream gene transcription; knockdown of TIMELESS had the opposite effects. TIMELESS may play a role in the development of NPC and could represent a valuable prognostic factor and potential therapeutic target.
28583307	Antibody responses, B cell subset distribution in blood and the blood transcriptome were analyzed in younger and aged human subjects before and after vaccination with the inactivated influenza vaccine. In the aged, but not the younger, individuals we saw a clear difference in antibody titers including those at baseline depending on the time of vaccination and sample collection. Differences in baseline titers in aged individuals treated in the morning or afternoon in turn affected responsiveness to the vaccine. In both younger and aged individuals, the time of sample collection also affected relative numbers of some of the B cell subsets in blood. A global gene expression analysis with whole blood samples from the aged showed small but statistically significant differences depending on the time of sample collection. Our data do not indicate that timing of vaccination affects immune responsiveness of the aged, but rather shows that in clinical influenza vaccine trials timing of collection of samples can have a major and potentially misleading influence on study outcome. In future vaccine trials, timing of vaccination and sample collection should be recorded carefully to allow for its use as a study covariant.
28581353	In this case control study, we investigated the process of adaptation to night shift (NS) work and recovery back to a day schedule among nurses working a fast-rotation three-shift schedule.There is limited knowledge of how specific patterns of a fast-rotation shift affect nurses' performance.	The cognitive performance of off-duty nurses (OD; n = 21), those working the first night of an NS (1NS; n = 21) and the last night of two ( n = 21), three ( n = 20), and four (4NS; n = 21) successive NSs were compared. Changes in sleep propensity, cognitive function, and anxiety were compared in the daytime after working four successive NSs followed by 24 hr off (4NS-off; n = 18) and in those off duty.	The visual attention task (VAT) of cognitive function was significantly worse in the 1NS group and significantly better on the last night in the 4NS group than in the other NS groups. The nurses in the 4NS-off group were less alert and had poorer VAT performance than the OD group during the daytime.	The nurses working on NS experienced a decrease in VAT performance due to acute changes in circadian rhythm but also significant performance adaptation after four consecutive NSs. One off-duty day was insufficient to recover back to a daytime shift after four consecutive NSs.	In a fast-rotation three-shift schedule, performance adaptation occurred in the nurses who worked four consecutive NSs, and more than one off-duty day are needed to recover back to daytime shift after those NSs.	
28580282	Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown.Metabolic parameters of wild-type (WT) and ClockΔ19 mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT-Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied.	Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock-dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways.	Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders.	
28580187	Accumulating epidemiological studies have implicated a strong link between age associated metabolic diseases and cancer, though direct and irrefutable evidence is missing. In this review, we discuss the connection between Warburg effects and tumorigenesis, as well as adaptive responses to environment such as circadian rhythms on molecular pathways involved in metabolism. We also review the central role of the sirtuin family of proteins in physiological modulation of cellular processes and age-associated metabolic diseases. We also provide a macroscopic view of how the circadian rhythm affects metabolism and may be involved in cell metabolism reprogramming and cancer pathogenesis. The aberrations in metabolism and the circadian system may lead to age-associated diseases directly or through intermediates. These intermediates may be either mutated or reprogrammed, thus becoming responsible for chromatin modification and oncogene transcription. Integration of circadian rhythm and metabolic reprogramming in the holistic understanding of metabolic diseases and cancer may provide additional insights into human diseases.
28579842	Sleep plays a vital role in brain function and systemic physiology across many body systems. Problems with sleep are widely prevalent and include deficits in quantity and quality of sleep; sleep problems that impact the continuity of sleep are collectively referred to as sleep disruptions. Numerous factors contribute to sleep disruption, ranging from lifestyle and environmental factors to sleep disorders and other medical conditions. Sleep disruptions have substantial adverse short- and long-term health consequences. A literature search was conducted to provide a nonsystematic review of these health consequences (this review was designed to be nonsystematic to better focus on the topics of interest due to the myriad parameters affected by sleep). Sleep disruption is associated with increased activity of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, metabolic effects, changes in circadian rhythms, and proinflammatory responses. In otherwise healthy adults, short-term consequences of sleep disruption include increased stress responsivity, somatic pain, reduced quality of life, emotional distress and mood disorders, and cognitive, memory, and performance deficits. For adolescents, psychosocial health, school performance, and risk-taking behaviors are impacted by sleep disruption. Behavioral problems and cognitive functioning are associated with sleep disruption in children. Long-term consequences of sleep disruption in otherwise healthy individuals include hypertension, dyslipidemia, cardiovascular disease, weight-related issues, metabolic syndrome, type 2 diabetes mellitus, and colorectal cancer. All-cause mortality is also increased in men with sleep disturbances. For those with underlying medical conditions, sleep disruption may diminish the health-related quality of life of children and adolescents and may worsen the severity of common gastrointestinal disorders. As a result of the potential consequences of sleep disruption, health care professionals should be cognizant of how managing underlying medical conditions may help to optimize sleep continuity and consider prescribing interventions that minimize sleep disruption.
28579782	Patients with non-24-hour sleep-wake rhythm disorder (N24SWD) exhibit a sleep pattern that is asynchronous with the external light-dark cycle, typically involving a cycling, relapsing-remitting pattern of sleep disturbances, including nighttime insomnia and daytime sleepiness. Here, we report the case of a patient with N24SWD comorbid with major depressive disorder, who was successfully treated with a low dose of aripiprazole.A 47-year-old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning. The patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time. At the age of 40 years, the patient's sleep-wake cycle began to extend without exacerbation of depressive symptoms. The patient was diagnosed with N24SWD at the age of 43 years. Ramelteon 8 mg/d and then melatonin 1 mg/d were administered, but these did not provide effective treatment. In January 2016, after treatment with aripiprazole 3 mg/d in the morning for 4 weeks, the patient's sleep-wake cycle became markedly synchronized to the environmental light-dark cycle. Her sleep-wake cycle remained synchronized when the same dose of aripiprazole was administered for at least 6 months.	Treatment-refractory asynchrony of the sleep-wake cycle in an N24SWD patient with depression was successfully treated with aripiprazole. Although the detailed mechanism of action is unclear, aripiprazole may be an appropriate treatment for patients with circadian rhythm sleep-wake disorders.	
28578930	Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.
28578301	Changes in levels of the stress-sensitive hormone cortisol from morning to evening are referred to as diurnal cortisol slopes. Flatter diurnal cortisol slopes have been proposed as a mediator between chronic psychosocial stress and poor mental and physical health outcomes in past theory and research. Surprisingly, neither a systematic nor a meta-analytic review of associations between diurnal cortisol slopes and health has been conducted to date, despite extensive literature on the topic. The current systematic review and meta-analysis examined associations between diurnal cortisol slopes and physical and mental health outcomes. Analyses were based on 179 associations from 80 studies for the time period up to January 31, 2015. Results indicated a significant association between flatter diurnal cortisol slopes and poorer health across all studies (average effect size, r=0.147). Further, flatter diurnal cortisol slopes were associated with poorer health in 10 out of 12 subtypes of emotional and physical health outcomes examined. Among these subtypes, the effect size was largest for immune/inflammation outcomes (r=0.288). Potential moderators of the associations between diurnal cortisol slopes and health outcomes were examined, including type of slope measure and study quality indices. The possible roles of flatter slopes as either a marker or a mechanism for disease etiology are discussed. We argue that flatter diurnal cortisol slopes may both reflect and contribute to stress-related dysregulation of central and peripheral circadian mechanisms, with corresponding downstream effects on multiple aspects of biology, behavior, and health.
28577421	Arylalkylamine N-acetyltransferase (AANAT) activity, aanat gene expression and melatonin production have been reported to exhibit prominent circadian rhythm in the pineal organ of most species of fish. Three types of aanat genes are expressed in fish, but the fish pineal organ predominantly expresses aanat2 gene. Increase and decrease in daylength is invariably associated with increase and decrease in temperature, respectively. But so far no attempt has been made to delineate the role of photoperiod and temperature in regulation of the circadian rhythm of aanat2 gene expression in the pineal organ of any fish with special reference to seasons. Therefore, we studied effects of various lighting regimes (12L-12D, 16L-8D, 8L-16D, LL and DD) at a constant temperature (25°C) and effects of different temperatures (15°, 25° and 35°C) under a common photoperiod 12L-12D on circadian rhythm of aanat2 gene expression in the pineal organ of Clarias gariepinus during summer and winter seasons. Aanat2 gene expression in fish pineal organ was studied by measuring aanat2 mRNA levels using Real-Time PCR. Our findings indicate that the pineal organ of C. gariepinus exhibits a prominent circadian rhythm of aanat2 gene expression irrespective of photoperiods, temperatures and seasons, and the circadian rhythm of aanat2 gene expression responds differently to different photoperiods and temperatures in a season-dependent manner. Existence of circadian rhythm of aanat2 gene expression in pineal organs maintained in vitro under 12L-12D and DD conditions as well as a free running rhythm of the gene expression in pineal organ of the fish maintained under LL and DD conditions suggest that the fish pineal organ possesses an endogenous circadian oscillator, which is entrained by light-dark cycle.
28577110	Aging is associated with changes in several basic parameters of circadian timing system (CTS) in mammals leading to circadian dysfunction. We had reported earlier that upon aging and in rotenone induced Parkinson's disease (RIPD) rat model there were significant alterations in the core clock genes expression levels and daily pulses. To identify biomarkers of aging and PD chronomics of proteomic day-night profiles in suprachiasmatic nucleus (SCN), pineal and substantia nigra (SN) in 3 month (m), 12, 24 m and RIPD rat model were studied at two time points i.e. Zeitgeber Time (ZT)-6 (mid-day) and ZT-18 (mid-night). Proteome analysis was done by using two dimensional (2-D) electrophoresis and the spots showing robust day-night variations were identified by using MALDI TOF/TOF analysis. In 3 m rats the number of proteins showing day-night variations were relatively more than 12, 24 m and RIPD rat model in SCN and SN. But in pineal there was increase in number of protein spots showing day-night variations in 24 m. Mass spectroscopy of the protein spots showing robust day night variation in aging and RIPD rats were identified. As melatonin, a multitasking molecule, an endogenous synchronizer of rhythm, an antioxidant and an antiaging drug, declines with aging, the effects of melatonin administration on differential alterations in chronomics of 2-D protein profiles in aging and RIPD male Wistar rats were studied. We report here that the melatonin could be playing an important role in modulating the chronomics of 2-D protein profiles. Additionally, various proteins were identified for the first time in this study showing significant day night variation in SCN, pineal and SN may prove useful towards targeting novel treatments for circadian dysfunction, good health and longevity.
28576855	We have revealed that even in humans, activated intrarenal renin-angiotensin-aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (UNaV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24-h ambulatory BP monitoring before and during two-day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (UAGTV, μg/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (UDAV, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24-h Holter-ECG) of non-Gaussianity index λ25s as sympathetic nerve activity; and power of high-frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with UAGTV (r = -0.47, P = 0.04) and positively with UDAV (r = 0.58, P = 0.009). HF was a determinant of night/day BP ratio (β = -0.50, F = 5.8), rather than DC or λ25s During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime UNaV preceded restoration of BP rhythm, accompanied by decreased UAGTV (r = -0.88, P = 0.05) and increased UDAV (r = 0.87, P = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.
28576852	Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm.
28576728	In mammals, the master circadian clock resides in the suprachiasmatic nucleus (SCN). The SCN is characterized by robust circadian oscillations of clock gene expression and neuronal firing. The synchronization of circadian oscillations among individual cells in the SCN is attributed to intercellular coupling. Previous studies have shown that gap junctions, specifically those composed of connexin-36 (Cx36) subunits, are required for coupling of electrical firing among SCN neurons at a time scale of milliseconds. However, it remains unknown whether Cx36 gap junctions also contribute to coupling of circadian (∼24h) rhythms of clock gene expression. Here, we investigated circadian expression patterns of the clock gene Period 2 (Per2) in the SCN of Cx36-deficient mice using luminometry and single-cell bioluminescence imaging. Surprisingly, we found that synchronization of circadian PER2 expression rhythms is maintained in SCN explants from Cx36-deficient mice. Since Cx36 expression levels change with age, we also tested circadian running-wheel behavior of juvenile (3-4weeks old) and adult (9-30weeks old) Cx36-deficient mice. We found that impact of connexin-36 expression on circadian behavior changes greatly during postnatal development. However, consistent with the intact synchrony among SCN cells in cultured explants, Cx36-deficient mice had intact locomotor circadian rhythms, although adults displayed a lengthened period in constant darkness. Our data indicate that even though Cx36 may be required for electrical coupling of SCN cells, it does not affect coupling of molecular clock gene rhythms. Thus, electrical coupling of neurons and coupling of circadian clock gene oscillations can be regulated independently in the SCN.
28573870	Sleep is important in maintaining the body's circadian rhythm and in maintaining health. Aim was to investigate sleep and physical activity among people who have inflammatory arthritis and their engagement with Health Professionals.Members from a national charitable organisation for patients with arthritis and a national rheumatology health professionals society were invited to participate in separate cross-sectional surveys hosted on SurveyMonkey(R)TM.	Ninety people responded and report an average of 5.7 (SD 1.46) hours sleep per night. A majority (61%) report their sleep quality as bad, with 31% taking medications at least once a week to help sleep. There was a statistically significant association between longer years with symptoms, taking medication at least once a week and limited in their activities, when rating their sleep quality as bad. Twenty eight (65%) health professional's responded with 53% discussing sleep with their patients.	People with inflammatory arthritis report low sleep with those having symptoms longer, taking medications regularly and having limitations with their activities, reporting poorer sleep quality. Only half of health professionals discuss sleep. More research is needed in investigating poor sleep quality, disturbances, and physical activity in order to promote health and well-being in this population. Implications for Rehabilitation People with inflammatory arthritis fall far below the National Sleep Foundations' "sleep needs spectrum", which is concerning as those who have reduced levels of sleep have been associated with decreased quality of life and physical function. Due to the importance of receiving sufficient sleep, there is a need to develop education and training for health professionals in the importance of engaging their patients in their sleep quality and disturbances. The effects of physical activity interventions on poor sleep need to be examined to show if it is a positive non-pharmacological treatment approach for the management of poor sleep in patients with inflammatory arthritis.	
28572861	In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients.The integration of DNA methylation profile (n = 14) with the gene expression profile (n = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients (n = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup (p < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p = 0.005) or PAX9 (RR = 1.87, p = 0.001). High expression of CRY1 (HR: 3.53, p < 0.001) or PAX9 (HR: 3.14, p < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172-9.272, p = 0.016) was also predictive of shorter overall survival in CLL.	The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients.	
28570677	Plants adapt to the environment by either long-term genome evolution or by acclimatization processes where the cellular processes and metabolism of the plant are adjusted within the existing potential in the genome. Here we studied the adaptation strategies in date palm, Phoenix dactylifera, under mild heat, drought and combined heat and drought by transcriptomic and metabolomic profiling. In transcriptomics data, combined heat and drought resembled heat response, whereas in metabolomics data it was more similar to drought. In both conditions, soluble carbohydrates, such as fucose, and glucose derivatives, were increased, suggesting a switch to carbohydrate metabolism and cell wall biogenesis. This result is consistent with the evidence from transcriptomics and cis-motif analysis. In addition, transcriptomics data showed transcriptional activation of genes related to reactive oxygen species in all three conditions (drought, heat, and combined heat and drought), suggesting increased activity of enzymatic antioxidant systems in cytosol, chloroplast and peroxisome. Finally, the genes that were differentially expressed in heat and combined heat and drought stresses were significantly enriched for circadian and diurnal rhythm motifs, suggesting new stress avoidance strategies.
28569119	Body temperature is known to vary with circadian phase and to be influenced by factors that can mask its circadian expression. We wanted to test whether skin temperature rhythms were sensitive to an abrupt shift of the sleep schedule and to the resetting effects of light. Nineteen healthy subjects spent 6 days in time isolation and underwent a simulated night-shift procedure. They were assigned to either a control group ( n = 10) or bright light group ( n = 9) and measurements were taken under a baseline day-oriented schedule and during the 4th cycle of a night-oriented schedule. In the bright light group, participants were exposed to a 3-cycle 8-h exposure of ~6,500 lux at night, while the control group remained in dim light conditions (~3 lux). Skin temperature was recorded in 10 and 4 participants from the control and bright light groups, respectively. We found significant circadian rhythms of plasma melatonin, core body temperature (CBT), and skin temperature at baseline for both groups ( p < 0.001 for all). Rhythms of melatonin, CBT, and skin temperature following night shifts were significantly phase delayed by about 7 to 9 h ( p < 0.05) in response to bright light at night, whereas there was no shift in the control group. In addition, we found that at bedtime melatonin does not consistently increase before the increase in distal skin temperature and subsequent decrease in CBT, in contrast to what has been previously reported. The present study shows that, in constant posture conditions, skin temperature rhythms have an evoked component sensitive to abrupt changes in the timing of sleep. They also comprise an endogenous component that is sensitive to the resetting effects of bright light exposure. These results have applications for the determination of circadian phase, as skin temperature is less intrusive than rectal temperature recordings.
28569118	This article is part of a Journal of Biological Rhythms series exploring analysis and statistics topics relevant to researchers in biological rhythms and sleep research. The goal is to provide an overview of the most common issues that arise in the analysis and interpretation of data in these fields. In this article on time series analysis for biological rhythms, we describe some methods for assessing the rhythmic properties of time series, including tests of whether a time series is indeed rhythmic. Because biological rhythms can exhibit significant fluctuations in their period, phase, and amplitude, their analysis may require methods appropriate for nonstationary time series, such as wavelet transforms, which can measure how these rhythmic parameters change over time. We illustrate these methods using simulated and real time series.
28568314	We investigated the effects of a circadian disadvantage (i.e. playing in a different time zone) on the winning percentages in three major sport leagues in North America: the National Basketball Association, the National Hockey League and the National Football League. We reviewed 5 years of regular season games in the National Basketball Association, National Hockey League and National Football League, and noted the winning percentage of the visiting team depending on the direction of travel (west, east, and same time zone) and game time (day and evening games). T-tests and analysis of variance were performed to evaluate the effects of the circadian disadvantage, its direction, the number of time zones travelled, and the game time on winning percentages in each major league. The results showed an association between the winning percentages and the number of time zones traveled for the away evening games, with a clear disadvantage for the teams travelling westward. There was a significant difference in the teams' winning percentages depending on the travelling direction in the National Basketball Association (F2,5908  = 16.12, P < 0.0001) and the National Hockey League (F2,5639  = 4.48, P = 0.011), and a trend was found in the National Football League (F2,1279  = 2.86, P = 0.058). The effect of the circadian disadvantage transcends the type of sport and needs to be addressed for greater equity among the western and eastern teams in professional sports. These results also highlight the importance of circadian rhythms in sport performance and athletic competitions.
28567500	Impaired sleep and alertness affect the majority of Parkinson's disease (PD) patients, negatively impacting safety and quality of life. The etiology of impaired sleep-wake cycle in PD is multifactorial and encompasses medication side effects, nocturnal PD motor symptoms, and presence of co-existent sleep and neuropsychiatric disorders. The primary neurodegenerative process of PD involves brain regions that regulate the sleep-wake cycle, such as brainstem and hypothalamic nuclei. Sleep disorders in PD include insomnia, REM sleep behavior disorder (RBD), sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian disruption. Despite its high prevalence in the PD population, there is a paucity of clinical studies that have investigated treatment of sleep dysfunction associated with PD. Therefore, we aim to review available evidence and outline treatment strategies for improvement of disorders of sleep and wakefulness in PD patients. Evidence supporting the efficacy of pharmacological and non-pharmacological treatment strategies in PD is limited. There is thus a great need but also opportunity for development of well-designed clinical trials for impaired sleep and alertness in PD. Providing education about sleep hygiene and strategies for its implementation represents the initial step in management. Prompt diagnosis and treatment of co-existent primary sleep and psychiatric disorders are critical, as this may significantly improve sleep and alertness. While the optimal treatment for insomnia in PD has not been established, available strategies include cognitive-behavioral therapy, medications with soporific properties, and light therapy. Safety measures, clonazepam, and melatonin are the mainstay of treatment for RBD. Continuous positive airway pressure is an effective treatment for SDB in PD. The treatment algorithm for RLS associated with PD mirrors that used for idiopathic RLS. Circadian disruption has emerged as an important etiology of impaired sleep-wake cycles in PD, and circadian-based interventions hold promise for novel treatment approaches.
28562605	Agassiz's desert tortoise (Gopherus agassizii) is a long-lived species native to the Mojave Desert and is listed as threatened under the US Endangered Species Act. To aid conservation efforts for preserving the genetic diversity of this species, we generated a whole genome reference sequence with an annotation based on deep transcriptome sequences of adult skeletal muscle, lung, brain, and blood. The draft genome assembly for G. agassizii has a scaffold N50 length of 252 kbp and a total length of 2.4 Gbp. Genome annotation reveals 20,172 protein-coding genes in the G. agassizii assembly, and that gene structure is more similar to chicken than other turtles. We provide a series of comparative analyses demonstrating (1) that turtles are among the slowest-evolving genome-enabled reptiles, (2) amino acid changes in genes controlling desert tortoise traits such as shell development, longevity and osmoregulation, and (3) fixed variants across the Gopherus species complex in genes related to desert adaptations, including circadian rhythm and innate immune response. This G. agassizii genome reference and annotation is the first such resource for any tortoise, and will serve as a foundation for future analysis of the genetic basis of adaptations to the desert environment, allow for investigation into genomic factors affecting tortoise health, disease and longevity, and serve as a valuable resource for additional studies in this species complex.
28560311	Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly (p < 0.0001) increased mean ± SEM repetitive firing rates in SCN neurons during the day (6.4 ± 0.5 Hz) and at night (4.3 ± 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). IA was also significantly (p < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 ± 11.8 pA/pF; night: 55.3 ± 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 ± 10.2 pA/pF; night: 120.6 ± 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and IA was larger at night. In addition, Kv4.1-targeted shRNA expression significantly (p < 0.001) increased mean ± SEM nighttime input resistance (Rin; 2256 ± 166 MΩ), compared to nontargeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly (p < 0.01) shortened, by ∼0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded IA channels in regulating circadian rhythms in neuronal excitability and behavior.
28559123	Recent treatment guidelines support treatment of biological rhythm abnormalities as a part of treatment of bipolar disorder, but still, literature examining various domains (Sleep, Activity, Social, and Eating) of biological rhythm and its clinical predictors are less.The main aim of our study is to compare various domains of biological rhythm among remitted bipolar I subjects and healthy controls. We also explored for any association between clinical variables and biological rhythm among bipolar subjects.	40 subjects with Bipolar I disorder and 40 healthy controls who met inclusion and exclusion criteria were recruited for the study. Diagnoses were ascertained by a qualified psychiatrist using MINI 5.0. Sociodemographic details, biological rhythm (BRIAN-Biological Rhythm Interview of assessment in Neuropsychiatry) and Sleep functioning (PSQI- Pittsburgh Sleep Quality Index) were assessed in all subjects.	Mean age of the Bipolar subjects and controls were 41.25±11.84years and 38.25±11.25 years respectively. Bipolar subjects experienced more biological rhythm disturbance when compared to healthy controls (total BRIAN score being 34.25±9.36 vs 28.2±6.53) (p=0.002). Subsyndromal depressive symptoms (HDRS) had significant positive correlation with BRIAN global scores(r=0.368, p=0.02). Linear regression analysis showed that number of episodes which required hospitalization (β=0.601, t=3.106, P=0.004), PSQI (β=0.394, t=2.609, p=0.014), HDRS (β=0.376, t=2.34, t=0.036) explained 31% of variance in BRIAN scores in remitted bipolar subjects.	Biological rhythm disturbances seem to persist even after clinical remission of bipolar illness. More studies to look into the impact of subsyndromal depressive symptoms on biological rhythm are needed.	
28558980	The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine. Non-linear mixed effects modelling was used to describe the concentration-time profiles of morphine and its metabolite M3G in plasma and brain tissue. We found that the concentrations of morphine in the brain and of M3G in plasma depended on the time of day, which could be quantified by a 24-hour rhythm in the efflux of morphine from brain tissue back into the circulation, with the lowest efflux during the two light-dark phase transitions with a difference between peak and trough of 20%. The active processes involved in the clearance of morphine and its metabolite M3G from plasma also showed 24-hour variation with the highest value in the middle of the dark phase being 54% higher than the lowest value at the start of the light phase. Hence, time of day presents a considerable source of variation in the pharmacokinetics of morphine, which could be used to optimize the dosing strategy of morphine.
28558863	To investigate parental knowledge about adolescent sleep needs, and other beliefs that may inform their support for or objection to later school start times.In 2014, we conducted a cross-sectional, Internet-based survey of a nationally representative sample of parents as part of the C.S. Mott Children's Hospital National Poll on Children's Health. Parents with teens aged 13-17 years reported their children's sleep patterns and school schedules, and whether the parents supported later school start times (8:30 am or later). Responses associated with parental support of later school start times were examined with logistic regression analysis.	Overall, 88% of parents reported school start times before 8:30 am, and served as the analysis sample (n = 554). In this group, 51% expressed support for later school start times. Support was associated with current school start times before 7:30 am (odds ratio [OR] = 3.1 [95% confidence interval (CI) 1.2, 8.4]); parental opinion that their teen's current school start time was "too early" (OR = 3.8 [1.8, 7.8]); and agreement with American Academy of Pediatrics recommendations about school start times (OR = 4.7 [2.2, 10.1]). Support also was associated with anticipation of improved school performance (OR = 3.0 [1.5, 5.9]) or increased sleep duration (OR = 4.0 [1.8, 8.9]) with later school start times. Conversely, parents who anticipated too little time for after-school activities (OR = 0.5 [0.3, 0.9]) and need for different transportation plans (OR = 0.5 [0.2, 0.9]) were often less supportive.	Parental education about healthy sleep needs and anticipated health benefits may increase their support for later school start times. Educational efforts should also publicize the positive experiences of communities that have made this transition, with regard to limited adverse effect on after-school activity schedules and transportation.	
28558035	In Drosophila, neuropeptide Pigment Dispersing Factor (PDF) is expressed in small and large ventral Lateral Neurons (sLNv and lLNv), among which sLNv are critical for activity rhythms in constant darkness. Studies show that this is mediated by rhythmic accumulation and likely secretion of PDF from sLNv dorsal projections, which in turn synchronises molecular oscillations in downstream circadian neurons. Using targeted expression of a neurodegenerative protein Huntingtin in LNv, we evoke a selective loss of neuropeptide PDF and clock protein PERIOD from sLNv soma. However, PDF is not lost from sLNv dorsal projections and lLNv. These flies are behaviourally arrhythmic in constant darkness despite persistence of PDF oscillations in sLNv dorsal projections and synchronous PERIOD oscillations in downstream circadian neurons. We find that PDF oscillations in sLNv dorsal projections are not sufficient for sustenance of activity rhythms in constant darkness and this is suggestive of an additional component that is possibly dependent on sLNv molecular clock and PDF in sLNv soma. Additionally, despite loss of PERIOD in sLNv, their activity rhythms entrain to light/dark cycles indicating that sLNv molecular clocks are not necessary for entrainment. Under constant light, these flies lack PDF from both soma and dorsal projections of sLNv, and when subjected to light/dark cycles, show morning and evening anticipation and accurately phased morning and evening peaks. Thus, under light/dark cycles, PDF in sLNv is not necessary for morning anticipation.
28556778	Temperature-sensing neurons in the Drosophila brain cooperate with the central circadian clock to help regulate body temperature.
28556462	Hippocampal rhythms in clock gene expression, enzymatic activity, and long-term potentiation (LTP) are thought to underlie day-night differences in memory acquisition and recall. Glycogen synthase kinase 3-beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region-specific differences over the light-dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3-KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day-night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day-night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).
28555616	Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals.
28554803	Nuclear receptors regulate gene expression by differentially binding to coactivators or corepressors in a ligand-dependent manner, which further recruits a set of epigenome-modifying enzymes that remodel chromatin conformation. Histone acetylation is a major epigenomic change controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC3 is the only HDAC that confers the enzymatic activity to the complexes nucleated by nuclear receptor corepressors NCoR and SMRT. To address the metabolic function of HDAC3, we have deleted it specifically in mouse skeletal muscles. We have performed the following omics profiling in skeletal muscles of these mice: (1) RNA-seq profiling of total RNA; (2) Global nuclear run-on (GRO-seq) analysis of nascent RNAs; (3) Chromatin immuno-precipitation (ChIP-seq) of HDAC3 at both early evening and early morning; (4) proteomics profiling with mass spectrometry; (5) snap-shot metabolomics profiling of water-soluble metabolites at the basal condition; (6) snap-shot metabolomics profiling of lipid species at the basal condition; (7) kinetic fluxomics analysis of glucose utilization using 13C6-glucose In vivo during treadmill running exercise. These approaches have provided several novel insights into how nuclear receptors regulate circadian rhythm of skeletal muscle fuel metabolism, which has been published elsewhere. Here we present the original datasets and technical details during the execution, analysis, and interpretation of these omics studies.
28553739	Many biochemical, physiological, and behavioral processes such as glucose metabolism, body temperature, and sleep-wake cycles show regular daily rhythms. These circadian rhythms are adjusted to the environmental light-dark cycle by a central pacemaker located in the suprachiasmatic nucleus (SCN) in order for the processes to occur at appropriate times of day. Here, we investigated the expression and function of a synaptic organizing protein, C1QL3, in the SCN. We found that C1ql3 is robustly expressed in the SCN. C1ql3 knockout mice have a reduced density of excitatory synapses in the SCN. In addition, these mice exhibited less consolidated activity to the active portions of the day and period lengthening following a 15-minute phase-delaying light pulse. These data identify C1QL3 as a signaling molecule that is highly expressed in SCN neurons, where it contributes to the formation and/or maintenance of glutamatergic synapses and plays a role in circadian behaviors, which may include circadian aftereffects.
28553673	Motor activity in humans and other animals possesses fractal temporal fluctuations that co-exists with circadian or daily activity rhythms. The perturbations in fractal activity patterns are often accompanied by altered circadian/daily rhythms. The goal of this study is to test whether fractal regulation in motor activity provides physiological information independent from 24-h/circadian rhythmicity. To achieve the goal, we studied locomotor activity recordings of rats with the lesion of the suprachiasmatic nucleus (SCN) that are known to have diminished circadian/daily activity rhythms and perturbed fractal regulation. By restricting feeding time (i.e., food was only availability in the dark period of the 12h: 12h light-dark cycles), we found that mean activity levels in these animals displayed significant 24-h rhythms. In contrast, the restricted feeding had no influences on the perturbed fractal regulation in these SCN-lesioned animals, i.e., activity fluctuations in these animals remained random over a wide range of time scales from 2-20h. Our results indicate that 24-h rhythm of food availability can restore/improve circadian/daily rhythms in the SCN-lesioned animals but not necessarily improve the disrupted fractal activity regulation in these animals. This study provides clear and direct evidence that fractal activity patterns offer complementary information about motor activity regulation at multiple time scales that is beyond 24-h rhythm control.
28553258	Organisms have evolved to cope with geophysical cycles of different period lengths. In this review, we focus on the adaptations of animals to the lunar cycle, specifically, on the occurrence of biological rhythms with monthly (circalunar) or semi-monthly (circasemilunar) period lengths. Systematic experimental investigation, starting in the early twentieth century, has allowed scientists to distinguish between mythological belief and scientific facts concerning the influence of the lunar cycle on animals. These studies revealed that marine animals of various taxa exhibit circalunar or circasemilunar reproductive rhythms. Some of these rely on endogenous oscillators (circalunar or circasemilunar clocks), whereas others are directly driven by external cues, such as the changes in nocturnal illuminance. We review current insight in the molecular and cellular mechanisms involved in circalunar rhythms, focusing on recent work in corals, annelid worms, midges, and fishes. In several of these model systems, the transcript levels of some core circadian clock genes are affected by both light and endogenous circalunar oscillations. How these and other molecular changes relate to the changes in physiology or behavior over the lunar cycle remains to be determined. We further review the possible relevance of circalunar rhythms for terrestrial species, with a particular focus on mammalian reproduction. Studies on circalunar rhythms of conception or birth rates extend to humans, where the lunar cycle was suggested to also affect sleep and mental health. While these reports remain controversial, factors like the increase in "light pollution" by artificial light might contribute to discrepancies between studies. We finally discuss the existence of circalunar oscillations in mammalian physiology. We speculate that these oscillations could be the remnant of ancient circalunar oscillators that were secondarily uncoupled from a natural entrainment mechanism, but still maintained relevance for structuring the timing of reproduction or physiology. The analysis and comparison of circalunar rhythms and clocks are currently challenging due to the heterogeneity of samples concerning species diversity, environmental conditions, and chronobiological conditions. We suggest that future research will benefit from the development of standardized experimental paradigms, and common principles for recording and reporting environmental conditions, especially light spectra and intensities.
28553207	Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.
28552991	Elucidating the genetic mechanisms of adaptation to the hydrothermal vent in organisms at genomic level is significant for understanding the adaptive evolution process in the extreme environment. We performed RNA-seq on four different tissues of a vent crab species, Austinograea alayseae, producing 725,461 unigenes and 134,489 annotated genes. Genes related to sensory, circadian rhythm, hormone, hypoxia stress, metal detoxification and immunity were identified. It was noted that in the degenerated eyestalk, transcription of phototransduction related genes which are important for retinal function was greatly reduced; three crucial neuropeptide hormones, one molt-inhibiting and two crustacean hyperglycemic hormone precursors were characterized with conserved domains; hypoxia-inducible factor 1 and two novel isoforms of metallothioneins in the vent crabs were discovered. An analysis of 6,932 orthologs among three crabs A. alayseae, Portunus trituberculutus and Eriocheir sinensis revealed 19 positive selected genes (PSGs). Most of the PSGs were involved in immune responses, such as crustins and anti-lipopolysaccharide factor, suggesting their function in the adaptation to environment. The characterization of the first vent crab transcriptome provides abundant resources for genetic and evolutionary studies of this species, and paves the way for further investigation of vent adaptation process in crabs.
28552939	Plant B-box domain proteins (BBX) mediate many light-influenced developmental processes including seedling photomorphogenesis, seed germination, shade avoidance and photoperiodic regulation of flowering. Despite the wide range of potential functions, the current knowledge regarding BBX proteins in major crop plants is scarce. In this study, we identify and characterize the StBBX gene family in potato, which is composed of 30 members, with regard to structural properties and expression profiles under diurnal cycle, etiolation and de-etiolations. Based on domain organization and phylogenetic relationships, StBBX genes have been classified into five groups. Using real-time quantitative PCR, we found that expression of most of them oscillates following a 24-h rhythm; however, large differences in expression profiles were observed between the genes regarding amplitude and position of the maximal and minimal expression levels in the day/night cycle. On the basis of the time-of-day/time-of-night, we distinguished three expression groups specifically expressed during the light and two during the dark phase. In addition, we showed that the expression of several StBBX genes is under the control of the circadian clock and that some others are specifically associated with the etiolation and de-etiolation conditions. Thus, we concluded that StBBX proteins are likely key players involved in the complex diurnal and circadian networks regulating plant development as a function of light conditions and day duration.
28551698	Shift-work is associated with circadian rhythm disruption and an increased risk of obesity and type 2 diabetes. We sought to determine the effect of rotational shift-work on glucose metabolism in humans.We studied 12 otherwise healthy nurses performing rotational shift-work using a randomised crossover study design. On each occasion, participants underwent an isotope-labelled mixed meal test during a simulated day shift and a simulated night shift, enabling simultaneous measurement of glucose flux and beta cell function using the oral minimal model. We sought to determine differences in fasting and postprandial glucose metabolism during the day shift vs the night shift.	Postprandial glycaemic excursion was higher during the night shift (381±33 vs 580±48 mmol/l per 5 h, p<0.01). The time to peak insulin and C-peptide and nadir glucagon suppression in response to meal ingestion was also delayed during the night shift. While insulin action did not differ between study days, the beta cell responsivity to glucose (59±5 vs 44±4 × 10-9 min-1; p<0.001) and disposition index were decreased during the night shift.	Impaired beta cell function during the night shift may result from normal circadian variation, the effect of rotational shift-work or a combination of both. As a consequence, higher postprandial glucose concentrations are observed during the night shift.	
28551367	We present a multiscale mathematical model for the regulation of the cell cycle by the circadian clock. Biologically, the model describes the proliferation of a population of heterogeneous cells connected to each other. The model consists of a high dimensional transport equation structured by molecular contents of the cell cycle-circadian clock coupled oscillator. We propose a computational method for resolution adapted from the concept of particle methods. We study the impact of molecular dynamics on cell proliferation and show an example where discordance of division rhythms between population and single cell levels is observed. This highlights the importance of multiscale modeling where such results cannot be inferred from considering solely one biological level.
28550253	Sleep disturbances are routinely encountered in Alzheimer's disease (AD) and affect about 25-40% of patients in the mild-to-moderate stages of the disease. In many, sleep pathology may represent a symptom of the underlying neurodegeneration. However, a history of sleep disruption occurring years prior to onset of cognitive symptoms could represent a potential risk factor for AD. The aim of the present narrative review was to evaluate current evidence linking sleep disturbances with AD development and to understand the mechanisms that may contribute to this. Although the mechanisms by which poor sleep may contribute to AD genesis is not fully understood, emerging evidence linking disturbances in the sleep wake cycle with Aβ deposition is shedding light on the relationship between sleep pathology and the subsequent development of AD. Aβ burden appears to be enhanced by sleep-wake cycle disruptions and is suspected as being an important mechanism by which sleep disruptions contribute in AD development. Other mechanisms triggered by sleep disruption may also be involved in AD development, such as brain hypoxia, oxidative stress, circadian activity rhythms disturbances, overexpression of orexins, and blood-brain barrier impairment. Further understanding of the link between sleep disturbances and future development of AD is still needed before sleep disturbances are clearly marked as a preventable risk factor for AD. In these circumstances, early lifestyle interventions to help increase the quantity and quality of sleep may have a favorable outcome on decreasing the incidence of AD and this needs to be investigated further.
28549429	Impairment of sleep and circadian rhythm is a typical feature of bipolar disorder (BD). We carried out an exploratory cross-sectional case-control study to extend the knowledge of sleep characteristics in offspring at risk for BD.We investigated 42 offspring of bipolar parents (OB) (mean age 12.5 ± 3.2) and 42 sex and age matched comparison offspring of healthy parents. We administered the Pediatric Sleep Questionnaire, the Morningness/Eveningness Questionnaire and The General Behavior Inventory Sleep Subscale (GBISS) to assess circadian preference, and to identify sleep impairment symptoms. In addition, the participants completed 14 days of actigraphy to characterise sleep and wake patterns. The current psychopathology profile was assessed using Kiddie Schedule for Affective Disorders and Schizophrenia.	Prevalence of sleep disturbance symptoms was higher among OB than controls (headache after waking up, 17.9% vs. 2.4%, p = 0.03; excessive daytime sleepiness, 38.5% vs. 10.0%, p = 0.004; apparent tiredness at wake-up times, 43.6% vs. 15.0%, p = 0.007 and nightmares, 21.6% vs. 2.4%, p = 0.01), but the differences between groups were not significant after adjusting for current psychopathology. OB had higher GBISS total score (parental version, p < 0.001; self-assessment, p = 0.07) than the controls. OB had higher preference for eveningness than the controls (p = 0.047). According to the actigraphy, OB had longer sleep onset latency (p = 0.048) than the controls.	Evidence suggests that the offspring of bipolar parents experience sleep disturbance symptoms, which was associated with psychopathology in this study. Prospective longitudinal sleep studies would clarify whether sleep disturbance could be a predictor of mood disorder onset in this high-risk population.	
28549320	Bioluminescence is referred to the light emission by a living organism due to a specific biochemical reaction. This interesting feature of the organisms could highly influences behavioral and ecosystem dynamics. Luminescence, mostly observed in marine species, is generally higher in deep-living genera than in benthic or shallow organisms. However, among creatures living in land, fireflies, beetles, springtails and fungi have shown some bioluminescent activities. Classically, the emission of light is catalyzed by luciferase from a substrate. Interestingly, light-emitting organisms are more abundant and widespread in marine than terrestrial environments. Novel tools derived from understanding bioluminescent reactions have led to countless valuable applications in modern biotechnology and biochemical engineering. Here, we overview some main properties bioluminescence in marine organism from bacteria to fishes following the latest advances and new discoveries of state-of-the-art bioluminescent tools in molecular biology, bioluminescent bioassays and imaging. The overview showed available and wide biotechnological tools of bioluminescence take advantage of its high detectability, high sensitive, low toxic and quantum efficiency which make wide usage as reporter of many biological functions in different fields, such as studying bacterial pathogens, ecotoxicology, food toxicity, tracking cells of interest in vivo, protein-protein interactions, gene expression and circadian rhythms. With the recent invention of luminescent reporters, future possibilities for the development of additional reporter applications are promising.
28548639	Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output.
28547658	Purinergic P2X and P2Y receptors are involved in mediating intercellular signalling via purines such as adenosine triphosphate (ATP). P2X and P2Y receptors have been implicated in numerous body functions including learning, memory and sleep. All of these body functions show time-of-day-dependent variations controlled by the master circadian oscillator located in the suprachiasmatic nucleus (SCN). Evidence exists for a role of purinergic signalling in intercellular coupling within SCN. However, few studies have been performed on the expression of purinergic receptors in SCN. Therefore, we analyse the expression of seven P2X (P2X1-7) and eight P2Y (P2Y1-2, 4, 6, 11-14) receptors in mouse SCN and address their time-of-day-dependent variation by using immunohistochemistry and real-time polymerase chain reaction. At the early light phase, P2X and P2Y receptors show a low to moderate, homogenously distributed immunoreaction throughout SCN. P2Y13 reveals strong immunoreaction in fibres within the core region of SCN. From the fifteen analysed P2 receptors, seven exhibit a time-of-day-dependent variation in SCN. P2X1 immunoreaction is very low in the early light phase with a minor increase at the end of the dark phase. P2X4 immunoreaction strongly increases during the dark phase in soma cells in the core region and in a dense network of fibres in the shell region of SCN. P2X3 immunoreaction is moderately elevated during the dark phase. Conversely, immunoreaction for P2Y2, P2Y12 and P2Y14 moderately increases at the early light phase and P2Y6 immunoreaction displays a moderate increase at the mid-light phase. Thus, this study demonstrates a time-of-day-dependent variation of P2 receptors in mouse SCN.
28545154	Circadian rhythms are intrinsic ~24 hour cycles that regulate diverse aspects of physiology, and in turn are regulated by interactions with the external environment. Casein kinase 1 delta (CK1δ, CSNK1D) is a key regulator of the clock, phosphorylating both stabilizing and destabilizing sites on the PER2 protein, in a mechanism known as the phosphoswitch. CK1δ can itself be regulated by phosphorylation on its regulatory domain, but the specific sites involved, and the role this plays in control of circadian rhythms as well as other CK1-dependent processes is not well understood. Using a sensitized PER2::LUC reporter assay, we identified a specific phosphorylation site, T347, on CK1δ, that regulates CK1δ activity towards PER2. A mutant CK1δ T347A was more active in promoting PER2 degradation. This CK1δ regulatory site is phosphorylated in cells in trans by dinaciclib- and staurosporine-sensitive kinases, consistent with their potential regulation by cyclin dependent and other proline-directed kinases. The regulation of CK1δ by site-specific phosphorylation via the cell cycle and other signaling pathways provides a mechanism to couple external stimuli to regulation of CK1δ-dependent pathways including the circadian clock.
28543984	Circadian clocks influence most behaviours and physiological activities in animals, including daily fluctuations in metabolism. However, how the clock gene cycle influences insects' responses to pesticides has rarely been reported. Here, we provide evidence that cycle affects imidacloprid efficacy by mediating the expression of cytochrome P450 genes in the brown planthopper (BPH) Nilaparvata lugens, a serious insect pest of rice. Survival bioassays showed that the susceptibility of BPH adults to imidacloprid differed significantly between the two time points tested [Zeitgeber Time 8 (ZT8) and ZT4]. After cloning the cycle gene in the BPH (Nlcycle), we found that Nlcycle was expressed at higher levels in the fat body and midgut, and its expression was rhythmic with two peaks. Knockdown of Nlcycle affected the expression levels and rhythms of cytochrome P450 genes as well as susceptibility to imidacloprid. The survival rates of BPH adults after treatment with imidacloprid did not significantly differ between ZT4 and ZT8 after double-stranded Nlcycle treatment. These findings can be used to improve pesticide use and increase pesticide efficiency in the field.
28543681	An interaction between Mycobacterium tuberculosis and macrophages constitutes an essential step in tuberculosis development, as macrophages exert both positive and negative effects on M. tuberculosis-triggered organ lesions. In this study, we focused on the regulation of the expression of matrix metalloproteinases (MMPs), which is responsible for lung matrix degradation and bacteria dissection, in macrophages following M. tuberculosis infection. Female BALB/c mice were intravenously injected with the M. tuberculosis strain H37Rv at 0 h zeitgeber time (ZT0) or 12 h zeitgeber time (ZT12). The expression and activity of MMP-1, -2, -3, and -9 in lungs and spleens were then evaluated. In vitro, peritoneal macrophages were harvested at ZT0 or at ZT12 and infected with 10 MOI M. tuberculosis. The expression of MMPs, microRNA-223 and BMAL1 was analyzed by qRT-PCR and/or Western blot. The binding of BMAL1 3'-UTR by miR-223 was confirmed by luciferase activity assay. Additionally, wild-type BMAL1 or NLSmut BMAL1 plasmids were transfected to evaluate the effect of BMAL1 on MMPs. The results showed a differential expression of MMPs in mice tissues infected at different times. M. tuberculosis infection caused enhanced MMP-1, -9, and miR-223 expression, with inhibited BMAL1 expression. MiR-223 modulated BMAL1 expression via the direct binding of BMAL1 3'-UTR. Furthermore, wild-type BMAL1 other than NLSmut BMAL1 attenuated MMPs expression in M. tuberculosis-infected macrophages. Overall, this study demonstrated a potential involvement of circadian rhythm in MMP activation by M. tuberculosis in macrophages. J. Cell. Biochem. 9999: 1-9, 2017. © 2017 Wiley Periodicals, Inc.
28542864	Seizures in mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis are thought to develop with various latency intervals after an initial transient brain insult. To study seizure dynamics after an initial transient precipitating insult in a systematic fashion, we utilized continuous video-electroencephalography (EEG) monitoring after the induction of status epilepticus (SE) in a mouse MTLE model.Continuous 24/7 video/telemetric hippocampal EEG recordings in the systemic pilocarpine MTLE mouse model.	After SE, we observed emerging seizures interfering with the circadian EEG rhythms. The physiologic circadian EEG pattern of mice was transiently suppressed for 2.9 (mean) ± (SEM) 0.5 days after SE. This period was accompanied predominately by nonconvulsive seizure activity, followed by convulsive seizures at later stages. After the circadian rhythm was restored, spontaneous generalized seizures occurred mainly in a clustered manner in a narrow time window between 4 and 7 p.m. (light cycle 7 a.m./7 p.m.). Moreover, we demonstrate that depth-electrode implantation surgery transiently disturbs the physiologic EEG circadian cycle; variation of the time point of SE induction after electrode insertion surgery revealed a substantial impact on the epilepsy phenotype, which was more severe when SE occurred after postsurgical reappearance of EEG circadian cycling.	These data have several experimental and pathophysiologic implications. The impact of depth-electrode surgery on the phenotype has to be tightly controlled. In mice monitored after pilocarpine-induced SE, the "epileptogenesis" period is characterized by the dynamics of epileptiform activity toward behavioral recurrent seizure patterns. The striking clustering of spontaneous seizures at the transition from sleep to activity stages of mice has to be taken into account for future studies on the model. Improving our understanding of the molecular mechanisms that determine the circadian dynamics of seizure threshold remains an intriguing task for the future.	
28541391	In 2007, the International Agency for Research on Cancer declared shift work involving circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. This study examined associations between rotating night shift work and breast cancer risk in two prospective cohorts, the Nurses' Health Studies (NHS: 1988-2012, n = 78,516; NHS2: 1989-2013, n = 114,559), with 9,541 incident invasive breast malignancies and 24 years of follow-up. Women in NHS with 30+ years of shift work had no increased risk of breast cancer (Hazard ratio (HR) = 0.95, 95% Confidence interval (95% CI): 0.77, 1.17; Ptrend = 0.63), compared to never shift workers, though follow-up occurred primarily post-retirement from shift work. In the younger NHS2, breast cancer risk was significantly increased for women with 20+ years of shift work at baseline, reflecting young adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; Ptrend = 0.23), and was marginally significantly increased for women with 20+ years of cumulative shift work, using updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; Ptrend = 0.74). In conclusion, long-term rotating night shift work was associated with increased risk of breast cancer among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.
28540583	Melatonin (MEL) is a conserved molecule with respect to its synthesis pathway and functions. In crayfish, MEL content in eyestalks (Ey) increases at night under the photoperiod, and this indoleamine synchronizes the circadian rhythm of electroretinogram amplitude, which is expressed by retinas and controlled by the cerebroid ganglion (CG). The aim of this study was to determine whether MEL content in eyestalks and CG or circulating MEL in hemolymph (He) follows a circadian rhythm under a free-running condition; in addition, it was tested whether MEL might directly influence the spontaneous electrical activity of the CG. Crayfish were maintained under constant darkness and temperature, a condition suitable for studying the intrinsic properties of circadian systems. MEL was quantified in samples obtained from He, Ey, and CG by means of an enzyme-linked immunosorbent assay, and the effect of exogenous MEL on CG spontaneous activity was evaluated by electrophysiological recording. Variation of MEL content in He, Ey, and CG followed a circadian rhythm that peaked at the same circadian time (CT). In addition, a single dose of MEL injected into the crayfish at different CTs reduced the level of spontaneous electrical activity in the CG. Results suggest that the circadian increase in MEL content directly affects the CG, reducing its spontaneous electrical activity, and that MEL might act as a periodical signal to reinforce the organization of the circadian system in crayfish.
28540509	L-Tryptophan (Trp) and some of its metabolites regulate the circadian rhythm in mammals. We aimed to investigate the effects of short-term supplementation of Trp in isocaloric meals on growth performance using the parameters of multiple blood biomarkers and free amino acids in growing pigs. A total of 32 Landrace × Yorkshire barrows with a mean body weight of 8.64 (±1.13) kg were randomly assigned to four groups and then fed with various concentrations of Trp diets daily. Our results showed that sequential supplementation of different concentrations of Trp in isocaloric meals decreased the feed:gain (F:G) ratio (P = 0.079) and plasma urea and albumin (P = 0.019), whereas the level of total protein did not. Among the essential and conditionally essential amino acids, the concentrations of histidine, isoleucine, proline, threonine, arginine, and valine in the plasma decreased (P < 0.05), whereas the concentrations of Trp, glycine, serine, and methionine increased (P < 0.01). In addition, concentrations of branched chain amino acids also significantly decreased (P = 0.004), while the rate of conversion of Trp to branched chain amino acids increased (P < 0.001). Taken together, we show that administration of a high concentration of Trp in breakfast with decreasing concentrations of Trp in lunch and dinner positively affected feed utilization and improved feed efficiency, at least in part, through the optimization of amino acid interconversions and nitrogen utilization.
28539174	Whether or not an individual's drug metabolising capacity declines with advancing age is a vexing question. There is no clear evidence that drug metabolism itself ('the biologically-assisted chemical alteration of the administered parent molecule') is less efficient in healthy old age than at younger ages, whereas a decreased capacity may be associated with ill-health and frailty. However, elderly individuals do show a reduced enzyme induction capability and are less able to tolerate overdoses. It appears that the majority of deleterious clinical outcomes related to drug therapy in an elderly (usually ill or frail) population may be ascribed to various anatomical and physiological age-related changes. These may affect both pharmacodynamics and pharmacokinetics, but not necessarily drug metabolism. Information gleaned from animal studies undertaken mainly in rodents does not seem to be of relevance to humans and studies in healthy aged human populations may not highlight possible problems. However, certain circumstances may influence metabolic competence, and phenotyping rather than genotyping is of more value in identifying those susceptible to adverse drug reactions. This short review discusses the potential contributions of four factors (inflammation, circadian rhythm, gut microbes, epigenetic aspects) which may lead to alterations in drug metabolism with increasing age.
28538305	Time of day is a key factor that influences the optimization of athletic performance. Intercollegiate coaches oftentimes hold early morning strength training sessions for a variety of factors including convenience. However, few studies have specifically investigated the effect of early morning vs. late afternoon strength training on performance indices of fatigue. This is athletically important because circadian and/or ultradian rhythms and alterations in sleep patterns can affect training ability. Therefore, the purpose of the present study was to examine the effects of morning vs. afternoon strength training on an acute performance index of fatigue (countermovement jump height, CMJ), player readiness (Omegawave), and self-reported sleep quantity. We hypothesized that afternoon training sessions would be associated with increased levels of performance, readiness, and self-reported sleep. A retrospective analysis was performed on data collected over the course of the preseason on 10 elite National Collegiate Athletic Association Division 1 male basketball players. All basketball-related activities were performed in the afternoon with strength and conditioning activities performed either in the morning or in the afternoon. The average values for CMJ, power output (Power), self-reported sleep quantity (sleep), and player readiness were examined. When player load and duration were matched, CMJ (58.8 ± 1.3 vs. 61.9 ± 1.6 cm, p = 0.009), Power (6,378.0 ± 131.2 vs. 6,622.1 ± 172.0 W, p = 0.009), and self-reported sleep duration (6.6 ± 0.4 vs. 7.4 ± 0.25 p = 0.016) were significantly higher with afternoon strength and conditioning training, with no differences observed in player readiness values. We conclude that performance is suppressed with morning training and is associated with a decrease in self-reported quantity of sleep.
28537802	Seasonal pattern (SP) and metabolic syndrome (MetS) are major contributors to poor outcome in bipolar disorders (BD). Patients with seasonal bipolar depression present increased appetite, carbohydrate cravings, weight gain, and hypersomnia, which can increase the development of MetS. MetS also appears to be associated with seasonal mood changes in the general population. This study examines whether a SP in BD is associated with an increased risk of MetS and its sub-components. One thousand four hundred and seventy-one outpatients with BD were systematically enrolled from 2009 to 2016. Inclusion required a disease duration of at least 5 years, with 486 (33%) patients with SP (SP+) and 985 (67%) without (SP-) according to the DSM IV-TR criteria. When using continuous measures of metabolic components, SP+ patients, as compared to SP-, suffered from higher levels for systolic blood pressure (p = 0.01), low-density lipoprotein cholesterol (p = 0.009), fasting glucose (p = 0.007), triglycerides levels (p = 0.03), a larger abdominal circumference (p = 0.02), and a higher body mass index (p = 0.07). In the covariance analysis, adjusted for gender, age, and bipolar subtype, as well as the number of depressive and hypomanic episode, SP+ patients had a significantly higher level of fasting glucose and higher systolic blood pressure. The frequency of MetS did not differ between groups (21.2% in SP- versus 23.9% in SP+). When using categorical definitions for abnormal metabolic components (International Diabetes Federation criteria), there were no differences between groups, except that SP+ patients were more overweight/obese as compared to SP- patients (55.03% versus 46.7%, respectively; p = 0.002) and tended to have more frequently high fasting glucose (18.2% versus 14.3%, respectively; p = 0.07). MetS was frequent in patients with BD, however not associated with SP. Patients with SP appeared more vulnerable to overweight/obesity and presented with higher levels of MetS subcomponents although these parameters were mainly in the normal range. All patients with BD should benefit from early screening and targeted management of cardio-vascular risk factors.
28536575	Aging is an emerging worldwide threat to public health, even in the workplace, as it links with risk of illness and death. Bewildered inflammatory responses and stressful conditions associate with age-related disorders. Additionally, circadian rhythm disruption, a critical health issue in night-shift workers, correlates with premature aging. We investigated the hypothesis of a link between altered inflammatory response, detected by plasmatic long pentraxin 3 (PTX3), and biological aging, measured by leukocyte telomere length (LTL), attrition, and possibly induced by night-shift work. Within the framework of a cross-sectional study, such possible relationships were appraised by simultaneous equation model (SEM) technique among day and night-shift hospital workers. PTX3 levels, modulated by several aging conditions [i.e., body mass index (BMI) (beta = -0.22; p = 0.022), C-reactive protein (CRP) (beta = -0.07; p = 0.000), and cardiovascular diseases with hypertension included (CVD) (beta = -0.12; p = 0.000)], positively associate with LTL (coefficient = 0.15; p = 0.033). LTL, in turn is reduced by CVD (beta = -0.15; p = 0.000), binge drinking (beta = -0.10; p = 0.004), and CRP (beta = -0.05; p = 0.026). On the other hand, night-shift work, found to be remarkably free from aging risk factors [i.e., age (beta = -0.13; p = 0.017), BMI (beta = -0.17; p = 0.030), CVD (beta = -0.14; p = 0.000), and binge drinking (beta = -0.13; p = 0.000)], does associate almost significantly with reversed PTX3 (coefficient = -0.09; p = 0.089) and even with CRP (beta = 0.17; p = 0.000). In conclusion, the SEM analysis indicates that PTX3 is positively linked to LTL. The finding suggests a possible new role of this long pentraxin that, by orchestrating an efficient governance of inflammatory processes, may protect telomere from attrition, ensuring therefore the genetic stability of cells. The higher CRP levels among night-shift workers suggest that night-shift work is associated with increased systemic inflammation. This would make nocturnal workers more susceptible to premature aging.
28536247	Cell-autonomous circadian oscillations strongly influence tissue physiology and pathophysiology of peripheral organs including the heart, in which the circadian clock is known to determine cardiac metabolism and the outcome of for instance ischemic stress. Human pluripotent stem cells represent a powerful tool to study developmental processes in vitro, but the extent to which human embryonic stem (ES) cell-derived cardiomyocytes establish circadian rhythmicity in the absence of a systemic context is unknown. Here we demonstrate that while undifferentiated human ES cells do not possess an intrinsic functional clock, oscillatory expression of known core clock genes emerges spontaneously during directed cardiac differentiation. We identify a set of clock-controlled output genes that contain an oscillatory network of stress-related transcripts. Furthermore, we demonstrate that this network results in a time-dependent functional response to doxorubicin, a frequently used anti-cancer drug with known cardiotoxic side effects. Taken together, our data provide a framework from which the effect of oscillatory gene expression on cardiomyocyte physiology can be modeled in vitro, and demonstrate the influence of a functional clock on experimental outcome.
28535270	Melanopsin expressing intrinsically photosensitive retinal ganglion cells (ipRGC) input to multiple brain regions including those for pupil control, circadian rhythms, sleep and mood regulation. Here we measured ipRGC function and its relationship to sleep quality and depression in patients with advanced AMD.The melanopsin-mediated post-illumination pupil response (PIPR) was measured in 53 patients with advanced AMD (age 78.8 ± 8.8 years) and in 20 healthy controls (age 72.5 ± 3.3 years). Sleep quality and efficiency was assessed using the Pittsburgh Sleep Quality Index (PSQI). Risk of depression was determined using the Center for Epidemiologic Studies Depression questionnaire.	The group with AMD showed significantly reduced pupil constrictions (P = 0.039); PIPR amplitudes (P = 0.003); global sleep scores (P = 0.01); and higher levels of depression (P < 0.001) than the control group. There was a significant correlation between the PIPR amplitude and global sleep score in the AMD group (P = 0.01). The amplitude of PIPR significantly correlated with sleep efficiency (P = 0.008; regression, P = 0.01, R2 = 0.13), but not sleep quality (P = 0.23) in the AMD group. There was no correlation between PIPR and depression scores.	Intrinsically photosensitive RGC dysfunction in advanced AMD contributes to the observed reduction in sleep efficiency. The correlation between the melanopsin-mediated PIPR and sleep may indicate reduced photic input to the suprachiasmatic nucleus and ventrolateral preoptic area due to ipRGC dysfunction in AMD.	
28534696	Alzheimer's disease and related dementias (ADRD) can cause sleep and behavioral problems that are problematic for ADRD patients and their family caregivers. Light therapy has shown promise as a nonpharmacological treatment, and preliminary studies demonstrate that timed light exposure can consolidate and improve nighttime sleep efficiency, increase daytime wakefulness and reduce evening agitation without the adverse effects of pharmacological solutions. Compliance with light treatment and the accurate measurement of light exposures during treatment, however, have presented barriers for the adoption of light therapy for ADRD. Recent research showing that the circadian system is maximally sensitive to short-wavelength light opens the way for the potential application of lower, more-targeted light intensities to maximize compliance and individualize light dose/timing in therapeutic settings.
28534145	Gamma-hydroxybutyric acid (GHB) acts as an agonist of the GABAB receptor, where GHB induces a depressant effect in the central nervous system. Besides its therapeutic application, GHB is also used as a date rape drug. However, the detection of GHB ingestion proves to be difficult due to its narrow detection window. The aim of this pilot study was to assess differential gene expressions after GHB intake to identify potential biomarkers for the detection of GHB intake. To this aim, alteration in gene expression of ALDH5A1, AKR7A2, EREG, and PEA15 was investigated via quantitative PCR (qPCR). Data normalization was based on a previously established and empirically derived normalization strategy. Blood samples of patients (n = 3) therapeutically taking sodium oxybate solution (GHB) and of donors without GHB intake (n = 49) were analyzed and compared. All qPCR procedures and results are reported according to the MIQE guidelines. Investigation of suitable reference genes using established algorithms suggested PPIB and FPGS as best-suited normalizers. Alterations in gene expression relating to GHB intake could not be confirmed to a forensically sufficient degree. However, significant differences in expression of EREG in the control group were observed, when time-point of sample collection was considered, indicating circadian rhythm. The study's main limitation is the small number of study subjects. Herein, we are first to present an empirically derived strategy for a robust normalization of qPCR data from the analysis of GHB-induced gene expression in human blood. We present results of the analysis of differential expression of ALDH5A1, AKR7A2, EREG, and PEA15 in the GHB-negative population. Finally, we report our findings on the effect of GHB intake on the expression of these genes and their presumable potential as GHB biomarkers.
28533787	Low temperature is one of the major environmental stresses that affects plant growth and development, and leads to decrease in crop yield and quality. Thellungiella salsuginea (salt cress) exhibits high tolerance to chilling, is an appropriate model to investigate the molecular mechanisms of cold tolerance. Here, we compared transcription changes in the roots and leaves of T. salsuginea under cold stress using RNA-seq. We identified 2,782 and 1,430 differentially expressed genes (DEGs) in leaves and roots upon cold treatment, respectively. The expression levels of some genes were validated by quantitative real-time-PCR (qRT-PCR). Among these DEGs, 159 (11.1%) genes in roots and 232 (8.3%) genes in leaves were annotated as various types of transcription factors. We found that five aquaporin genes (three TIPs, one PIPs, and one NIPs) responded to cold treatment. In addition, the expression of COR47, ICE1, and CBF1 genes of DREB1/CBF-dependent cold signaling pathway genes altered in response to low temperature. KEGG pathway analysis indicated that these cold regulated genes were enriched in metabolism, photosynthesis, circadian rhythm, and transcriptional regulation. Our findings provided a complete picture of the regulatory network of cold stress response in T. salsuginea. These cold-responsive genes could be targeted for detail functional study and utilization in crop cold tolerance improvement.
28533170	In mammals, the rhythmic secretion of melatonin from the pineal gland is driven by the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The robust nightly peak of melatonin secretion is an output signal of the circadian clock and is supposed to deliver the circadian message to the whole of the organism. Since the circadian system regulates many behavioral and physiological processes, its disruption by external (shift-work, jet-lag) or internal desynchronization (blindness, aging) causes many different health problems. Externally applied melatonin is used in humans as a chronobiotic drug to treat desynchronization and circadian disorders, and the success of these treatments does, at first glance, underline the supposed pivotal role of melatonin in the synchronization of the circadian system. On the other hand, pinealectomy in experimental animals and humans does not abolish their rhythms of rest and activity. Furthermore, mice with deficient melatoninergic systems neither display overt defects in their rhythmic behavior nor do they show obvious signs of disease susceptibility, let alone premature mortality. During the last years, our laboratory has investigated several mouse stains with intact or compromised internal melatonin signaling systems in order to better understand the physiological role of the melatoninergic system. These and other investigations which will be reviewed in the present contribution confirm the synchronizing effect of endogenous melatonin and the melatoninergic system. However, these effects are subtle. Thus melatonin does not appear as the master of internal synchronization, but as one component in a cocktail of synchronizing agents.
28532353	Circadian rhythms are self-sustained, approximately 24-h rhythms of physiology and behavior. These rhythms are entrained to an exactly 24-h period by the daily light-dark cycle. Remarkably, mice lacking all rod and cone photoreceptors still demonstrate photic entrainment, an effect mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells utilize melanopsin (OPN4) as their photopigment. Distinct from the ciliary rod and cone opsins, melanopsin appears to function as a stable photopigment utilizing sequential photon absorption for its photocycle; this photocycle, in turn, confers properties on ipRGCs such as sustained signaling and resistance from photic bleaching critical for an irradiance detection system. The retina itself also functions as a circadian pacemaker that can be autonomously entrained to light-dark cycles. Recent experiments have demonstrated that another novel opsin, neuropsin (OPN5), is required for this entrainment, which appears to be mediated by a separate population of ipRGCs. Surprisingly, the circadian clock of the mammalian cornea is also light entrainable and is also neuropsin-dependent for this effect. The retina thus utilizes a surprisingly broad array of opsins for mediation of different light-detection tasks.
28532231	High but nonstressful temperatures profoundly affect plant growth and developmental processes, termed thermomorphogenesis. Thermo-induced hypocotyl elongation is a typical thermomorphogenic trait, which contributes to cooling plant organs. It is known that external light signals and the circadian clock coordinate rhythmic hypocotyl growth. However, it was unclear how light, temperature, and circadian rhythms are harmonized during hypocotyl thermomorphogenesis. We have recently demonstrated that the E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) is activated at warm temperatures. It is notable that warm temperatures induce the nuclear import of COP1, facilitating degradation of ELONGATED HYPOCOTYL 5 (HY5) and this biochemical event is uncoupled from light conditions. Furthermore, the thermo-induced HY5 protein turnover occurs independent of circadian rhythms, indicating that the COP1-HY5 module conveys warm temperature information. Meanwhile, the clock components, including CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), convey timing information for the rhythmic thermomorphogenic growth. These molecular mechanisms enable a coincidence between warm temperature signaling and circadian rhythms, which explains the distinct rhythms of hypocotyl growth at warm temperatures.
28529757	Grapes are categorized as a non-climacteric type of fruit which its ripening is not associated to important rises in respiration and ethylene synthesis. The starch metabolism shares a certain role in the carbohydrate metabolic pathways during grape berry development, and is regarded as an important transient pool in the pathway of sugar accumulation. However, the comprehensive role of starch and its contribution to the quality and flavor of grape berry have not been explored thoroughly. In this study, the expression levels of genes enzyme activities and carbohydrate concentrations related to starch metabolism, were analyzed to understand the molecular mechanism of starch accumulation during grape berry development. The results indicated that starch granules in grape berry were located at the chloroplast in the sub-epidermal tissues, acting as the temporary reserves of photosynthetic products to meet the needs for berry development, and relatively high starch contents could be detected at véraison stage. Moreover, both ADP-glucose pyrophosphorylase (EC 2.7.7.27) and sucrose phosphate synthase (EC 2.3.1.14) involved in starch synthesis displayed elevated gene expression and enzymes activities in the sub-epidermal tissue, while α- and β-amylases involved in its degradation were highly transcribed and active in the central flesh, explaining the absence of starch in this last tissue. Change in the gene expression and activities of ADP-glucose pyrophosphorylase, β-amylase and sucrose phosphate synthase revealed that they were regulated by the circadian rhythms in the fruitlets compared with those in the leaves. Both the morphological, enzymological and transcriptional data in this study provide advanced understandings on the function of starch during berry development and ripening that are so important for berry quality. This study will further facilitate our understanding of the sugar metabolism in grape berry as well as in other plant species.
28527179	The capacity for biological timekeeping arose at least three times through evolution, in prokaryotic cyanobacteria, in cells that evolved into higher plants, and within the group of organisms that eventually became the fungi and the animals. Neurospora is a tractable model system for understanding the molecular bases of circadian rhythms in the last of these groups, and is perhaps the most intensively studied circadian cell type. Rhythmic processes described in fungi include growth rate, stress responses, developmental capacity, and sporulation, as well as much of metabolism; fungi use clocks to anticipate daily environmental changes. A negative feedback loop comprises the core of the circadian system in fungi and animals. In Neurospora, the best studied fungal model, it is driven by two transcription factors, WC-1 and WC-2, that form the White Collar Complex (WCC). WCC elicits expression of the frq gene. FRQ complexes with other proteins, physically interacts with the WCC, and reduces its activity; the kinetics of these processes is strongly influenced by progressive phosphorylation of FRQ. When FRQ becomes sufficiently phosphorylated that it loses the ability to influence WCC activity, the circadian cycle starts again. Environmental cycles of light and temperature influence frq and FRQ expression and thereby reset the internal circadian clocks. The molecular basis of circadian output is also becoming understood. Taken together, molecular explanations are emerging for all the canonical circadian properties, providing a molecular and regulatory framework that may be extended to many members of the fungal and animal kingdoms, including humans.
28526480	Living for extended periods in Antarctica exposes base personnel to extremes of daylength (photoperiod) and temperature. At the British Antarctic Survey base of Halley, 75°S, the sun does not rise for 110 d in the winter and does not set for 100 d in summer. Photoperiod is the major time cue governing the timing of seasonal events such as reproduction in many species. The neuroendocrine signal providing photoperiodic information to body physiology is the duration of melatonin secretion which reflects the length of the night: longer in the short days of winter and shorter in summer. Light of sufficient intensity and spectral composition serves to suppress production of melatonin and to set the circadian timing and the duration of the rhythm. In humans early observations suggested that bright (>2000 lux) white light was needed to suppress melatonin completely. Shortly thereafter winter depression (Seasonal Affective Disorder or SAD) was described, and its successful treatment by an artificial summer photoperiod of bright white light, sufficient to shorten melatonin production. At Halley dim artificial light intensity during winter was measured, until 2003, at a maximum of approximately 500 lux in winter. Thus a strong seasonal and circadian time cue was absent. It seemed likely that winter depression would be common in the extended period of winter darkness and could be treated with an artificial summer photoperiod. These observations, and predictions, inspired a long series of studies regarding human seasonal and circadian status, and the effects of light treatment, in a small overwintering, isolated community, living in the same conditions for many months at Halley. We found little evidence of SAD, or change in duration of melatonin production with season. However the timing of the melatonin rhythm itself, and/or that of its metabolite 6-sulphatoxymelatonin (aMT6s), was used as a primary marker of seasonal, circadian and treatment changes. A substantial phase delay of melatonin in winter was advanced to summer phase by a two pulse 'skeleton' bright white light treatment. Subsequently a single morning pulse of bright white light was effective with regard to circadian phase and improved daytime performance. The circadian delay evidenced by melatonin was accompanied by delayed sleep (logs and actigraphy): poor sleep is a common complaint in Polar regions. Appropriate extra artificial light, both standard white, and blue enriched, present throughout the day, effectively countered delay in sleep timing and the aMT6s rhythm. The most important factor appeared to be the maximum light experienced. Another manifestation of the winter was a decline in self-rated libido (men only on base at this time). Women on the base showed lower aspects of physical and mental health compared to men. Free-running rhythms were seen in some subjects following night shift, but were rarely found at other times, probably because this base has strongly scheduled activity and leisure time. Complete circadian adaptation during a week of night shift, also seen in a similar situation on North Sea oil rigs, led to problems readapting back to day shift in winter, compared to summer. Here again timed light treatment was used to address the problem. Sleep, alertness and waking performance are critically dependent on optimum circadian phase. Circadian desynchrony is associated with increased risk of major disease in shift workers. These studies provide some groundwork for countering/avoiding circadian desynchrony in rather extreme conditions.
28526259	By affecting the internal timing mechanisms of the brain, light regulates human physiology and behavior, perhaps most notably the sleep-wake cycle. Humans spend over 90% of their waking hours indoors, yet light in the built environment is not designed to affect circadian rhythms.Using a device calibrated to measure light that is effective for the circadian system (circadian-effective light), collect personal light exposures in office workers and relate them to their sleep and mood.	The research was conducted in 5 buildings managed by the US General Services Administration.	This study recruited 109 participants (69 females), of whom 81 (54 females) participated in both winter and summer.	Self-reported measures of mood and sleep, and objective measures of circadian-effective light and activity rhythms were collected for 7 consecutive days.	Compared to office workers receiving low levels of circadian-effective light in the morning, receiving high levels in the morning is associated with reduced sleep onset latency (especially in winter), increased phasor magnitudes (a measure of circadian entrainment), and increased sleep quality. High levels of circadian-effective light during the entire day are also associated with increased phasor magnitudes, reduced depression, and increased sleep quality.	The present study is the first to measure personal light exposures in office workers using a calibrated device that measures circadian-effective light and relate those light measures to mood, stress, and sleep. The study's results underscore the importance of daytime light exposures for sleep health.	
28525781	This paper reports on a study of sleep amongst men and women who are living in residential rehabilitation centres in the UK and who are receiving support for their recovery from addiction to alcohol and other forms of substance use. Conceptually and methodologically, the paper draws on the work of the French sociologist Lefebvre and, in particular, his rhythmanalysis. We argue that this approach offers a useful way of exploring sleep in terms of biological, experiential, temporal, spatial and social rhythms. It also has the potential to facilitate interdisciplinary dialogue. Empirical data comprising qualitative interviews with 28 individuals, sleep diaries, and actigraphy reports (which measure movement as a proxy for sleep) are examined in combination to generate insights into the challenges associated with sleep in recovery from substance misuse. We examine how sleep in recovery involves an alignment of the spatiotemporal rhythms of rehabilitation and the multiple embodied rhythms of individuals. Institutionalised routines reproduce and impose ideas of day/night sleep cycles which are presumed to accord with 'natural' circadian rhythms. Although study participants very much want to achieve these 'natural hegemonies' of sleep, alignment of individual and institutional rhythms is difficult to achieve. We develop the notion of 'sleep waves' as an analytic to capture the multifaceted elements of sleep and to argue that sleep waves recur but are also shaped by complex networks of rhythms, rituals and routines. Sleep waves can become relatively stabilised in rehabilitation settings, but the anticipation of moving on disturbs rhythms and generates anxieties which can affect recovery.
28525301	The discovery of a third type of photoreceptors in the mammalian retina, intrinsically photosensitive retinal ganglion cells (ipRGCs), has had a revolutionary impact on chronobiology. We can now properly account for numerous non-vision-related functions of light, including its effect on the circadian system. Here, we give an overview of ipRGCs and their function as it relates specifically to mood and biological rhythms. Although circadian disruptions have been traditionally hypothesized to be the mediators of light's effects on mood, here we present an alternative model that dispenses with assumptions of causality between the two phenomena and explains mood regulation by light via another ipRGC-dependent mechanism.
28523961	An individual's chronotype influences his or her physiological rhythms. Some studies have looked at the effect of time of day on the responses to exercise, but studies on the effect of long-term training are lacking. To report the effects of an 8-week training period during the polar night in non-athletes of different chronotypes living at 70°N.	 In all, 10 morning (M), 10 neither (N) and 10 evening (E) types were recruited, and their aerobic capacity (VO2max), strength, flexibility and balance before and after the training period were tested.	3 E-types, 5 N-types and 6 M-types completed the protocol. An increase in VO2max and strength was observed for the whole group. The best negative correlation (r=-0.5287) was found between the Morningness-Eveningness Questionnaire (MEQ) score and the increase in VO2max, and the best positive correlation (r=0.4395) was found between MEQ and the increase in strength. Changes in balance and flexibility did not show any clear trends.	In an environment with no outdoor daylight, it seems that the response to 8 weeks of aerobic training is larger in the E- than in the M-types, although the M-types showed a larger improvement in strength.	
28522986	There is increasing awareness on the role played by circadian rhythm abnormalities in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). The characterization of the circadian dysfunction parallels the mounting evidence that the hallmarks of neurodegeneration also affect the retina and frequently lead to loss of retinal ganglion cells (RGCs) and to different degrees of optic neuropathy. In the RGC population, there is the subgroup of cells intrinsically photosensitive and expressing the photopigment melanopsin [melanopsin-containing retinal ganglion cells (mRGCs)], which are now well known to drive the entrainment of circadian rhythms to the light-dark cycles. Thus, the correlation between the pathological changes affecting the retina and mRGCs with the circadian imbalance in these neurodegenerative diseases is now clearly emerging, pointing to the possibility that these patients might be amenable to and benefit from light therapy. Currently, this connection is better established for AD and PD, but the same scenario may apply to other neurodegenerative disorders, such as Huntington's disease. This review highlights similarities and differences in the retinal/circadian rhythm axis in these neurodegenerative diseases posing a working frame for future studies.
28522975	We explored the assembly of intestinal microbiota in healthy male participants during the run-in (5 day) and experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR)], and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, balanced fluid, and dietary intakes, controlled circadian rhythm, microbial ambiental burden, and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4,000 m simulated altitude), respectively. A number of parameters linked to intestinal transit spanning Bristol Stool Scale, defecation rates, zonulin, α1-antitrypsin, eosinophil derived neurotoxin, bile acids, reducing sugars, short chain fatty acids, total soluble organic carbon, water content, diet composition, and food intake were measured (167 variables). The abundance, structure, and diversity of butyrate producing microbial community were assessed using the two primary bacterial butyrate synthesis pathways, butyryl-CoA: acetate CoA-transferase (but) and butyrate kinase (buk) genes. Inactivity negatively affected fecal consistency and in combination with hypoxia aggravated the state of gut inflammation (p < 0.05). In contrast, gut permeability, various metabolic markers, the structure, diversity, and abundance of butyrate producing microbial community were not significantly affected. Rearrangements in the butyrate producing microbial community structure were explained by experimental setup (13.4%), experimentally structured metabolites (12.8%), and gut metabolite-immunological markers (11.9%), with 61.9% remaining unexplained. Many of the measured parameters were found to be correlated and were hence omitted from further analyses. The observed progressive increase in two immunological intestinal markers suggested that the transition from healthy physiological state toward the developed symptoms of low magnitude obesity-related syndromes was primarily driven by the onset of inactivity (lack of exercise in NBR) that were exacerbated by systemic hypoxia (HBR) and significantly alleviated by exercise, despite hypoxia (HAmb). Butyrate producing community in colon exhibited apparent resilience toward short-term modifications in host exercise or hypoxia. Progressive constipation (decreased intestinal motility) and increased local inflammation marker suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine.
28522096	To compare sleep and circadian variability in adults with delayed sleep-wake phase disorder (DSWPD) to healthy controls.Forty participants (22 DSWPD, 18 healthy controls) completed a ten-day protocol, consisting of DLMO assessments on two consecutive nights, a five-day study break, followed by two more DLMO assessments. All participants were instructed to sleep within one hour of their self-reported average sleep schedule for the last four days of the study break. We analyzed the participants' wrist actigraphy data during these four days to examine intraindividual variability in sleep timing, duration and efficiency. We also examined shifts in the DLMO from before and after the study break.	Under the same conditions, people with DSWPD had significantly more variable wake times and total sleep time than healthy controls (p ≤ 0.015). Intraindividual variability in sleep onset time and sleep efficiency was similar between the two groups (p ≥ 0.30). The DLMO was relatively stable across the study break, with only 11% of controls but 27% of DSWPDs showed more than a one hour shift in the DLMO. Only in the DSWPD sample was greater sleep variability associated with a larger shift in the DLMO (r = 0.46, p = 0.03). These results suggest that intraindividual variability in sleep can be higher in DSWPD versus healthy controls, and this may impact variability in the DLMO. DSWPD patients with higher intraindividual variability in sleep are more likely to have a shifting DLMO, which could impact sleep symptoms and the optimal timing of light and/or melatonin treatment for DSWPD.	
28516429	Circadian rhythm which governs basic physiological activities like sleeping, feeding and energy consumption is regulated by light-controlled central clock genes in the pacemaker neuron. The timekeeping machinery with unique transcriptional and post-transcriptional feedback loops is controlled by different small regulatory RNAs in the brain. Roles of the multiple neuronal genes, especially post-transcriptional regulation, splicing, polyadenylation, mature mRNA editing, and stability of translation products, are controlled by epigenetic activities orchestrated via small RNAs. Collectively, these mechanisms regulate clock and light-controlled genes for effecting pacemaker activity and entrainment. Regulatory small RNAs of the circadian circuit, timekeeping mechanism, synchronization of regular entrainment, oscillation, and rhythmicity are regulated by diversified RNA molecules. Regulatory small RNAs operate critical roles in brain activities including the neuronal clock activity. In this report, we propose the emergence of the earlier unexpected small RNAs for a historic perspective of epigenetic regulation of the brain clock system.
28515677	The polysialic acid (PSA) is a large glycan that is added to cell-surface proteins during their post-translational maturation. In the brain, PSA modulates distances between cells and controls the plasticity of the nervous system. In the hypothalamus, PSA is involved in many aspects of energy balance including food intake, osmoregulation, circadian rhythm, and sleep. In this work, we investigated the role of hypothalamic PSA in the regulation of plasma cholesterol levels and distribution. We report that HFD consumption in mice rapidly increased plasma cholesterol, including VLDL, LDL, and HDL-cholesterol. Although plasma VLDL-cholesterol was normalized within the first week, LDL and HDL were still elevated after 2 weeks upon HFD. Importantly, we found that hypothalamic PSA removal aggravated LDL elevation and reduced HDL levels upon HFD. These results indicate that hypothalamic PSA controls plasma lipoprotein profile by circumventing the rise of LDL-to-HDL cholesterol ratio in plasma during overfeeding. Although mechanisms by which hypothalamic PSA controls plasma cholesterol homeostasis remains to be elucidated, these findings also suggest that low level of hypothalamic PSA might be a risk factor for dyslipidemia and cardiovascular diseases.
28515338	A new analytical method allows reconstruction of circadian gene expression in human biopsy samples.
28515313	Cold temperatures lead to nullification of circadian rhythms in many organisms. Two typical scenarios explain the disappearance of rhythmicity: the first is oscillation death, which is the transition from self-sustained oscillation to damped oscillation that occurs at a critical temperature. The second scenario is oscillation arrest, in which oscillation terminates at a certain phase. In the field of nonlinear dynamics, these mechanisms are called the Hopf bifurcation and the saddle-node on an invariant circle bifurcation, respectively. Although these mechanisms lead to distinct dynamical properties near the critical temperature, it is unclear to which scenario the circadian clock belongs. Here we reduced the temperature to dampen the reconstituted circadian rhythm of phosphorylation of the recombinant cyanobacterial clock protein KaiC. The data led us to conclude that Hopf bifurcation occurred at ∼19 °C. Below this critical temperature, the self-sustained rhythms of KaiC phosphorylation transformed to damped oscillations, which are predicted by the Hopf bifurcation theory. Moreover, we detected resonant oscillations below the critical temperature when temperature was periodically varied, which was reproduced by numerical simulations. Our findings suggest that the transition to a damped oscillation through Hopf bifurcation contributes to maintaining the circadian rhythm of cyanobacteria through resonance at cold temperatures.
28514644	The interaction between hormonal circadian rhythms and feeding behaviour is not well understood. This study aimed to deepen our understanding of mechanisms underlying circadian feeding behaviour in animals, using pigs, Sus scrofa, as a case study. Pigs show an alternans feeding pattern, that is, a small peak of feed intake at the beginning of the day and a larger peak at the end of the day. We simulated the feeding behaviour of pigs over a 24h period. The simulation model contained mechanisms that regulate feeding behaviour of animals, including: processing of feed in the gastrointestinal tract, fluctuation in energy balance, circadian rhythms of melatonin and cortisol and motivational decision-making. From the interactions between these various processes, feeding patterns (e.g. feed intake, meal frequency, feeding rate) emerge. These feeding patterns, as well as patterns for the underlying mechanisms (e.g. energy expenditure), fitted empirical data well, indicating that our model contains relevant mechanisms. The circadian rhythms of cortisol and melatonin explained the alternans pattern of feeding in pigs. Additionally, the timing and amplitude of cortisol peaks affected the diurnal and nocturnal peaks in feed intake. Furthermore, our results suggest that circadian rhythms of other hormones, such as leptin and ghrelin, are less important in circadian regulation of feeding behaviour than previously thought. These results are relevant to animal species with a metabolic and endocrine system similar to that of pigs, such as humans. Moreover, the modelling approach to understand feeding behaviour can be applied to other animal species.
28514121	Work in repeated changing shifts, in general, and night-shifts, in particular, is considered a necessity, encompassing many professions, among them physicians and nurses. This type of work has been shown to adversely affect the normal function of the human body circadian rhythm. This negative influence in turn, is considered to increase characteristic types of morbidity such as metabolic syndrome, type 2 diabetes and increased rate of cardiovascular morbidity. Women working in night-shifts in particular, have been found to face increased rates of breast cancer, as well as menstrual disturbances and decreased fertility. Despite many physiologic explanations for the deleterious effects of changing or night-shifts on human's health, there is no clear notion for the prevention or treatment of these health hazards. In light of the necessity for such a mode of employment in our modern world, the issues of taking care of the affected workers should be considered on a national scale.
28513549	Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through progressive neurodegeneration. In this study, we analyzed the brain of the mouse model for Hunter syndrome, a LSD mostly presenting with neurological involvement. Whole transcriptome analysis of the cerebral cortex and midbrain/diencephalon/hippocampus areas was performed through RNA-seq. Genes known to be involved in several neurological functions showed a significant differential expression in the animal model for the disease compared to wild type. Among the pathways altered in both areas, axon guidance, calcium homeostasis, synapse and neuroactive ligand-receptor interaction, circadian rhythm, neuroinflammation and Wnt signaling were the most significant. Application of RNA sequencing to dissect pathogenic alterations of complex syndromes allows to photograph perturbations, both determining and determined by these disorders, which could simultaneously occur in several metabolic and biochemical pathways. Results also emphasize the common, altered pathways between neurodegenerative disorders affecting elderly and those associated with pediatric diseases of genetic origin, perhaps pointing out a general common course for neurodegeneration, independent from the primary triggering cause.
28511934	Manganese (Mn) neurotoxicity displays non-motor dysfunction and motor impairment like Parkinson's disease (PD), and is called as Manganism. Circadian disruption is a non-motor symptom found in PD and Manganism. Clock genes are essential to drive and maintain circadian rhythm, but little is known about Mn exposure on circadian clock genes expression. Both the brain and liver are targets of Mn, we hypothesize that repeated Mn administration could affect clock gene expression in the hypothalamus and livers. Male Sprague-Dawley rats were intraperitoneally injected Mn2+ 1mg and 5mg/kg as MnCl2·4H2O, every other day for 30 days. Mn neurotoxicity was evaluated by behavioral changes and loss of dopaminergic neurons via immunohistochemistry. The expression of circadian clock genes was determined via RT-qPCR. Repeated Mn administration dose-dependently retarded the body weight gain, impaired the rotarod activity, decreased the number of dopaminergic neurons in the substantia nigra, and activated microglia in the brain. Expressions of circadian core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock) and neuronal PAS domain protein2 (Npas2), and clock feedback gene cryptochrome1 (Cry1), period genes (Per1 and Per2) in the hypothalamus and liver were decreased after exposure to Mn in a dose-dependent manner, while expressions of clock-targeted genes nuclear receptor Rev-Erbα (Nr1d1) and D-box-binding protein (Dbp) were increased. Peripheral clock in the liver appears to be more susceptible to Mn-induced abnormal clock gene expression. In summary, repeated Mn administration produced dysregulation of circadian clock gene expressions in both the brain and liver.
28511018	The goal of this study was to evaluate the effect of the food availability period on body weight, self-selection of macronutrients, adiposity, lipoprotein, and serum glucose profiles without changing energy intake. Young male rats were divided into 2 groups according to the availability of food during the light and dark phases of the cycle, forming 2 groups: control group (CG) and group with inverted feeding pattern (IFPG). Before inversion of food availability on the 80th day, circadian food intake was measured every 4 h over 24 h during 3 days. The glycemic curve, an oral test for glucose tolerance, and self-selection of macronutrients were evaluated. Blood samples were collected for analysis of fasting glucose, triglycerides, and total cholesterol fractions. The IFPG showed an increase in fasting glucose in the dark phase of the cycle, changes in the glycemic curve, and oral glucose tolerance test. It also showed increased abdominal and liver fat and distinct choice of macronutrients compared with the CG. A change in the availability of food according to the phase of the circadian cycle produces changes in glucose and feeding circadian rhythm culminating in increased abdominal and hepatic fat. These effects can increase the risk of metabolic disorders and installation of chronic diseases.

28510251	Biological rhythms can be defined as changes in physiological or behavioral variables that repeat at certain time intervals. Rhythms that last approximately 24 h are referred to as circadian rhythms. Modern lifestyles have drastically affected human habits, as well as the population's eating habits. These changes have generated an epidemic of metabolic syndromes, such as obesity and diabetes. In an attempt to combat obesity, populations have attempted to use many different herbal remedies and plant-based drugs, the most common of which is Camellia sinensis, or green tea. Most of the studies on the effects of C. sinensis on maintaining body weight have reported the involvement of this substance in lipid oxidation. The objective of this study was to evaluate how the administration of C. sinensis at different times of day influenced changes in body weight, blood glucose levels, and food intake of mice kept under different diet conditions. The structural organization of abdominal adipose tissue was also evaluated, as were certain aspects of lipid metabolism and overall synthetic activity in the liver, adipose tissue, and ovaries. The results obtained suggest that the intake of green tea in the light phase of the day stimulates weight loss, regardless of the diet ingested. Neither glucose levels nor the structural organization of adipose tissue was found to be altered in any of the experimental groups. Neither diet nor the time at which the green tea was administered was found to have any effects on the amount of food the mice consumed. The time at which green tea was consumed and the type of diet both influenced LXRαβ nuclear receptor expression, as well as the expression of fibrillarin in the liver and ovaries, although this influence was tissue specific.
28508438	Delirium is highly prevalent within critical care and is linked to adverse clinical outcomes, increased mortality and impaired quality of life. Development of delirium is thought to be caused by multiple risk factors, including disruption of the circadian rhythm. Chronotherapeutic interventions, such as light therapy, music and use of eye shades, have been suggested as an option to improve circadian rhythm within intensive care units.This review aims to answer the question: Can chronotherapy reduce the prevalence of delirium in adult patients in critical care?	This study is a systematic review of quantitative studies.	Six major electronic databases were searched, and a hand search was undertaken using selected key search terms. Research quality was assessed using the critical appraisal skills programme tools. The studies were critically appraised by both authors independently, and data were extracted. Four themes addressing the research question were identified and critically evaluated.	Six primary research articles that investigated different methods of chronotherapy were identified, and the results suggest that multi-component non-pharmacological interventions are the most effective for reducing the prevalence of delirium in critical care. The melatonergic agonist Ramelteon demonstrated statistically significant reductions in delirium; however, the reliability of the results in answering the review question was limited by the research design. The use of bright light therapy (BLT) and dynamic light application had mixed results, with issues with the research design and outcomes measured limiting the validity of the findings.	Multi-component non-pharmacological interventions, such as noise and light control, can reduce delirium in critical care, whereas other interventions, such as BLT, have mixed outcomes. Melatonin, as a drug, may be a useful alternative to sedative-hypnotics.	Chronotherapy can reduce the incidence of delirium within critical care, although further research is warranted. Staff education is essential in the implementation of chronotherapy.	
28507521	Many sports competitions take place during television prime time, a time of the day when many athletes have already exceeded their time of peak performance. We assessed the effect of different light exposure modalities on physical performance and melatonin levels in athletes during prime time. Seventy-two young, male elite athletes with a median (interquartile range) age of 23 (21; 29) years and maximum oxygen uptake (VO2max) of 63 (58; 66) ml/kg/min were randomly assigned to three different light exposure groups: bright light (BRIGHT), blue monochromatic light (BLUE), and control light (CONTROL). Each light exposure lasted 60 min and was scheduled to start 17 h after each individual's midpoint of sleep (median time: 9:17 pm). Immediately after light exposure, a 12-min time trial was performed on a bicycle ergometer. The test supervisor and participants were blinded to the light condition each participant was exposed to. The median received light intensities and peak wavelengths (photopic lx/nm) measured at eye level were 1319/545 in BRIGHT, 203/469 in BLUE, and 115/545 in CONTROL. In a multivariate analysis adjusted for individual VO2max, total work performed in 12 min did not significantly differ between the three groups. The amount of exposure to non-image forming light was positively associated with the performance gain during the time trial, defined as the ratio of the work performed in the first and last minute of the time trial, and with stronger melatonin suppression. Specifically, a tenfold increase in the exposure to melanopic light was associated with a performance gain of 8.0% (95% confidence interval: 2.6, 13.3; P = 0.004) and a melatonin decrease of -0.9 pg/ml (95% confidence interval: -1.5, -0.3; P = 0.006). Exposure to bright or blue light did not significantly improve maximum cycling performance in a 12-min all-out time trial. However, it is noteworthy that the estimated difference of 4.1 kJ between BRIGHT and CONTROL might represent an important performance advantage justifying further studies. In conclusion, we report novel evidence that evening light exposure, which strongly impacts the human circadian timing system, enables elite athletes to better maintain performance across a 12-min cycling time trial.
28506881	This article focuses on stress vulnerability in schizophrenia through an integrated clinical and biological approach. The objective of this article is to better understand the relationships between vulnerability, stress and schizophrenia. First, the concept of vulnerability is defined and several models of vulnerability in schizophrenia are reviewed. Second, a section is developed on the biology of stress, and more specifically on the stress responses of the hypothalamo-pitutary adrenal (HPA) axis. Then, studies of cortisol circadian rhythms are summarized, suggesting hyper-reactivity of the HPA axis in patients with schizophrenia and high risk individuals for schizophrenia. The results support the models of stress vulnerability in schizophrenia and the hypothesis of high cortisol levels as an endophenotype in this disorder. In conclusion, this article highlights the interest of studying the cortisol circadian rhythms in schizophrenia and opens the perspective to identify high risk individuals for schizophrenia by measuring circadian patterns of salivary cortisol.
28506462	The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination.
28506121	Circadian rhythms permeate all levels of biology to temporally regulate cell and whole-body physiology, although the cell-autonomous mechanism that confers ∼24-h periodicity is incompletely understood. Reports describing circadian oscillations of over-oxidized peroxiredoxin abundance have suggested that redox signaling plays an important role in the timekeeping mechanism. Here, we tested the functional contribution that redox state and primary metabolism make to mammalian cellular timekeeping.We found a circadian rhythm in flux through primary glucose metabolic pathways, indicating rhythmic NAD(P)H production. Using pharmacological and genetic perturbations, however, we found that timekeeping was insensitive to changes in glycolytic flux, whereas oxidative pentose phosphate pathway (PPP) inhibition and other chronic redox stressors primarily affected circadian gene expression amplitude, not periodicity. Finally, acute changes in redox state decreased PER2 protein stability, phase dependently, to alter the subsequent phase of oscillation.	Circadian rhythms in primary cellular metabolism and redox state have been proposed to play a role in the cellular timekeeping mechanism. We present experimental data testing that hypothesis.	Circadian flux through primary metabolism is cell autonomous, driving rhythmic NAD(P)+ redox cofactor turnover and maintaining a redox balance that is permissive for circadian gene expression cycles. Redox homeostasis and PPP flux, but not glycolysis, are necessary to maintain clock amplitude, but neither redox nor glucose metabolism determines circadian period. Furthermore, cellular rhythms are sensitive to acute changes in redox balance, at least partly through regulation of PER protein. Redox and metabolic state are, thus, both inputs and outputs, but not state variables, of cellular circadian timekeeping. Antioxid. Redox Signal. 00, 000-000.	
28503165	Living organisms are highly complex systems that must maintain a dynamic equilibrium or homeostasis that requires energy to be sustained. Stress is a state in which several extrinsic or intrinsic disturbing stimuli, the stressors, threaten, or are perceived as threatening, homeostasis. To achieve homeostasis against the stressors, organisms have developed a highly sophisticated system, the stress system, which provides neuroendocrine adaptive responses, to restore homeostasis. These responses must be appropriate in terms of size and/or duration; otherwise, they may sustain life but be associated with detrimental effects on numerous physiologic functions of the organism, leading to a state of disease-causing disturbed homeostasis or cacostasis. In addition to facing a broad spectrum of external and/or internal stressors, organisms are subject to recurring environmental changes associated with the rotation of the planet around itself and its revolution around the sun. To adjust their homeostasis and to synchronize their activities to day/night cycles, organisms have developed an evolutionarily conserved biologic system, the "clock" system, which influences several physiologic functions in a circadian fashion. Accumulating evidence suggests that the stress system is intimately related to the circadian clock system, with dysfunction of the former resulting in dysregulation of the latter and vice versa. In this review, we describe the functional components of the two systems, we discuss their multilevel interactions, and we present how excessive or prolonged activity of the stress system affects the circadian rhythm of glucocorticoid secretion and target tissue effects.
28503116	Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock.First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed.	The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects.	This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.	
28503020	Circadian coordination of metabolism, physiology, and behaviour is found in all living kingdoms. Clock genes are transcriptional regulators, and their rhythmic activities generate daily rhythms in clock-controlled genes which result in cellular and organismal rhythms. Insects provide numerous examples of rhythms in behaviour and reproduction, but less is known about control of metabolic processes by circadian clocks in insects. Recent data suggest that several pathways involved in protecting cells from oxidative stress may be modulated by the circadian system, including genes involved in glutathione (GSH) biosynthesis. Specifically, rhythmic expression of the gene encoding the catalytic subunit (Gclc) of the rate-limiting GSH biosynthetic enzyme was detected in Drosophila melanogaster heads. The aim of this study was to determine which clocks in the fly multi-oscillatory circadian system are responsible for Gclc rhythms. Genetic disruption of tissue-specific clocks in D. melanogaster revealed that transcriptional rhythms in Gclc mRNA levels occur independently of the central pacemaker neurons, because these rhythms persisted in heads of behaviourally arrhythmic flies with a disabled central clock but intact peripheral clocks. Disrupting the clock specifically in glial cells abolished rhythmic expression of Gclc, suggesting that glia play an important role in Gclc transcriptional regulation, which may contribute to maintaining homeostasis in the fly nervous system.
28502923	G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.
28502584	Survivors of hypoxic-ischemic brain damage (HIBD), besides impairment of psychomotor development, often develop circadian rhythm disorders, although the underlying mechanisms are largely unknown. Here, we first verified that mRNA and protein expression of pineal aralkylamine N-acetyltransferase (Aanat), a key regulator for melatonin (MT) synthesis, along with MT, were severely impaired after HIBD. In addition, we demonstrated that neonatal HIBD disrupted the circadian rhythmicity of locomotor activities in juvenile rats. Based on bioinformatics analysis of a high throughput screening of miRNA expression changes after HIBD (Ding et al., 2015), we identified one microRNA, miR-325-3p, as a potential candidate responsible for the down regulation of Aanat after HIBD. Luciferase reporter assays demonstrated a specific interaction between miR-325-3p and Aanat mRNA 3'-UTR. miR-325-3p blocked norepinephrine (NE) induced Aanat activation in cultured pinealocytes. In addition, miR-325-3p inhibition partially rescued Aanat induction by NE, which was significantly reduced under oxygen glucose deprivation. By elucidating the role of pineal miR-325-3p on Aanat expression upon injury, our study provides new insights into the pathophysiological mechanisms of circadian dysfunction and potential therapeutic targets after HIBD.
28502554	Rodents, particularly rats and mice, are the most commonly used laboratory animals and are extensively used in neuroscience research, including as translational models for human disorders. It is common practice to carry out scientific procedures on rats and mice during the daytime, which is the inactive period for these nocturnal species. However, there is increasing evidence for circadian and light-induced effects on rodent physiology and behaviour which may affect the validity of results obtained from mice and rats in neuroscience studies. For example, testing animals during their inactive periods may produce abnormal results due to cognitive deficits, lack of motivation to perform the task or stress from being disturbed during the resting period. In addition, conducting procedures during an animal's resting period may also pose an animal welfare issue, as procedures may be experienced as more stressful than if these were done during the active phase. In this paper we set out the need to consider the impact of time of day and lighting conditions, when scientific procedures or routine husbandry are performed, on both the welfare of mice and rats used in neuroscience research and on data quality. Wherever possible, husbandry and experimental procedures should be conducted at times of day when the animals would be active, and under naturalistic lighting conditions, to minimise stress and maximise data quality and translatability.
28502410	Physiological tracers of circadian rhythms and a performance awareness index were examined as predictors of cognitive performance during two sleep deprivation conditions common to occupational shiftwork. Study 1: Thirty-three sleep-deprived participants completed a simulated nightshift. Study 2: Thirty-two partially sleep-deprived participants completed a simulated dayshift. A standardized logic test was used to measure cognitive performance. Body temperature and heart rate were measured as chronobiological indices of endogenous circadian rhythms. Performance awareness was calculated as a correlation between actual and perceived performance. These studies demonstrated a parallelism between performance awareness and the circadian rhythm. Chronobiological changes were predictive of performance awareness during the simulated nightshift but not dayshift. Only oral temperature was a significant independent predictor. Oral temperature predicted an individual's awareness of their own performance better than their own subjective awareness. These findings suggest that using circadian rhythms in applied ergonomics may reduce occupational risk due to low performance awareness.
28500983	Alteration of circadian rhythms and sleep disruption are prominent trait-like features of bipolar disorder (BD). Diffusion tensor imaging (DTI) measures suggest a widespread alteration of white matter (WM) microstructure in patients with BD. Sleep promotes myelination and oligodendrocyte precursor cells proliferation. We hypothesized a possible association between DTI measures of WM microstructure and sleep quantity measures in BD.We studied 69 inpatients affected by a depressive episode in course of type I BD. We used whole brain tract-based spatial statistics on DTI measures of WM microstructure: axial, radial, and mean diffusivity (AD, RD, MD), and fractional anisotropy (FA). Self-assessed measures of time asleep (TA) and total sleep time (TST) were extracted from the Pittsburgh Sleep Quality Index (PSQI). Actigraphic recordings were performed on a subsample of 23 patients.	We observed a positive correlation of DTI measures of FA with actigraphic measures of TA and TST, and with PSQI measure of TA. DTI measures of RD inversely associated with actigraphic measure of TA, and with PSQI measures of TA and TST. Several WM tracts were involved, including corpus callosum, cyngulate gyrus, uncinate fasciculus, left superior and inferior longitudinal and fronto-occipital fasciculi, thalamic radiation, corona radiata, retrolenticular part of internal capsule and corticospinal tract.	The study is correlational in nature, and no conclusion about a causal connection can be drawn.	Reduced FA with increased RD and MD indicate higher water diffusivity associated with less organized myelin and/or axonal structures. Our findings suggest an association between sleep disruption and these measures of brain microstructure in specific tracts contributing to the functional connectivity in BD.	
28500869	Daily, animals need to decide when to stop engaging in cognitive processes and behavioral responses to the environment, and go to sleep. The main processes regulating the daily organization of sleep and wakefulness are circadian rhythms and homeostatic sleep pressure. In addition, motivational processes such as food seeking and predator evasion can modulate sleep/wake behaviors. Here, we discuss the principal processes regulating the propensity to stay awake or go to sleep-focusing on neuronal and behavioral aspects. We first introduce the neuronal populations involved in sleep/wake regulation. Next, we describe the circadian and homeostatic drives for sleep. Then, we highlight studies demonstrating various effects of motivational processes on sleep/wake behaviors, and discuss possible neuronal mechanisms underlying their control.
28500697	Plant cryptochromes are photoreceptors that regulate flowering, circadian rhythm and photomorphogenesis in response to blue and UV-A light. It has been demonstrated that the oxidized flavin cofactor is photoreduced to the neutral radical state via separate electron and proton transfer. Conformational changes have been found in the C-terminal extension, but few studies have addressed the changes in secondary structure in the sensory photolyase homology region (PHR). Here, we investigated the PHR of the plant cryptochrome from the green alga Chlamydomonas reinhardtii by light-induced infrared difference spectroscopy in combination with global 13 C and 15 N isotope labeling. Assignment of the signals is achieved by establishing a labeling strategy for cryptochromes that preserves the flavin at natural abundance. We demonstrate by UV/vis spectroscopy that the integrity of the sample is maintained and by mass spectrometry that the global labeling was highly efficient. As a result, difference bands are resolved at full intensity that at natural abundance are compensated by the overlap of flavin and protein signals. These bands are assigned to prominent conformational changes in the PHR by blue light illumination. We postulate that not only the partial unfolding of the C-terminal extension but also changes in the PHR may mediate signaling events.
28500133	Rev-erbβ is a heme-responsive transcription factor that regulates genes involved in circadian rhythm maintenance and metabolism, effectively bridging these critical cellular processes. Heme binding to Rev-erbβ indirectly facilitates its interaction with the nuclear receptor co-repressor (NCoR1), resulting in repression of Rev-erbβ target genes. Fe3+-heme binds in a 6-coordinate complex with axial His and Cys ligands, the latter provided by a heme-regulatory motif (HRM). Rev-erbβ was thought to be a heme sensor based on a weak Kd value for the Rev-erbβ·heme complex of 2 μm determined with isothermal titration calorimetry. However, our group demonstrated with UV-visible difference titrations that the Kd value is in the low nanomolar range, and the Fe3+-heme off-rate is on the order of 10-6 s-1 making Rev-erbβ ineffective as a sensor of Fe3+-heme. In this study, we dissected the kinetics of heme binding to Rev-erbβ and provided a Kd for Fe3+-heme of ∼0.1 nm Loss of the HRM axial thiolate via redox processes, including oxidation to a disulfide with a neighboring cysteine or dissociation upon reduction of Fe3+- to Fe2+-heme, decreased binding affinity by >20-fold. Furthermore, as measured in a co-immunoprecipitation assay, substitution of the His or Cys heme ligands in Rev-erbβ was accompanied by a significant loss of NCoR1 binding. These results demonstrate the importance of the Rev-erbβ HRM in regulating interactions with heme and NCoR1 and advance our understanding of how signaling through HRMs affects the major cellular processes of circadian rhythm maintenance and metabolism.
28499976	Goal-oriented arm movements are characterized by a balance between speed and accuracy. The relation between speed and accuracy has been formalized by Fitts' law and predicts a linear increase in movement duration with task constraints. Up to now this relation has been investigated on a short-time scale only, that is during a single experimental session, although chronobiological studies report that the motor system is shaped by circadian rhythms. Here, we examine whether the speed-accuracy trade-off could vary during the day. Healthy adults carried out arm-pointing movements as accurately and fast as possible toward targets of different sizes at various hours of the day, and variations in Fitts' law parameters were scrutinized. To investigate whether the potential modulation of the speed-accuracy trade-off has peripheral and/or central origins, a motor imagery paradigm was used as well. Results indicated a daily (circadian-like) variation for the durations of both executed and mentally simulated movements, in strictly controlled accuracy conditions. While Fitts' law was held for the whole sessions of the day, the slope of the relation between movement duration and task difficulty expressed a clear modulation, with the lowest values in the afternoon. This variation of the speed-accuracy trade-off in executed and mental movements suggests that, beyond execution parameters, motor planning mechanisms are modulated during the day. Daily update of forward models is discussed as a potential mechanism.
28499924	Hypercholesterolemia is a well-known risk factor for a wide range of diseases in developed countries. Here, we report that mice lacking functional LDLR (low density lipoprotein receptor), an animal model of human familial hypercholesterolemia, show circadian abnormalities. In free running behavioral experiments in constant darkness, these mice showed a prolonged active phase and distinctly bimodal rhythms. Even when the circadian rhythms were entrained by light and dark cycles, these mice showed a significant attenuation of behavioral onset intensity at the start of the dark period. Further, we hypothesized that the combination of hypercholesterolemia and circadian abnormalities may affect cardiovascular disease progression. To examine this possibility, we generated LDLR-deficient mice with impaired circadian rhythms by simultaneously introducing a mutation into Period2, a core clock gene, and found that these mice showed a significant enlargement of artery plaque area with an increase in inflammatory cytokine IL-6 levels. These results suggest that circadian dysfunction may be associated with the development or progression of cardiovascular diseases.
28498447	Differentiated embryonic chondrocyte expressed gene 1 (DEC1) and differentiated embryonic chondrocyte expressed gene 2 (DEC2) belong to the Hairy/Enhancer of Split subfamily of basic helix‑loop‑helix factors. Previous studies have demonstrated that DEC proteins are involved in the regulation of circadian rhythms, response to hypoxia, and tumorigenesis. However, the roles of DEC1 and DEC2 in apoptosis of esophageal carcinoma remain unclear. In the present study, alterations in expression of apoptosis‑related markers in human esophageal squamous cell carcinoma TE‑11 cells treated with cisplatin were examined by western blot, while overall cell viability and apoptosis were analyzed by MTS assay and hematoxylin and eosin staining, respectively. Following cisplatin treatment, expression of DEC2 was downregulated, whereas expression of DEC1 was upregulated. DEC2 overexpression during cisplatin treatment markedly inhibited expression of the pro‑apoptotic factor Bim and slightly increased the anti‑apoptotic factor Bcl‑xL. However, overexpression of DEC1 during cisplatin treatment failed to affect expression of these markers. Additionally, overexpression of DEC2 improved cell viability and decreased cell apoptosis induced by cisplatin. These results suggested that DEC2 exhibits anti‑apoptotic effects in TE‑11 esophageal squamous cell carcinoma cells. Inhibiting DEC2 may therefore have therapeutic potential for the treatment of esophageal cancer, in combination with cisplatin.
28498398	The clinical symptoms of rheumatoid arthritis (RA) present with circadian variation, with joint stiffness and pain more prominent in the early morning. The mammalian clock genes, which include circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1, period and cryptochrome, regulate circadian rhythms. In order to identify the association between genetic polymorphisms in the circadian clock gene period 2 (PER2) and RA, the present study genotyped three PER2 single nucleotide polymorphisms (SNPs), rs934945, rs6754875, and rs2304674, using genetic information from 256 RA patients and 499 control subjects. Primary cultured rheumatoid synovial cells were stimulated with 10 µM lipopolysaccharide (LPS). Total protein was then extracted from the synovial cells following 12 and 24 h, and PER2 protein expression was assayed by immunoblotting. The rs2304674 SNP demonstrated a significant association with susceptibility to RA following Bonferroni correction. However, statistical analysis indicated that the SNPs were not associated with any clinical features of patients with RA. Immunoblotting analysis demonstrated that PER2 protein expression was decreased by LPS‑induced inflammation in RA synovial cells; however, this was not observed in normal synovial cells. The results suggest that the PER2 gene may be a risk factor for RA, and expression of the PER2 protein may be affected by inflammation. Therefore, PER2 may contribute to the pathogenesis of RA.
28498393	Recent studies have shown that disruption of the circadian rhythm was one of the endogenous factors contributing to tumorigenesis of various human malignancies, including colorectal cancer (CRC). However, the roles of circadian genes in the development of CRC are still unexplored. In this study, we investigated the expression pattern and the underlying mechanism of human Clock gene (hClock) in CRC progression. Multiple methods such as qRT-PCR, immunohistochemistry, and western blotting were performed to evaluate the expression pattern of the gene hClock, as well as to observe the changes of angiogenesis-related proteins and EMT-related proteins. Transwell cell migration assays and an animal tumor metastasis model were used to examine the impact of hClock on the metastatic ability of CRC cells in vitro and in vivo. Our results showed that the expression level of hClock significantly increased in human CRC tissues, which strongly associated with late TNM stage and positive lymph node metastasis. Moreover, a higher level of hClock expression was found in CRC cell lines with a higher metastatic potential. Furthermore, ectopic expression of hClock promoted the migration of SW480 CRC cells, while knockdown of hClock inhibited the tumor metastasis of SW620 CRC cells, and targeting hClock by shRNA effectively suppressed the metastatic ability of SW620 CRC cells in nude mice. Finally, we found that overexpression of hClock enhanced the expression of angiogenesis-related genes such as HIF-1α, ARNT and VEGF, and promoted epithelial-mesenchymal (-like) transition (EMT) in CRC cells, both of which are considered to be critical for tumor progression. These findings suggest that upregulation of the circadian gene hClock plays an important role in metastasis of colorectal cancer.
28497301	Cardiomyocytes possess a non-neuronal cardiac cholinergic system (NNCCS) regulated by a positive feedback system; however, its other regulatory mechanisms remain to be elucidated, which include the epigenetic control or regulation by the female sex steroid, estrogen. Here, the NNCCS was shown to possess a circadian rhythm; its activity was upregulated in the light-off phase via histone acetyltransferase (HAT) activity and downregulated in the light-on phase. Disrupting the circadian rhythm altered the physiological choline acetyltransferase (ChAT) expression pattern. The NNCCS circadian rhythm may be regulated by miR-345, independently of HAT, causing decreased cardiac ChAT expression. Murine cardiac ChAT expression and ACh contents were increased more in female hearts than in male hearts. This upregulation was downregulated by treatment with the estrogen receptor antagonist tamoxifen, and in contrast, estrogen reciprocally regulated cardiac miR-345 expression. These results suggest that the NNCCS is regulated by the circadian rhythm and is affected by sexual dimorphism.
28496287	The mammalian circadian clock is a complex multi-scale, multivariable biological control system. In the past two decades, methods from systems engineering have led to numerous insights into the architecture and functionality of this system. In this review, we examine the mammalian circadian system through a process systems lens. We present a mathematical framework for examining the cellular circadian oscillator, and show recent extensions for understanding population-scale dynamics. We provide an overview of the routes by which the circadian system can be systemically manipulated, and present in silico proof of concept results for phase resetting of the clock via model predictive control.
28495872	Although light is most commonly thought of as a visual cue, many animals possess mechanisms to detect light outside of the eye for various functions, including predator avoidance, circadian rhythms, phototaxis and migration. Here we confirm that planarians (like Caenorhabditis elegans, leeches and Drosophila larvae) are capable of detecting and responding to light using extraocular photoreception. We found that, when either eyeless or decapitated worms were exposed to near-ultraviolet (near-UV) light, intense wild-type photophobic behaviors were still observed. Our data also revealed that behavioral responses to green wavelengths were mediated by ocular mechanisms, whereas near-UV responses were driven by extraocular mechanisms. As part of a candidate screen to uncover the genetic basis of extraocular photoreception in the planarian species Schmidtea mediterranea, we identified a potential role for a homolog of the transient receptor potential channel A1 (TRPA1) in mediating behavioral responses to extraocular light cues. RNA interference (RNAi) to Smed-TrpA resulted in worms that lacked extraocular photophobic responses to near-UV light, a mechanism previously only identified in Drosophila These data show that the planarian TRPA1 homolog is required for planarian extraocular-light avoidance and may represent a potential ancestral function of this gene. TRPA1 is an evolutionarily conserved detector of temperature and chemical irritants, including reactive oxygen species that are byproducts of UV-light exposure. Our results suggest that planarians possess extraocular photoreception and display an unconventional TRPA1-mediated photophobic response to near-UV light.
28495465	Night-shift works are basically accompanied by reduced cognitive performance, sleepiness, and higher possibility for human error and related incidents. It is therefore crucial to improve individuals' performance and alertness in sensitive places like industries' control room with the ultimate goal of increasing efficiency and reducing the number of possible incidents. Previous research has indicated that blue light is a critical cue for entraining circadian rhythm. As a result, the present study was an attempt to investigate whether blue-enriched white light illumination was a practical strategy to decrease sleepiness and improve cognitive performance during night shifts.The study, which adopted a before-after interventional design, was conducted among 30 control room staff members of petrochemical industry. After baseline assessments under existing lighting conditions, every participant was exposed to two new lighting conditions (namely, 17,000K and 6500K blue-enriched white light), each lasting for a week. Assessments were conducted again at the end of these treatments. In order to measure the subjective sleepiness, Karolinska Sleepiness Scale (KSS) was utilized. Subjects also performed the Conners' Continuous Performance Test II (CPT-II) and 1-back test in order to gauge their cognitive performance, and melatonin assessment was carried out using salivary and Eliza technique. The data was analyzed using two-way repeated measure ANOVA.	The results indicated that, compared to normal lighting conditions, participants' sleepiness and melatonin rhythm significantly declined when they were exposed to blue-enriched white light. Furthermore, the experimental condition had a significant effect on the reduction of working memory errors. It also decreased omission errors and the reaction time during the sustained attention task.	Thus, using blue-enriched white light may be a proper ergonomic strategy for improving performance and alertness, especially during night, in sensitive environments like control rooms.	
28495218	Individuals with pharmacoresistant epilepsy remain a large and under-treated patient population. Continued technologic advancements in implantable neurostimulators have spurred considerable research efforts directed towards the development of novel antiepileptic stimulation therapies. However, the lack of adequate preclinical experimental platforms has precluded a detailed understanding of the differential effects of stimulation parameters on neuronal activity within seizure networks. In order to chronically monitor seizures and the effects of stimulation in a freely-behaving non-human primate with idiopathic epilepsy, we employed a novel simultaneous video-intracranial EEG recording platform using a state-of-the-art sensing-enabled, rechargeable clinical neurostimulator with real-time seizure detection and wireless data streaming capabilities. Using this platform, we were able to characterize the electrographic and semiologic features of the focal-onset, secondarily generalizing tonic-clonic seizures stably expressed in this animal. A series of acute experiments exploring low-frequency (2Hz) hippocampal stimulation identified a pulse width (150μs) and current amplitude (4mA) combination which maximally suppressed local hippocampal activity. These optimized stimulation parameters were then delivered to the seizure onset-side hippocampus in a series of chronic experiments. This long-term testing revealed that the suppressive effects of low-frequency hippocampal stimulation 1) diminish when delivered continuously but are maintained when stimulation is cycled on and off, 2) are dependent on circadian rhythms, and 3) do not necessarily confer seizure protective effects.
28494142	Patients with diabetes frequently develop orthostatic hypotension (OH). The present study was designed to examine the relationship of blood pressure (BP) circadian rhythms and outcomes in diabetes with OH.In the present study, 173 inpatients with type 2 diabetes were enrolled. Patients were divided into an OH group and a non-OH group according to the BP changes detected in the supine and standing position. Then, 24-h ambulatory BP was monitored. Patients were followed up for an average of 45 ± 10 months post-discharge. Outcomes - death and major adverse cardiac and cerebrovascular events, including heart failure, myocardial infarction and stroke - were recorded.	There were 61 patients (35.26%) in the OH group and 112 patients (64.74%) in the non-OH group. In the OH group, the night-time systolic BP and night-time diastolic BP were higher, the blood BP rhythms were predominantly of the riser type (67.21%). OH was as an independent marker of riser type circadian rhythm (adjusted odds ratio 4.532, 95% confidence interval 2.579-7.966). In the OH group, the incidence rates of mortality, and major adverse cardiac and cerebrovascular events were increased significantly compared with those in the non-OH group (11.48 vs 2.68%, P = 0.014; 37.70 vs 8.93%, P < 0.01).	In patients who had type 2 diabetes diagnosed with OH, the BP circadian rhythm usually showed riser patterns, and they had increased rates of mortality, and major adverse cardiac and cerebrovascular events.	
28493061	Many variables related to sport have been shown to have circadian rhythms. Chronotype is the expression of circadian rhythmicity in an individual, and three categories of chronotype are defined: morning types (M-types), evening types (E-types), and neither types (N-types). M-types show earlier peaks of several psychophysiological variables during the day than E-types. The effect of chronotype on athletic performance has not been extensively investigated.The objective of the present review was to study the effect of chronotype on athletic performance and the psychophysiological responses to physical activity.	The present review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. We searched PubMed, Scopus, and Web of Science for scientific papers using the keywords "chronotype", "circadian typology", "morningness", and "eveningness" in combination with each of the words "sport", "performance", and "athletic." Relevant reference lists were inspected. We limited the search results to peer-reviewed papers published in English from 1985 to 2015.	Ten papers met our inclusion criteria. Rating of perceived exertion and fatigue scores in relation to athletic performances are influenced by chronotype: M-types perceived less effort when performing a submaximal physical task in the morning than did N- and E-types. In addition, M-types generally showed better athletic performances, as measured by race times, in the morning than did N- and E-types. Other results concerning chronotype effect on physiological responses to physical activity were not always consistent: heterogeneous samples and different kinds of physical activity could partially explain these discrepancies.	Sports trainers and coaches should take into account the influence of both the time of day and chronotype effect when scheduling training sessions into specific time periods.	
28489826	Animals partition their daily activity rhythms through their internal circadian clocks, which are synchronized by oscillating day-night cycles of light. The fruitfly Drosophila melanogaster senses day-night cycles in part through rhodopsin-dependent light reception in the compound eye and photoreceptor cells in the Hofbauer-Buchner eyelet. A more noteworthy light entrainment pathway is mediated by central pacemaker neurons in the brain. The Drosophila circadian clock is extremely sensitive to light. However, the only known light sensor in pacemaker neurons, the flavoprotein cryptochrome (Cry), responds only to high levels of light in vitro. These observations indicate that there is an additional light-sensing pathway in fly pacemaker neurons. Here we describe a previously uncharacterized rhodopsin, Rh7, which contributes to circadian light entrainment by circadian pacemaker neurons in the brain. The pacemaker neurons respond to violet light, and this response depends on Rh7. Loss of either cry or rh7 caused minor defects in photoentrainment, whereas loss of both caused profound impairment. The circadian photoresponse to constant light was impaired in rh7 mutant flies, especially under dim light. The demonstration that Rh7 functions in circadian pacemaker neurons represents, to our knowledge, the first role for an opsin in the central brain.
28488943	Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness-Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.
28488901	Shift workers suffer from a constellation of symptoms associated with disruption of circadian rhythms including sleep abnormalities, and abnormal hormone secretion (e.g. melatonin, cortisol). Recent, but limited, evidence suggests that shift workers have elevated levels of circulating white blood cells (WBCs) compared to their day working counterparts. Interestingly, recent reviews highlight the strong linkage between the immune system and circadian rhythms which includes, but is not limited to, circulating cell populations and functions. The elevated levels of these WBCs may be associated with the increased chronic disease risk observed among this group. The purpose of this analysis was to examine the cross-sectional association between long- and short-term (3, 5, 7, and 14 days) shiftwork (SW) and counts of WBCs among officers in the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) cohort. Data collection for this analysis took place among 464 police officers working in Buffalo, New York, USA between 2004 and 2009. Precise SW histories were obtained using electronic payroll records. Officers were assigned a shift type based on the shift (i.e. day, evening, night) that they spent a majority (i.e. ≥50%) of their time from 1994 to the data collection date for long-term SW. The same process was applied to SW over 3, 5, 7, and 14 days prior to data collection. A fasted blood sample collected in the morning of a non-work day was used for characterization of WBCs (total), neutrophils, monocytes, lymphocytes, eosinophils, and basophils. Potential confounding factors included demographic characteristics (e.g. age, sex, race), occupational characteristics (e.g. rank), health behaviors (e.g. smoking, alcohol consumption, diet), anthropometrics, and other biomarkers (e.g. lipids, hemoglobin A1C, leptin). Generalized linear models were used to estimate least square means of the immune cells according to SW categorization for long- and short-term SW histories. Compared to the day shift group, those working long-term night shifts had greater absolute numbers of total WBCs, neutrophils, lymphocytes, and monocytes (all p < 0.05). Those working mainly on the night shift over 7-days had elevated counts of WBCs, lymphocytes, and monocytes (p < 0.05) compared to those mainly working day shifts. Results based on 3-, 5-, and 14-day SW were similar to the 7-day results. This study corroborates other studies with similar findings. However, this analysis provided insights into the effect of both long- and short-term SW on the number of circulating WBCs. SW may lead to disruption of circadian-influenced components of the immune system, which in term, may result in various chronic diseases. These findings, plus previous findings, may provide evidence that SW may lead to immune system dysregulation. Future research is needed to understand whether increases in immune cells among shift workers may be associated with the increased disease risk among this group.
28487255	Although sleep is a key element in adolescent development, teens are spending increasing amounts of time online with health risks related to excessive use of electronic media (computers, smartphones, tablets, consoles…) negatively associated with daytime functioning and sleep outcomes. Adolescent sleep becomes irregular, shortened and delayed in relation with later sleep onset and early waking time due to early school starting times on weekdays which results in rhythm desynchronization and sleep loss. In addition, exposure of adolescents to the numerous electronic devices prior to bedtime has become a great concern because LEDs emit much more blue light than white incandescent bulbs and compact fluorescent bulbs and have therefore a greater impact on the biological clock. A large number of adolescents move to evening chronotype and experience a misalignment between biological and social rhythms which, added to sleep loss, results in e.g. fatigue, daytime sleepiness, behavioral problems and poor academic achievement. This paper on adolescent circadian disruption will review the sensitivity of adolescents to light including LEDs with the effects on the circadian system, the crosstalk between the clock and the pineal gland, the role of melatonin, and the behavior of some adolescents(media use, alcohol consumption, binge drinking, smoking habits, stimulant use…). Lastly, some practical recommendations and perspectives are put forward. The permanent social jet lag resulting in clock misalignment experienced by a number of adolescents should be considered as a matter of public health.
28486525	Molecular mechanisms responsible for 24 h circadian oscillations, entrainment to external cues, encoding of day length and the time-of-day effects have been well studied experimentally. However, it is still debated from the molecular network point of view whether each cell in suprachiasmatic nuclei harbors two molecular oscillators, where one tracks dawn and the other tracks dusk activities. A single cell dual morning and evening oscillator was proposed by Daan et al., based on the molecular network that has two sets of similar non-redundant per1/cry1 and per2/cry2 circadian genes and each can independently maintain their endogenous oscillations. Understanding of dual oscillator dynamics in a single cell at molecular level may provide insight about the circadian mechanisms that encodes day length variations and its response to external zeitgebers. We present here a realistic dual oscillator model of circadian rhythms based on the series of hypotheses proposed by Daan et al., in which they conjectured that the circadian genes per1/cry1 track dawn while per2/cry2 tracks dusk and they together constitute the morning and evening oscillators (dual oscillator). Their hypothesis also provides explanations about the encoding of day length in terms of molecular mechanisms of per/cry expression. We frame a minimal mathematical model with the assumption that per1 acts a morning oscillator and per2 acts as an evening oscillator and to support and interpret this assumption we fit the model to the experimental data of per1/per2 circadian temporal dynamics, phase response curves (PRC's), and entrainment phenomena under various light-dark conditions. We also capture different patterns of splitting phenomena by coupling two single cell dual oscillators with neuropeptides vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP) as the coupling agents and provide interpretation for the occurrence of splitting in terms of ME oscillators, though they are not required to explain the morning and evening oscillators. The proposed dual oscillator model based on Daan's hypothesis supports per1 and per2 playing the role of morning and evening oscillators respectively and this may be the first step towards the understanding of the core molecular mechanism responsible for encoding the day length.
28486137	The transition from vegetative to reproductive growth, a key event in the lifecycle of a plant, is affected by environmental stresses. The flowering-time regulator GIGANTEA (GI) may be contributing to susceptibility of the regulation of photoperiodic flowering, circadian rhythm control, and abiotic stress resistance in Arabidopsis. However, the role of GI in sweet potato remains unknown. Here, we isolated and characterized a GI gene (IbGI) from sweet potato (Ipomoea batatas [L.] Lam). The IbGI cDNA sequence was isolated based on information from a sweet potato transcriptome database. IbGI mRNA transcript levels showed robust circadian rhythm control during the light-dark transition, and the expression of IbGI was stronger in leaves and roots than in stems. IbGI protein is predominantly localized to the nucleus. IbGI expression was upregulated by high temperature, drought, and salt stress but downregulated by cold stress. Overexpressing IbGI in the Arabidopsis gi-2 mutant background rescued its late flowering phenotype and reduced its salt tolerance. Taken together, these results indicate that IbGI shares functions in regulating flowering, the circadian rhythm, and tolerance to some stresses with other GI orthologs.
28486120	Neurons in the suprachiasmatic nuclei (SCN) of the hypothalamus are described as master pacemaker cells for biological rhythms. However, a series of recent studies demonstrate the importance of another cell type, astrocytes, for biological timekeeping.
28484984	Salivary secretion displays day-night variations that are controlled by the circadian clock. The central clock in the suprachiasmatic nucleus (SCN) regulates daily physiological rhythms by prompting peripheral oscillators to adjust to changing environments. Aquaporin 5 (Aqp5) is known to play a key role in salivary secretion, but the association between Aqp5 and the circadian rhythm is poorly understood. The aim of our study was to evaluate whether Aqp5 expression in submandibular glands (SMGs) is driven by the central clock in the SCN or by autonomous oscillations. We observed circadian oscillations in the activity of period circadian protein homolog 2 and luciferase fusion protein (PER2::LUC) in cultured SMGs with periodicity depending on core clock genes. A daily rhythm was detected in the expression profiles of Aqp5 in SMGs in vivo. In cultured SMGs ex vivo, clock genes showed distinct circadian rhythms, whereas Aqp5 expression did not. These data indicate that daily Aqp5 expression in the mouse SMG is driven by the central clock in the SCN.
28484672	Opacities of the lens are typical age-related phenomena which have a high influence on photoreception and consequently circadian rhythm. In mouse lemurs, a small bodied non-human primate, a high incidence (more than 50% when >seven years) of cataracts has been previously described during aging. Previous studies showed that photoperiodically induced accelerated annual rhythms alter some of mouse lemurs' life history traits. Whether a modification of photoperiod also affects the onset of age dependent lens opacities has not been investigated so far. The aim of this study was therefore to characterise the type of opacity and the mouse lemurs' age at its onset in two colonies with different photoperiodic regimen.Two of the largest mouse lemur colonies in Europe were investigated: Colony 1 having a natural annual photoperiodic regime and Colony 2 with an induced accelerated annual cycle. A slit-lamp was used to determine opacities in the lens. Furthermore, a subset of all animals which showed no opacities in the lens nucleus in the first examination but developed first changes in the following examination were further examined to estimate the age at onset of opacities. In total, 387 animals were examined and 57 represented the subset for age at onset estimation.	The first and most commonly observable opacity in the lens was nuclear sclerosis. Mouse lemurs from Colony 1 showed a delayed onset of nuclear sclerosis compared to mouse lemurs from Colony 2 (4.35 ± 1.50 years vs. 2.75 ± 0.99 years). For colony 1, the chronological age was equivalent to the number of seasonal cycles experienced by the mouse lemurs. For colony 2, in which seasonal cycles were accelerated by a factor of 1.5, mouse lemurs had experienced 4.13 ± 1.50 seasonal cycles in 2.75 ± 0.99 chronological years.	Our study showed clear differences in age at the onset of nuclear sclerosis formation between lemurs kept under different photoperiodic regimes. Instead of measuring the chronological age, the number of seasonal cycles (N = four) experienced by a mouse lemur can be used to estimate the risk of beginning nuclear sclerosis formation. Ophthalmological examinations should be taken into account when animals older than 5-6 seasonal cycles are used for experiments in which unrestricted visual ability has to be ensured. This study is the first to assess and demonstrate the influence of annual photoperiod regime on the incidence of lens opacities in a non-human primate.	
28483056	A wide variety of physiological processes including flowering are controlled by the circadian clock in plants. In Arabidopsis, LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) constitute the central oscillator, and their gain of function and loss of function disrupt the circadian clock and affect flowering time through FLOWERING LOCUS T (FT), a gene encoding a florigen. Chrysanthemum is a typical short-day (SD) plant and responds to shortening of day length by the transition from the vegetative to reproductive phase. We identified FLOWERING LOCUS T-LIKE 3 (FTL3) and ANTI-FLORIGENIC FT/TFL1 FAMILY PROTEIN (AFT) as a florigen and antiflorigen, respectively, in a wild diploid chrysanthemum (Chrysanthemum seticuspe f. boreale). CsFTL3 and CsAFT are induced under SD or a noninductive photoperiod, respectively, and their balance determines the floral transition and anthesis. Meanwhile, the time-keeping mechanism that regulates the photoperiodic flowering in chrysanthemum is poorly understood. Here, we focused on a LHY/CCA1-like gene called CsLHY in chrysanthemum. We fused CsLHY to a gene encoding short transcriptional repressor domain (SRDX) and constitutively expressed it in chrysanthemum. Although the transcription of clock-related genes was conditionally affected, circadian rhythm was not completely disrupted in CsLHY-SRDX transgenic plants. These plants formed almost the same number of leaves before floral transition under SD and long-day conditions. Thus, CsLHY-SRDX chrysanthemum showed photoperiod-insensitive floral transition, but further development of the capitulum was arrested, and anthesis was not observed. Simultaneously with the flowering phenotype, CsFTL3 and CsAFT were downregulated in CsLHY-SRDX transgenic plants. These results suggest that CsLHY-SRDX affects CsFTL3 and CsAFT expression and causes photoperiod-insensitive floral transition without a severe defect in the circadian clock.
28482221	Nowadays, the application of chemiluminescence imaging is no longer limited to the monitoring of slow biological phenomena such as circadian rhythms and in vivo tracking of cells. The expanded color palette of bright chemiluminescent protein and near-infrared-emitting luciferins have greatly improved the sensitivity of in vivo tracking of cells as well as enabling real-time cellular chemiluminescence imaging with high spatial resolution. Furthermore, functional chemiluminescent indicators based on the novel concept have been developed, providing more information related to physiological and pathological processes in living organisms. In this short review, we summarized the recent protein- and substrate-based approaches for tuning the emission wavelength, as well as for development of the functional indicators.
28480817	The mammalian circadian pacemaker is commonly thought to be a rigid oscillator that generates output under a variety of circumstances that differ only in phase, period, and/or amplitude. Yet the pacemaker is composed of many cells that each can respond to varying circumstances in different ways. Computer simulations demonstrate that networks of such pacemaker cells behave differently under a light-dark cycle compared with constant darkness. The differences demonstrate that the circadian pacemaker is plastic: The pacemaker shapes its properties in response to the circumstances. A consequence is that properties of a pacemaker under a light-dark cycle cannot be derived from studies of the same system in constant darkness. In this paper we show that the dispersion of phase in a network of coupled oscillators can influence ensemble period: For the considered type of coupling, it is demonstrated that the more synchronous the cells are, the longer is the ensemble period. This is consistent with various data sets obtained in mammals, and even with a data set from fruit flies, in which circadian variation in behavior is regulated in a distinctly differently way from that in mammals. We conclude that environmental circumstances such as photoperiod and exposure to light pulses in otherwise darkness modify the phase distribution of the network and, thereby, the period of the ensemble. Our study supports the view that such properties as circadian period are not solely determined by clock genes but are also determined by the genes that regulate the communication in cellular networks.
28479363	There has been a growing interest in circadian regulation of the expression and function of drug transporters. In this study, we investigated circadian rhythm in the expression and function of multidrug resistance-associated protein 2 (Mrp2) in mouse liver and involvement of circadian clock in their regulations by using the circadian clock genes (period 1 and period 2) knockout mice. The mRNA and protein expression of Mrp2, P-glycoprotein, and breast cancer resistance protein was measured in the mouse liver at different times of the day. Circadian variation of hepatobiliary excretion of phenolsulfonphthalein, a model substrate of Mrp2, was also investigated in mice. Circadian oscillation of Mrp2 protein expression was clearly observed in the mouse liver with levels down at the light phase and up at the dark phase. The cumulative biliary excretion and biliary clearance of phenolsulfonphthalein from the liver to the bile was 2.37- and 1.74-fold greater in mice administered during the dark phase than in those administered during the light phase, respectively. The circadian oscillation in mRNA expression of Mrp2 disappeared in period 1 and period 2 double knockout mice. These results suggest that the expression and function of Mrp2 show the circadian rhythm, controlled by circadian clock genes.
28478550	Melatonin, through its different receptors, has pleiotropic functions in mammalian brain. Melatonin is secreted mainly by the pineal gland and exerts its effects via receptor-mediated and non-receptor-mediated actions. With recent advancement in neuroanatomical mapping, we may now understand better the localizations of the two G protein-coupled melatonin receptors MT1 and MT2. The abundance of these melatonin receptors in respective brain regions suggests that receptor-mediated actions of melatonin might play crucial roles in the functions of central nervous system. Hence, this review aims to summarize the distribution of melatonin receptors in the brain and to discuss the putative functions of melatonin in the retina, cerebral cortex, reticular thalamic nucleus, habenula, hypothalamus, pituitary gland, periaqueductal gray, dorsal raphe nucleus, midbrain and cerebellum. Studies on melatonin receptors in the brain are important because cumulative evidence has pointed out that melatonin receptors not only play important physiological roles in sleep, anxiety, pain and circadian rhythm, but might also be involved in the pathogenesis of a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Huntington's disease.
28477771	Different stages of sleep are associated with significant variability in cardiovascular function, which is mediated by marked changes in balance between 2 components of the autonomic system: parasympathetic and sympathetic. Autonomic control of circulation is essential in ensuring an adequate blood flow to vital organs through constant adjustments of arterial blood pressure, heart rate, and redistribution of blood flow. Fluctuations in components of the autonomic nervous system synchronize with electroencephalographic activity during arousal or different stages of sleep. As a result, these can lead to several cardiovascular consequences in those who have underlying heart disease or sleep-disordered breathing.
28477731	Growth hormone (GH) replacement in GH deficient (GHD) children secures normal linear growth, while in GHD adults it improves metabolic status, body composition and quality of life. Safety of GH treatment is an important issue in particular concerning the controversy of potential cancer risk. Unlike in congenital IGF-1 deficiency, there is no complete protection against cancer in GHD patients. Important modifiable risk factors in GHD patients are obesity, insulin resistance, sedentary behavior, circadian rhythm disruption, chronic low grade inflammation and concomitant sex hormone replacement. Age, family history, hereditary cancer predisposition syndromes or cranial irradiation may present non-modifiable risk factors. Quantifying the risk of cancer in relation to GH therapy in adult GHD patients is complex. There is evidence that links GH to cancer occurrence or promotion, but the evidence is progressively weaker when moving from in vitro studies to in vivo animal studies to epidemiological studies and finally to studies on GH treated patients. GH-IGF inhibition in experimental animals leads to decreased cancer incidence and progression. Epidemiological studies suggest an association of high normal circulating IGF-1 or GH to cancer incidence in general population. Data regarding cancer incidence in acromegaly are inconsistent but thyroid and colorectal neoplasias are the main source of concern. Replacement therapy with rhGH for GHD is generally safe. Overall the rate of de novo cancers was not increased in studies of GH-treated GHD patients. Additional caution is mandated in patients with history of cancer, strong family history of cancer and with advancing age. Childhood cancer survivors may be at increased risk for secondary neoplasms compared with general population. In this subgroup GH therapy should be used cautiously and with respect to other risk factors (cranial irradiation etc). We believe that the benefits of GH therapy against the morbidity of untreated GH deficiency outweigh the theoretical cancer risk. Proper monitoring of GH treatment with diligent cancer surveillance remains essential.
28477530	Evidence is accumulating that aldosterone may exert central actions and influence mental functions. The aim of the present study was to test the hypothesis that major depressive disorder affects the diurnal variation of salivary aldosterone and that aldosterone concentrations reflect the duration and severity of the depressive episode in a sex dependent manner. The sample consisted of 60 patients (37 postmenopausal women, 23 men) with major depressive disorder. Patients were examined two times, in acute depressive episode (admission to the hospital) and after reaching clinical remission (discharge). The samples of saliva were taken by the patients themselves twice a day (8.00-9.00 h in the morning and in the evening). Aldosterone concentrations were significantly higher in women compared to men and were significantly higher at the time of admission to the hospital compared to those at the discharge. Morning but not evening salivary aldosterone concentrations reflected the length of the depressive episode in women as well as the severity of the disorder in both sexes. Moreover, the patients with depression failed to exert known daily rhythmicity of aldosterone release. The present study brings several pieces of evidence suggesting the association of aldosterone with the pathophysiology of depression. Salivary aldosterone concentrations appear to reflect the outcome, the duration and the severity of the depressive episode in a sex dependent manner.
28476590	Operant training systems make use of water or food restriction and make it necessary to weigh animals to ensure compliance with experimental endpoints. In other applications periodic weighing is necessary to assess drug side-effects, or as an endpoint in feeding experiments. Periodic weighing while essential can disrupt animal circadian rhythms and social structure.Automatic weighing system within paired mouse homecages. Up to 10 mice freely move between two cages (28×18×9cm) which were connected by a weighing chamber mounted on a load cell. Each mouse was identified using an RFID tag placed under the skin of the neck. A single-board computer (Raspberry Pi; RPi) controls the task, logging RFID tag, load cell weights, and time stamps from each RFID detection until the animal leaves the chamber. Collected data were statistically analyzed to estimate mouse weights. We anticipate integration with tasks where automated imaging or behaviour is assessed in homecages.	Mice frequently move between the two cages, an average of 42+-16 times/day/mouse at which time we obtained weights. We report accurate determination of mouse weight and long term monitoring over 53days. Comparison with existing methods Although commercial systems are available for automatically weighing rodents, they only work with single animals, or are not open source nor cost effective for specific custom application.	This automated system permits automated weighing of mice ∼40 times per day. The system employs inexpensive hardware and open-source Python code.	
28475894	The liver plays a pivotal role in metabolism and xenobiotic detoxification, processes that must be particularly efficient when animals are active and feed. A major question is how the liver adapts to these diurnal changes in physiology. Here, we show that, in mice, liver mass, hepatocyte size, and protein levels follow a daily rhythm, whose amplitude depends on both feeding-fasting and light-dark cycles. Correlative evidence suggests that the daily oscillation in global protein accumulation depends on a similar fluctuation in ribosome number. Whereas rRNA genes are transcribed at similar rates throughout the day, some newly synthesized rRNAs are polyadenylated and degraded in the nucleus in a robustly diurnal fashion with a phase opposite to that of ribosomal protein synthesis. Based on studies with cultured fibroblasts, we propose that rRNAs not packaged into complete ribosomal subunits are polyadenylated by the poly(A) polymerase PAPD5 and degraded by the nuclear exosome.
28475596	Obesity is a major public health problem that is highly associated with insulin resistance and type 2 diabetes, two conditions associated with circadian disruption. To date, dieting is one of the only interventions that result in substantial weight loss, but restricting caloric intake is difficult to maintain long-term. The use of artificial sweeteners, particularly in individuals that consume sugar sweetened beverages (energy drinks, soda), can reduce caloric intake and possibly facilitate weight loss. The purpose of the present study was to examine the effects of the artificial sweetener, rebaudioside A (Reb-A), on circadian rhythms, in vivo insulin action, and the susceptibility to diet-induced obesity. Six month old male C57BL/6 mice were assigned to a control or Reb-A (0.1% Reb-A supplemented drinking water) group for six months. Circadian wheel running rhythms, body weight, caloric intake, insulin action, and susceptibility to diet-induced obesity were assessed. Time of peak physical activity under a 12:12 light-dark (LD) cycle, mean activity levels, and circadian period in constant dark were not significantly different in mice that consumed Reb-A supplemented water compared to normal drinking water, indicating that circadian rhythms and biological clock function were unaltered. Although wheel running significantly reduced body weight in both Reb-A and control mice (P = 0.0001), consuming Reb-A supplemented water did not alter the changes in body weight following wheel running (P = 0.916). In vivo insulin action, as assessed by glucose, insulin, and pyruvate tolerance tests, was not different between mice that consumed Reb-A treated water compared to normal drinking water. Finally, Reb-A does not appear to change the susceptibility to diet-induced obesity as both groups of mice gained similar amounts of body weight when placed on a high fat diet. Our results indicate that consuming Reb-A supplemented water does not promote circadian disruption, insulin resistance, or obesity.
28474785	Protein consumption and its association with changes in body composition, muscle function and different strategies to optimize the muscle protein synthetic response have received considerable attention. However, we are not aware of any epidemiological study examining the time-of-day consumption (afternoon versus evening) of protein on strength and lean mass. The purpose was to examine the associations between afternoon and evening protein consumption, at different protein thresholds (i.e. 15, 20, 25 and 30 g), in relation to leg lean mass and knee extensor strength in men. Dietary protein consumption was assessed using 24-h dietary interview format. Knee extensor strength was measured on an isokinetic dynamometer. Leg lean mass was estimated from whole-body DXA scans. Participants who consumed 20 g, 25 g and 30 g of protein in the evening had greater leg lean mass than those who consumed protein in the afternoon (P<0·05). However, there was no difference in leg lean mass for 15 g of protein consumption in the evening compared to the afternoon (P>0·05). For strength, there were no differences between evening and afternoon consumption of protein for 15 g, 20 g or 25 g (P>0·05); however, those consuming at least 30 g of protein in the evening had greater knee extensor strength compared to those consuming similar amounts in the afternoon (P = 0·05). These findings suggest that evening protein consumption is associated with greater leg lean mass and knee extensor strength when compared to afternoon protein consumption. Based on these findings, we cautiously hypothesize that there may be a circadian rhythm in muscle protein metabolism.
28473760	The synthetic estrogen 17α-ethinylestradiol (EE2) is an endocrine disrupting compound of concern due to its persistence and widespread presence in the aquatic environment. Effects of developmental exposure to low concentrations of EE2 in fish on reproduction and behavior not only persisted to adulthood, but have also been observed to be transmitted to several generations of unexposed progeny. To investigate the possible biological mechanisms of the persistent anxiogenic phenotype, we exposed zebrafish embryos for 80 days post fertilization to 0, 3, and 10 ng/L EE2 (measured concentrations 2.14 and 7.34 ng/L). After discontinued exposure, the animals were allowed to recover for 120 days in clean water. Adult males and females were later tested for changes in stress response and shoal cohesion, and whole-brain gene expression was analyzed with RNA sequencing. The results show increased anxiety in the novel tank and scototaxis tests, and increased shoal cohesion in fish exposed during development to EE2. RNA sequencing revealed 34 coding genes differentially expressed in male brains and 62 in female brains as a result of EE2 exposure. Several differences were observed between males and females in differential gene expression, with only one gene, sv2b, coding for a synaptic vesicle protein, that was affected by EE2 in both sexes. Functional analyses showed that in female brains, EE2 had significant effects on pathways connected to the circadian rhythm, cytoskeleton and motor proteins and synaptic proteins. A large number of non-coding sequences including 19 novel miRNAs were also differentially expressed in the female brain. The largest treatment effect in male brains was observed in pathways related to cholesterol biosynthesis and synaptic proteins. Circadian rhythm and cholesterol biosynthesis, previously implicated in anxiety behavior, might represent possible candidate pathways connecting the transcriptome changes to the alterations to behavior. Further the observed alteration in expression of genes involved in synaptogenesis and synaptic function may be important for the developmental modulations resulting in an anxiety phenotype. This study represents an initial survey of the fish brain transcriptome by RNA sequencing after long-term recovery from developmental exposure to an estrogenic compound.
28470767	Chronic fatigue syndrome (CFS) is characterized by long-lasting, disabling and unexplained fatigue that is often accompanied by unrefreshing sleep. The aim of this cross-sectional study was to investigate sleep-wake rhythm and perceived sleep in adolescent CFS patients compared to healthy individuals. We analysed baseline data on 120 adolescent CFS patients and 39 healthy individuals included in the NorCAPITAL project. Activity measures from a uniaxial accelerometer (activPAL) were used to estimate mid-sleep time (mid-point of a period with sleep) and time in bed. Scores from the Karolinska Sleep Questionnaire (KSQ) were also assessed. The activity measures showed that the CFS patients stayed significantly longer in bed, had a significantly delayed mid-sleep time and a more varied sleep-wake rhythm during weekdays compared with healthy individuals. On the KSQ, the CFS patients reported significantly more insomnia symptoms, sleepiness, awakening problems and a longer sleep onset latency than healthy individuals. These results might indicate that disrupted sleep-wake phase could contribute to adolescent CFS; however, further investigations are warranted.
28470123	Among nonphotic stimulants, a classic cholinergic agonist, carbachol, is known to have a strong and unique phase-resetting effect on the circadian clock: Intracerebroventricular carbachol treatment causes phase delays during the subjective early night and phase advances in the subjective late night, but the effects of this drug on the suprachiasmatic nucleus (SCN) in vivo and in vitro are still controversial. In the present study, we succeeded in reproducing the biphasic phase-shifting effect of carbachol on clock gene expression in organotypic SCN slices prepared from mice carrying a Per1-promoter fused luciferase gene ( Per1-luc). Since this biphasic effect of carbachol in Per1-luc SCN was prevented by atropine but not by mecamylamine, we concluded that these phase shifts were muscarinic receptor-dependent. Next, we analyzed the expression of muscarinic receptors in the SCN by in situ hybridization and found that M3 and M4 subtypes were expressed in SCN cells. These signals appeared neonatally and reached adult levels at postnatal day 10. Together, these findings suggest that carbachol has a phase-dependent phase-shifting effect on the SCN clock through muscarinic receptor subtypes expressed in the SCN.
28470122	Although it is well known that body temperature (Tb) is higher during the day in diurnal birds than at night, no data are available regarding exactly how Tb varies during a 24-h period, how this differs under different photoperiods, and how it responds to a change in photoperiod. This study used implanted temperature loggers in starlings ( Sturnus vulgaris) to address these questions. The duration of elevated Tb was directly related to photoperiod, but the amplitude of the daily cycle was significantly greater under shorter photoperiods. Under all photoperiods, Tb started to increase before dawn and continued to increase after dawn; there was no sudden change associated with dawn. In contrast, Tb decreased immediately and rapidly at dusk (significantly by 15 min). The daily cycle in Tb rapidly adjusted to a change in photoperiod. Following an acute increase in photoperiod, Tb increased immediately at the new earlier dawn but did not decrease until the new later dusk. Following a decrease in photoperiod, Tb did not increase after the time of the missed dawn; it only increased after the new later dawn. It decreased at the new earlier dusk. Following transfer to constant darkness, there was a moderate increase in Tb around the missed dawn, but then Tb gradually decreased before the missed dusk to lower values than during the previous night. The results suggest that the daily cycle in Tb is weakly circadian and may be entrained by dusk rather than dawn.
28470121	Deficits in cognitive functioning associated with shift work are particularly relevant to occupational performance; however, few studies have examined how cognitive functioning is associated with specific components of shift work. This observational study examined how circadian phase, nocturnal sleepiness, and daytime insomnia in a sample of shift workers ( N = 30) were associated with cognitive flexibility during the night shift. Cognitive flexibility was measured using a computerized task-switching paradigm, which produces 2 indexes of flexibility: switch cost and set inhibition. Switch cost represents the additional cognitive effort required in switching to a different task and can impact performance when multitasking is involved. Set inhibition is the efficiency in returning to previously completed tasks and represents the degree of cognitive perseveration, which can lead to reduced accuracy. Circadian phase was measured via melatonin assays, nocturnal sleepiness was assessed using the Multiple Sleep Latency Test, and daytime insomnia was assessed using the Insomnia Severity Index. Results indicated that those with an earlier circadian phase, insomnia, and sleepiness exhibited reduced cognitive flexibility; however, specific components of cognitive flexibility were differentially associated with circadian phase, insomnia, and sleepiness. Individuals with an earlier circadian phase (thus more misaligned to the night shift) exhibited larger switch costs, which was also associated with reduced task efficiency. Shift workers with more daytime insomnia demonstrated difficulties with cognitive inhibition, whereas nocturnal sleepiness was associated with difficulties in reactivating previous tasks. Deficits in set inhibition were also related to reduced accuracy and increased perseverative errors. Together, this study indicates that task performance deficits in shift work are complex and are variably impacted by different mechanisms. Future research may examine phenotypic differences in shift work and the associated consequences. Results also suggest that fatigue risk management strategies may benefit from increased scope and specificity in assessment of sleep, sleepiness, and circadian rhythms in shift workers.
28470120	The safety and efficacy of chemotherapeutics can vary as a function of the time of their delivery during the day. This study aimed to improve the treatment of glioblastoma (GBM), the most common brain cancer, by testing whether the efficacy of the DNA alkylator temozolomide (TMZ) varies with the time of its administration. We found cell-intrinsic, daily rhythms in both human and mouse GBM cells. Circadian time of treatment affected TMZ sensitivity of murine GBM tumor cells in vitro. The maximum TMZ-induced DNA damage response, activation of apoptosis, and growth inhibition occurred near the daily peak in expression of the core clock gene Bmal1. Deletion of Bmal1 (Arntl) abolished circadian rhythms in gene expression and TMZ-induced activation of apoptosis and growth inhibition. These data indicate that tumor cell-intrinsic circadian rhythms are common to GBM tumors and can regulate TMZ cytotoxicity. Optimization of GBM treatment by timing TMZ administration to daily rhythms should be evaluated in prospective clinical trials.
28469946	This study was to report a case of normotensive patient with primary aldosteronism who was admitted to our department recently. The patient was a 33-year-old male with right adrenal incidentaloma, but without any symptom. He has no history of hypertension, and blood pressure was normal when measured at multiple time points during hospitalization stay. The 24-hour ambulatory blood pressure prompted a normal blood pressure with the existence of circadian rhythm. The patient was diagnosed with primary aldosteronism by screening and confirmatory test. Due to the absence of symptom, surgery was not preferred. Blood pressure was found to be normal with the 2-month follow-up from discharge until now.
28469924	The craniopharyngiomas are solid cystic suprasellar tumors that can present extension to adjacent structures, conditioning pituitary and hypothalamic dysfunction. Within hypothalamic neuroendocrine dysfunction, we can find obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, imbalances in the regulation of body temperature, thirst, heart rate and/or blood pressure and alterations in dietary intake (like anorexia). We present a rare case of anorexia-cachexia syndrome like a manifestation of neuroendocrine dysfunction in a patient with a papillary craniopharyngioma. Anorexia-cachexia syndrome is a complex metabolic process associated with underlying illness and characterized by loss of muscle with or without loss of fat mass and can occur in a number of diseases like cancer neoplasm, non-cancer neoplasm, chronic disease or immunodeficiency states like HIV/AIDS. The role of cytokines and anorexigenic and orexigenic peptides are important in the etiology. The anorexia-cachexia syndrome is a clinical entity rarely described in the literature and it leads to important function limitation, comorbidities and worsening prognosis.Suprasellar lesions can result in pituitary and hypothalamic dysfunction.The hypothalamic neuroendocrine dysfunction is commonly related with obesity, behavioral changes, disturbed circadian rhythm and sleep irregularities, but rarely with anorexia-cachexia.Anorexia-cachexia syndrome is a metabolic process associated with loss of muscle, with or without loss of fat mass, in a patient with neoplasm, chronic disease or immunodeficiency states.Anorexia-cachexia syndrome results in important function limitation, comorbidities that influence negatively on treatment, progressive clinical deterioration and bad prognosis that can lead the patient to death.Anorexia-cachexia syndrome should be suspected in patients with emaciation and hypothalamic lesions.	
28469414	The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues. To address this question, we propose a semimechanistic mathematical model describing the circadian dynamics of peripheral clock genes in human hepatocyte under the control of metabolic and light rhythmic signals. The model takes the synergistically acting light/dark cycles and feeding rhythms as inputs and incorporates the activity of sirtuin 1, a cellular energy sensor and a metabolic enzyme activated by nicotinamide adenine dinucleotide. The clock gene dynamics was simulated under various light-feeding phase relations and intensities, to explore the feeding entrainment mechanism as well as the convolution of light and feeding signals in the periphery. Our model predicts that the peripheral clock genes in hepatocyte can be completely entrained to the feeding rhythms, independent of the light/dark cycle. Furthermore, it predicts that light-feeding phase relationship is a critical factor in robust circadian oscillations.
28469105	Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD.The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis.	L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01).	In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.	
28468917	The circadian regulation of gene expression allows plants and animals to anticipate predictable environmental changes. While the influence of the circadian clock has recently been shown to extend to ribosome biogenesis, the dynamics and regulation of the many small nucleolar RNA that are required in pre-ribosomal RNA folding and modification are unknown. Using a novel computational method, we show that 18S and 28S pre-rRNA are subject to circadian regulation in a nuclear RNA sequencing time course. A population of snoRNA with circadian expression is identified that is functionally associated with rRNA modification. More generally, we find the abundance of snoRNA known to modify 18S and 28S to be inversely correlated with the abundance of their target. Cyclic patterns in the expression of a number of snoRNA indicate a coordination with rRNA maturation, potentially through an upregulation in their biogenesis, or their release from mature rRNA at the end of the previous cycle of rRNA maturation, in antiphase with the diurnal peak in pre-rRNA. Few cyclic snoRNA have cyclic host genes, indicating the action of regulatory mechanisms in addition to transcriptional activation of the host gene. For highly expressed independently transcribed snoRNA, we find a characteristic RNA polymerase II and H3K4me3 signature that correlates with mean snoRNA expression over the day.
28468292	This prospective longitudinal survey compared the stress levels of students taught using an outdoor curriculum in a forest, with children in a normal school setting. We were especially interested in the effect outdoor teaching might have on the children's normal diurnal cortisol rhythm. 48 children (mean age = 11.23; standard deviation (SD) = 0.46) were enrolled, with 37 in the intervention group (IG), and 11 in the control group (CG). The intervention consisted of one full school day per week in the forest over the school year. Stress levels were measured in cortisol with three samples of saliva per day. Furthermore, the data allowed for statistical control of physical activity (PA) values. For data analysis, we used a linear mixed-effects model (LMM) with random intercept and general correlation matrix for the within-unit residuals. The LMM yields that IG have expected greater decline of cortisol compared to CG; rate 0.069 µg/L vs. 0.0102 µg/L (log-units/2 h), p = 0.009. PA does not show a statistically significant interaction with cortisol (p = 0.857), despite being higher in the intervention group (p < 0.001). The main effect in our measures was that the IG had a steady decline of cortisol during the school day. This is in accordance with a healthy child's diurnal rhythm, with a significant decline of cortisol from morning to noon. This effect is constant over the school year. The CG does not show this decline during either measurement day. Further research is needed to fully explain this interesting phenomenon.
28468274	In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.
28467920	Many of the established positive health benefits of exercise have been documented by historical discoveries in the field of exercise physiology. These investigations often assess limits: the limits of performance, or the limits of exercise-induced health benefits. Indeed, several key findings have been informed by studying highly trained athletes, in addition to healthy or unhealthy people. Recent progress has been made in regard to skeletal muscle metabolism and personalized exercise regimes. In this perspective, we review some of the historical milestones of exercise physiology, discuss how these inform contemporary knowledge, and speculate on future questions.
28466791	This review summarizes various mathematical models of cell-autonomous mammalian circadian clock. We present the basics necessary for understanding of the cell-autonomous mammalian circadian oscillator, modern experimental data essential for its reconstruction and some special problems related to the validation of mathematical circadian oscillator models. This work compares existing mathematical models of circadian oscillator and the results of the computational studies of the oscillating systems. Finally, we discuss applications of the mathematical models of mammalian circadian oscillator for solving specific problems in circadian rhythm biology.
28466664	To assess the level of various salivary and urinary markers of patients with electromagnetic hypersensitivity (EHS) and to compare them with those of a healthy control group.We analyzed samples from 30 EHS individuals and a matched control group of 25 individuals (non-EHS) aged between 22 and 66. We quantified cortisol both in saliva and urine, alpha amylase (sAA), immunoglobulin A and C Reactive Protein levels in saliva and neopterin in urine (uNeopterin).	sAA was found to be significantly higher (p < 0.005) in the EHS group. uNeopterin and sAA analysis showed a significant difference based on the duration of EHS.	Higher levels of sAA in EHS participants may suggest that the sympathetic adrenal medullar system is activated. However, most of the analyzed markers of the immune system, sympathetic activity and circadian rhythm did not vary significantly in the EHS group. There is a trend to the higher levels of some variables in subgroups according to the EHS duration.	
28466652	Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.
28465542	Light has a significant impact on many aspects of avian biology, physiology and behaviour. An increasing number of studies show that illumination may positively influences birds' offspring fitness by e.g. acceleration of embryo development, stimulation of skeleton growth or regulation of circadian rhythm. Because nest cavities have especially low illumination, suitable light levels may be especially important for species which nest there. We may therefore expect that birds breeding in relatively dim conditions should prefer brighter nest sites and/or evolve behavioral mechanisms to secure sufficient light levels in the nest. Using nest boxes with modified internal illumination, we experimentally tested whether light regime is a cue for nest site selection of secondary cavity-nesting species. Additionally, we investigated whether nest building strategies are tuned to internal illumination. Our results demonstrate that, nest boxes with elevated illumination were chosen twice as often as dark nest boxes. Moreover, birds built higher nests in dark nest boxes than birds in boxes with elevated illumination, which suggests a mechanism of compensating for low light conditions. Our results provide the first experimental support for the idea that nest site choice and nest building behaviour in cavity-nesting birds are influenced by ambient illumination.
28465284	Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.
28464854	Breast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized.Immunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity.	TIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth.	TIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.	
28464848	Sleep problems are very common in people with schizophrenia spectrum disorders, and impact negatively on functioning and wellbeing. Research regarding interventions to improve sleep in this population has been lacking. Little is known regarding these patient's perspectives on sleep problems and their treatment, providing very little foundation on which to develop acceptable and patient-centred treatments.This study aims to explore perspectives and priorities of participants with schizophrenia spectrum disorders regarding sleep and sleep disturbance, and their perspectives on existing treatments. An Interpretive Phenomenological Analysis (IPA) study was conducted; data were gathered through in depth interviews with 15 people with schizophrenia spectrum disorders and varying degrees of self-reported sleep disturbance, each case was analysed individually before cross-case comparisons were made.	Sleep maintenance and sleep quality were universally valued. Changes to sleep were interpreted as part of a perceived loss of normality relating to diagnosis. Participants differed in the extent of any hopes that sleep would improve. Sleep disturbances were linked to a reduced ability or opportunity to participate in valued activities, and were entangled with self-image due to a wish to be perceived as alert and in control. During difficult times, sleep could be seen as an escape. Concerns were expressed regarding the negative effects of using hypnotics or anti-psychotics to aid sleep, although typically antipsychotics were deemed more acceptable than hypnotics. Concerns regarding barriers to adherence and effectiveness of self-help approaches were common. Non-pharmacological interventions were noted to require a personalised whole-lifestyle approach.	This is the first study to explore sleep perspectives in participants with established schizophrenia spectrum disorders, recruited from a population receiving usual care. Findings re-enforce the importance of considering sleep within recovery focused practice. In developing and adapting interventions routine-based approaches should be considered. Approaches should attempt to make gradual changes more easily perceptible, should support motivation for behaviour change, and should consider the impact of regular psychotropic medications.	
28463712	Expanding our understanding of the factors that influence depression is crucial for prognosis and treatment. In light of increasing evidence of an association between disrupted circadian rhythms and affective symptoms, a meta-analysis was used to examine the relationship between an eveningness chronotype and depression.Electronic searches of the PsycINFO, Medline, Scopus, and Google Scholar databases were conducted in February 2016. Relevant reviews, related journals, and reference lists were manually searched. Statistical data were reported or transformed to a Fisher's z correlational coefficient for effect size analysis.	Data from 36 studies (n =15734) met the inclusion criteria and were analysed under a random effects model. Nearly all included studies utilised the Composite Scale of Morningness (CSM) or the Morningness-Eveningness Questionnaire (MEQ) as a measure of chronotype. Overall effect size from 58 effect sizes was small (z=-.20; 95% CI: -.18 to -.23). Effect sizes based on the CSM were significantly larger than those based on the MEQ. There was no evidence of publication bias.	The number of studies comparing different mood disorders or the potential moderating effects of gender and age were too few to draw conclusions regarding their respective effect sizes. Future research should utilise longitudinal designs to draw causal inferences on the directionality of this relationship.	Findings from this meta-analysis indicate an eveningness orientation is somewhat associated with more severe mood symptoms. Chronobiological approaches may contribute to the prevention and treatment of depressive disorders.	
28463109	Animals have sophisticated homeostatic controls. While mammalian body temperature fluctuates throughout the day, small ectotherms, such as Drosophila achieve a body temperature rhythm (BTR) through their preference of environmental temperature. Here, we demonstrate that pigment dispersing factor (PDF) neurons play an important role in setting preferred temperature before dawn. We show that small lateral ventral neurons (sLNvs), a subset of PDF neurons, activate the dorsal neurons 2 (DN2s), the main circadian clock cells that regulate temperature preference rhythm (TPR). The number of temporal contacts between sLNvs and DN2s peak before dawn. Our data suggest that the thermosensory anterior cells (ACs) likely contact sLNvs via serotonin signaling. Together, the ACs-sLNs-DN2s neural circuit regulates the proper setting of temperature preference before dawn. Given that sLNvs are important for sleep and that BTR and sleep have a close temporal relationship, our data highlight a possible neuronal interaction between body temperature and sleep regulation.
28461102	In this study, we examined the 24-hour plasma melatonin patterns of young adult (∼11 years of age) and old (∼24 years of age) rhesus macaques, and determined how they would be influenced by 30% caloric restriction (CR). Well-defined 24-hour plasma melatonin rhythms were observed in all the males but only the old animals showed significant attenuation of night-time melatonin levels. Moreover, 4.5 years of CR failed to prevent the age-associated decline in plasma melatonin levels in the old males and caused a significant decrease in the young adult males. Similar plasma melatonin rhythms were also observed in all the females but no age-related decline was detected, and 2 years of CR had no obvious effect on plasma melatonin levels. If anything, there was a trend for the CR to decrease melatonin levels in the young adult females. Taken together, the results fail to show any clear benefit of CR on plasma melatonin levels in old rhesus macaques and may even be detrimental to plasma melatonin levels in young adults.
28461004	Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to β-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.
28460798	Sleep disturbances are the main health complaints from personnel deployed in Antarctica. The current paper presents a systematic review of research findings on sleep disturbances in Antarctica. The available sources were divided in three categories: results based on questionnaire surveys or sleep logs, studies using actigraphy, and data from polysomnography results. Other areas relevant to the issue were also examined. These included chronobiology, since the changes in photoperiod have been known to affect circadian rhythms, mood disturbances, exercise, sleep and hypoxia, countermeasure investigations in Antarctica, and other locations lacking a normal photoperiod. Based on the combination of our reviewed sources and data outside the field of sleep studies, or from other geographical locations, we defined hypotheses to be confirmed or infirmed, which allowed to summarize a research agenda. Despite the scarcity of sleep research on the Antarctic continent, the present review pinpointed some consistent changes in sleep during the Antarctic winter, the common denominators being a circadian phase delay, poor subjective sleep quality, an increased sleep fragmentation, as well as a decrease in slow wave sleep. Similar changes, albeit less pronounced, were observed during summer. Additional multidisciplinary research is needed to elucidate the mechanisms behind these changes in sleep architecture, and to investigate interventions to improve the sleep quality of the men and women deployed in the Antarctic.
28460563	Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short- or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects.
28460319	Clinical and experimental findings show that melatonin may be used as an adjuvant to the treatment of epilepsy-related complications by alleviates sleep disturbances, circadian alterations and attenuates seizures alone or in combination with AEDs. In addition, it has been observed that there is a circadian component on seizures, which cause changes in circadian system and in melatonin production. Nevertheless, the dynamic changes of the melatoninergic system, especially with regard to its membrane receptors (MT1 and MT2) in the natural course of TLE remain largely unknown. The aim of this study was to evaluate the 24-hour profile of MT1 and MT2 mRNA and protein expression in the hippocampus of rats submitted to the pilocarpine-induced epilepsy model analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases. Melatonin receptor MT1 and MT2 mRNA expression levels were increased in the hippocampus of rats few hours after SE, with MT1 returning to normal levels and MT2 reducing during the silent phase. During the chronic phase, mRNA expression levels of both receptors return to levels close to control, however, presenting a different daily profile, showing that there is a circadian change during the chronic phase. Also, during the acute and silent phase it was possible to verify MT1 label only in CA2 hippocampal region with an increased expression only in the dark period of the acute phase. The MT2 receptor was present in all hippocampal regions, however, it was reduced in the acute phase and it was found in astrocytes. In chronic animals, there is a reduction in the presence of both receptors especially in regions where there is a typical damage derived from epilepsy. Therefore, we conclude that SE induced by pilocarpine is able to change melatonin receptor MT1 and MT2 protein and mRNA expression levels in the hippocampus of rats few hours after SE as well as in silent and chronic phases.
28458232	Numerous epidemiologic studies have identified an independent association between Alzheimer's disease (AD) and diabetes mellitus (DM), which remains unexplained. This review contends that the association is mediated by mild hypercortisolemia that is manifested in AD by early stages, as empirical evidence indicates that hypercortisolemia is diabetogenic even at subclinical levels. Subclinical Cushing's syndrome is discussed as the paradigm. It is proposed that hypercortisolemia increases the risk of pre-diabetes and DM during early AD and the preceding decades. That hypercortisolemia is exhibited during the AD prodromal stage has yet to be determined, but may be inferred from concurrent metabolic parameters as documented in the literature. Studies refuting association between AD and DM also are evaluated, and the relationship between AD and DM is deduced to be more complex than directly causal, with DM of longstanding duration having a protective role. Association between DM and AD may require reappraisal by APOE ε4 carrier status, in view of newly identified roles of APOE ε4 in pre-diabetes. That association of APOE ε4 with DM in AD may have been underestimated in epidemiologic studies also is highlighted. At the core of arguments and mechanisms presented in this review is the circadian rhythm of cortisol secretion, which is the main determinant of glycemic control in humans. Alterations to that rhythm and to the hypothalamic-pituitary-adrenal axis occurring in AD are examined. Consequently the cause of hypercortisolemia in AD, and therefore of association between AD and DM, is proposed to be adrenal hyper-responsiveness to adrenocorticotropic hormone.
28456660	An important factor in reducing variability in mouse test outcomes has been to develop assays that can be used for continuous automated home cage assessment. Our experience has shown that this has been most evidenced in long-term assessment of wheel-running activity in mice. Historically, wheel-running in mice and other rodents have been used as a robust assay to determine, with precision, the inherent period of circadian rhythms in mice. Furthermore, this assay has been instrumental in dissecting the molecular genetic basis of mammalian circadian rhythms. In teasing out the elements of this test that have determined its robustness - automated assessment of an unforced behaviour in the home cage over long time intervals - we and others have been investigating whether similar test apparatus could be used to accurately discriminate differences in distinct behavioural parameters in mice. Firstly, using these systems, we explored behaviours in a number of mouse inbred strains to determine whether we could extract biologically meaningful differences. Secondly, we tested a number of relevant mutant lines to determine how discriminative these parameters were. Our findings show that, when compared to conventional out-of-cage phenotyping, a far deeper understanding of mouse mutant phenotype can be established by monitoring behaviour in the home cage over one or more light:dark cycles.
28455107	Sleep is crucial for cognition, particularly for memory, given its complex association with neurodegenerative processes. The aim of the present study was to examine the association between sleep quality as well as sleep duration and memory performance in a Greek elderly population.Cross-sectional design in the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population representative study of Greek elderly (65years or older).	Data from 1589 participants free of sleep medication were included. Sleep quality was estimated by using the Sleep Scale from the Medical Outcomes Study. An extensive neuropsychological assessment examining memory was administered to each participant. Linear regression analyses were used to examine whether sleep quality (higher score, poor quality) and/or sleep duration were associated with memory expressed in the form of a z-score. Age, sex, education, and body mass index were included as covariates. The main analyses were conducted first on the total sample, then with the exclusion of demented participants, and finally with the exclusion of both demented and participants with Mild Cognitive Impairment (MCI). We then conducted further analyses on the non-demented, non-MCI group, initially stratified by Apolipoprotein E-ε4 gene. We further examined the role of co-morbidities, as well as the association between sleep duration groups and memory. We also explored any interaction effect between sex and sleep quality/duration on memory. We then examined the associations between components of sleep measures and memory scores. Lastly, we examined the associations between sleep quality/duration and verbal/non-verbal memory separately.	In the total sample, we noted significant associations between sleep duration and memory (B=-0.001, p≤0.0001), but not for sleep quality and memory (B=-0.038, p=0.121). After excluding the demented participants, the associations were significant for: sleep quality and memory (B=-0.054, p=0.023), and sleep duration and memory (B=-0.001, p≤0.0001). After excluding both the MCI and the demented subjects, the associations between sleep quality and memory (B=-0.065, p=0.006), and sleep duration and memory (B=-0.001, p=0.003) were still significant. The association between the sleep duration groups and memory function was also significant, such that poor memory performance was associated with the longer sleep duration group. The results remained significant even after controlling for the co-morbidities, as well as after adding in the model anxiety and depression as covariates. Associations between sleep quality and memory, and sleep duration and memory were present in the ApoE-ε4 non-carriers. The individual sleep questions that were probably shown to be driving the associations between sleep and memory were: time to fall asleep, sleep not quiet, getting enough sleep to feel rested upon waking in the morning, and getting the amount of sleep needed. Sleep duration was associated with both verbal and non-verbal memory, while sleep quality was only associated with verbal memory.	Poor sleep quality and longer sleep duration were linked to low memory performance, independent of demographic and clinical factors, in a large sample of cognitively healthy older Greek adults. Other parameters than sleep and memory measurements could play an important role on the association. Levels of melatonin, or circadian rhythms dysregulation might play a crucial role in the above associations.	
28454871	The purpose of this study is to examine how time of day affects injury risk of railroad maintenance of way employees and signalmen (roadway workers). Railroads reported 15,654 serious roadway worker injuries between 1997 and 2014. Roadway workers primarily work outdoors on or near railroad tracks and frequently encounter hazardous conditions. To avoid closing an active rail line during peak hours, railroads sometimes require roadway workers to work at night. Previous studies of roadway worker injury have not adequately accounted for exposure to time of day effects, nor have they investigated the human factors issues contributing to roadway worker injury.The Federal Railroad Administration (FRA) database of injury reports provided data for circadian rhythm models of the odds of fatal and nonfatal injuries. The FRA database and fatal injury investigation reports also permitted an analysis of the circumstances and the human factors issues associated with injuries that occur at different times of day.	Odds of injury increased during nighttime work. The odds of nonfatal injury for both roadway worker crafts rose above 9:1 in the early morning hours. The relative odds of a fatal injury also increased significantly at night. A human factors analysis suggested that during all three shifts most nonfatal injuries involve workload, but workload was not identified as a factor in fatal injuries.	Nighttime work is more hazardous for roadway workers than daytime work. Several factors related to fatigue and other conditions appear to increase the risk of injury during the outdoor, nighttime work required of roadway workers.	For practical reasons, nighttime roadway work is sometimes unavoidable. Therefore, new practices for nighttime work must be developed to adequately address fatigue and protect roadway workers from harm.	
28454605	The circadian clock is an internal system that is synchronized by external stimuli, such as light and temperature, and influences various physiological and developmental processes in living organisms. In the model plant Arabidopsis, transcriptional, translational and post-translational processes are interlocked by feedback loops among morning- and eveningphased genes. In a post-translational loop, plant-specific singlegene encoded GIGANTEA (GI) stabilize the F-box protein ZEITLUPE (ZTL), driving the targeted-proteasomal degradation of TIMING OF CAB EXPRESSION 1 (TOC1) and PSEUDORESPONSE REGULATOR 5 (PRR5). Inherent to this, we demonstrate the novel biochemical function of GI as a chaperone and/or co-chaperone of Heat-Shock Protein 90 (HSP90). GI prevents ZTL degradation as a chaperone and facilitates ZTL maturation together with HSP90/HSP70, enhancing ZTL activity in vitro and in planta. GI is known to be involved in a wide range of physiology and development as well as abiotic stress responses in plants, but it could also interact with diverse client proteins to increase protein maturation. Our results provide evidence that GI helps proteostasis of ZTL by acting as a chaperone and a co-chaperone of HSP90 for proper functioning of the Arabidopsis circadian clock. [BMB Reports 2017; 50(5): 235-236].
28454036	High levels of CO2 emissions in the atmosphere and toxic pollutants in air, water and food have serious repercussions on all life's systems, including living beings, environment and economy. Everyone on the Earth is concerned by pollution in some way or another, no matter where and how the pollution is produced as airborne and foodborne pollutants could circulate around the world in different ways, through for example climate components (wind, rain) and/or import and export of foodstuffs. Similarly to living beings that take advantage of day-night circadian rhythms to recover after diurnal hardships, the environment in its entirety could also be seen as a complex living system that needs regular breaks to assimilate or ingest toxic pollutants produced during intensive and continuous industrial processes. If greenhouses gas emissions and pollution rates continue to increase at the same rates as they are nowadays, uncontrollable climate effects might be inevitable and the air quality in some crowded cities in the world might be hardly respirable in the future. A global "Clean Environmental Week" is discussed as an attempt toward reducing air pollution and CO2 emissions through the interruption or reduction of industrial polluting activities regularly, for a week or so per year, to let the nature 'breathe' and recover from environmentally challenging pollutions. A clean environmental period of 10 days per year could reduce CO2 emissions by about one billion tons of CO2 per annum.
28452287	The AKT signaling pathway is important for circadian rhythms in mammals and flies ( Drosophila). However, AKT signaling in mammals is more complicated since there are 3 isoforms of AKT, each performing slightly different functions. Here we study the most ubiquitous AKT isoform, Akt1, and its role at the organismal level in the central and vascular peripheral clocks. Akt1-/- mice exhibit relatively normal behavioral rhythms with only minor differences in circadian gene expression in the liver and heart. However, circadian gene expression in the Akt1-/- aorta, compared with control aorta, follows a distinct pattern. In the Akt1-/- aorta, positive regulators of circadian transcription have lower amplitude rhythms and peak earlier in the day, and negative circadian regulators are expressed at higher amplitudes and peak later in the day. In endothelial cells, negative circadian regulators exhibit an increased amplitude of expression, while the positive circadian regulators are arrhythmic with a decreased amplitude of expression. This indicates that Akt1 conditions the normal circadian rhythm in the vasculature more so than in other peripheral tissues where other AKT isoforms or kinases might be important for daily rhythms.
28452286	Most organisms have a circadian system, entrained to daily light-dark cycles, that regulates 24-h rhythms of physiology and behavior. It is unclear, however, how circadian systems function in animals that exhibit seasonal metabolic suppression, particularly when this coincides with the long-term absence of a day-night cycle. The arctic ground squirrel, Urocytellus parryii, is a medium-sized, semi-fossorial rodent that appears above-ground daily during its short active season in spring and summer before re-entering a constantly dark burrow for 6 to 9 months of hibernation. This hibernation consists of multiple week-long torpor bouts interrupted by short (< 20 h) arousal intervals when metabolism and body temperature (Tb) return to normal levels. Here, we used immunohistochemistry to measure the expression of daily or circadian rhythms of the protein products of 3 circadian clock genes, PER1, PER2, BMAL1, and the neural activity marker c-FOS in the suprachiasmatic nucleus (SCN) of arctic ground squirrels before, during, and after the first torpor bout of hibernation. Before torpor, while under 12:12-h light:dark conditions, animals showed significant daily rhythms in their Tb, as well as in protein expression levels of PER1 and PER2, but not BMAL1. Upon entering first torpor (Tb < 30°C), animals were moved into constant darkness. When sampled at 6-h intervals-beginning 24 h after the last light out, with Tb 3°C to 4°C-there were no circadian oscillations in PER1, PER2, or c-FOS expression. Sampling across 24 h during the first spontaneous arousal interval, c-FOS expression was elevated only when Tb reached 20°C and PER1 and PER2 expression did not show any Tb- or time-dependent changes. These results suggest that the central circadian clock might have stopped functioning during hibernation in this species, and the timing of arousal from torpor in arctic ground squirrels is unlikely to be controlled by the circadian clock within the SCN.
28452285	Light is the most potent time cue that synchronizes (entrains) the circadian pacemaker to the 24-h solar cycle. This entrainment process is an interplay between an individual's daily light perception and intrinsic pacemaker period under free-running conditions. Establishing individual estimates of circadian phase and period can be time-consuming. We show that circadian phase can be accurately predicted (SD = 1.1 h for dim light melatonin onset, DLMO) using 9 days of ambulatory light and activity data as an input to Kronauer's limit-cycle model for the human circadian system. This approach also yields an estimated circadian period of 24.2 h (SD = 0.2 h), with longer periods resulting in later DLMOs. A larger amount of daylight exposure resulted in an earlier DLMO. Individuals with a long circadian period also showed shorter intervals between DLMO and sleep timing. When a field-based estimation of tau can be validated under laboratory studies in a wide variety of individuals, the proposed methods may prove to be essential tools for individualized chronotherapy and light treatment for shift work and jetlag applications. These methods may improve our understanding of fundamental properties of human circadian rhythms under daily living conditions.
28452078	Most of biological variables follow a daily rhythm. It holds true as well for sensory capacities as two decades of research have demonstrated that the odorant induced activity in the olfactory bulbs oscillates during the day. Olfactory bulbs are the first central nervous system structures, which receive inputs from the olfactory neurons located in the nose olfactory epithelium in vertebrates. So far, data on variation in odorant detection in the olfactory epithelium throughout the day are missing. Using electroolfactogram recordings in rats housed under daily light and dark cycles, we found that the olfactory epithelium responsiveness varies during the day with a maximum in the beginning of the light phase. This fluctuation was consistent with cycling of transduction pathway gene expression in the olfactory epithelium examined by qPCR. It was also consistent with the levels of two transduction pathway proteins (olfactory-type G protein and adenylyl cyclase III) examined by western blot. Daily variations were also observed at the level of olfactory sensory neurons responses recorded by patch-clamp. To rule out a potential effect of the feeding status of the animal, we examined the variation in odorant response in starved animals during the day. We observed a similar pattern to ad libidum fed animals. Taken together, our results reveal that the olfactory epithelium sensitivity varies during the day in part due to modulation of the very first step of odorant detection.
28450299	Physiological cardiovascular functions show daily diurnal variations, which are synchronized by intrinsic molecular clocks and environment-driven cues. The clinical manifestation of cardiovascular disease also exhibits diurnal variation, with an increased incidence in the early morning. This coincides with circadian oscillations of circulating parameters, such as hormones and leukocyte counts. We are just at the beginning of understanding how circadian rhythms of immune functions are related to cardiovascular disease progression and outcome after an acute ischemic event. Here, we briefly summarize clinical data on oscillations of circulating inflammatory parameters, as well as experimental evidences for the role of circadian clocks in atherosclerosis, postmyocardial infarction inflammatory responses, and cardiac healing.
28449894	To evaluate sleep consolidation and circadian activity rhythms in infants and toddlers with Down syndrome (DS) under light and socially entrained conditions within a familiar setting. Given previous human and animal data suggesting intact circadian regulation of melatonin across the day and night, it was hypothesized that behavioral indices of circadian rhythmicity would likewise be intact in the sample with DS.A cross-sectional study of 66 infants and young children with DS, aged 5-67 months, and 43 typically developing age-matched controls. Sleep and measures of circadian robustness or timing were quantified using continuous in-home actigraphy recordings performed over seven days. Circadian robustness was quantified via time series analysis of rest-activity patterns. Phase markers of circadian timing were calculated alongside these values. Sleep efficiency was also estimated based on the actigraphy recordings.	This study provided further evidence that general sleep quality is poor in infants and toddlers with DS, a population that has sleep apnea prevalence as high as 50% during the preschool years. Despite poor sleep quality, circadian rhythm and phase were preserved in children with DS and displayed similar developmental trajectories in cross-sectional comparisons with a typically developing (TD) cohort. In line with past work, lower sleep efficiency scores were quantified in the group with DS relative to TD children. Infants born with DS exhibited the worst sleep fragmentation; however, in both groups, sleep efficiency and consolidation increased across age. Three circadian phase markers showed that 35% of the recruitment sample with DS was phase-advanced to an earlier morning schedule, suggesting significant within-group variability in the timing of their daily activity rhythms.	Circadian rhythms of wake and sleep are robust in children born with DS. The present results suggest that sleep fragmentation and any resultant cognitive deficits are likely not confounded by corresponding deficits in circadian rhythms.	
28449556	Sleep disturbances such as insomnia, hypersomnia, and circadian rhythm disturbance are common in normal elderly and Alzheimer's disease (AD) patients. To date, special attention has been paid to sleep disturbance in the clinical course of AD insofar as the interaction of sleep disturbance with the pathogenesis of AD may impact the clinical course and cognitive function of AD patients. This review covers the bidirectional relationship between sleep disturbance and AD pathogenesis; the associations between sleep disturbance and AD-specific neurotransmitters, brain structure, and aspects of sleep disturbance in each phase of AD; and the effects of sleep disturbance on the cognitive functions of patients in each phase of AD. We consider several factors required to exactly interpret the results and suggest a direction for future studies on the role of sleep disturbance in AD.
28448626	MicroRNAs (miRs) are important regulators of a wide range of biological processes. Antagomir studies suggest an implication of miR-132 in the functionality of the mammalian circadian clock. miR-212 and miR-132 are tandemly processed from the same transcript and share the same seed region. We found the clock modulator miR-132 and miR-212 to be expressed rhythmically in the central circadian clock. Consequently, mRNAs implicated in circadian functions may likely be targeted by both miRs. To further characterize the circadian role we generated mice with stable deletion of the miR-132/212 locus and compared the circadian behavior of mutant and wild-type control animals on two genetic backgrounds frequently used in chronobiological research, C57BL/6N and 129/Sv. Surprisingly, the wheel-running activity phenotype of miR mutant mice was highly background specific. A prolonged circadian free-running period in constant darkness was found in 129/Sv, but not in C57BL/6N miR-132/212 knockout mice. In contrast, in C57BL/6N, but not in 129/Sv miRNA-132/212 knockout mice a lengthened free-running period was observed in constant light conditions. Furthermore, miR-132/212 knockout mice on 129/Sv background exhibited enhanced photic phase shifts of locomotor activity accompanied by reduced light induction of Period gene transcription in the SCN. This phenotype was absent in miRNA-132/212 knockout mice on a C57BL/6N background. Together, our results reveal a strain and light regimen-specific function of miR-132/212 in the circadian clock machinery suggesting that miR-132 and miR-212 act as background-dependent circadian rhythm modulators.
28448534	A wide search for ischemic preconditioning (IPC) mechanisms of cardioprotection identified the light elicited circadian rhythm protein Period 2 (Per2) to be cardioprotective. Studies on cardiac metabolism found a key role for light elicited Per2 in mediating metabolic dependence on carbohydrate metabolism. To profile Per2 mediated pathways following IPC of the mouse heart, we performed a genome array and identified 352 abundantly expressed and well-characterized Per2 dependent micro RNAs. One prominent result of our in silico analysis for cardiac Per2 dependent micro RNAs revealed a selective role for miR-21 in the regulation of hypoxia and metabolic pathways. Based on this Per2 dependency, we subsequently found a diurnal expression pattern for miR-21 with higher miR-21 expression levels at Zeitgeber time (ZT) 15 compared to ZT3. Gain or loss of function studies for miR-21 using miRNA mimics or miRNA inhibitors and a Seahorse Bioanalyzer uncovered a critical role of miR-21 for cellular glycolysis, glycolytic capacity, and glycolytic reserve. Exposing mice to intense light, a strategy to induce Per2, led to a robust induction of cardiac miR-21 tissue levels and decreased infarct sizes, which was abolished in miR-21-/- mice. Similarly, first translational studies in humans using intense blue light exposure for 5 days in healthy volunteers resulted in increased plasma miR-21 levels which was associated with increased phosphofructokinase activity, the rate-limiting enzyme in glycolysis. Together, we identified miR-21 as cardioprotective downstream target of Per2 and suggest intense light therapy as a potential strategy to enhance miR-21 activity and subsequent carbohydrate metabolism in humans.
28447151	The environment which living organisms inhabit is not constant and many factors, such as light, temperature, and food availability, display cyclic and predictable variations. To adapt to these cyclic changes, animals present biological rhythms in many of their physiological variables, timing their functions to occur when the possibility of success is greatest. Among these variables, many endocrine factors have been described as displaying rhythms in vertebrates. The aim of the present review is to provide a thorough review of the existing knowledge on the rhythms of the endocrine system of fish by examining the hormones that show rhythmicity, how environmental factors control these rhythms and the variation in the responses of the endocrine system depending on the time of the day. We mainly focused on the hypothalamic-pituitary axis, which can be considered as the master axis of the endocrine system of vertebrates and regulates a great variety of functions, including reproduction, growth, metabolism, energy homeostasis, stress response, and osmoregulation. In addition, the rhythms of other hormones, such as melatonin and the factors, produced in the gastrointestinal system of fish are reviewed.
28447065	Diets and feeding regimens affect many physiological systems in the organism and may contribute to the development or prevention of various pathologies including cardiovascular diseases or metabolic syndromes. Some of the dietary paradigms, such as calorie restriction, have many well-documented positive metabolic effects as well as the potential to extend longevity in different organisms. Recently, the circadian clocks were put forward as integral components of the calorie restriction mechanisms. The circadian clocks generate the circadian rhythms in behavior, physiology, and metabolism; circadian disruption is associated with reduced fitness and decreased longevity. Here we focus on recent advances in the interplay between the circadian clocks and dietary paradigms. We discuss how the regulation of the circadian clocks by feeding/nutrients and regulation of nutrient signaling pathways by the clocks may contribute to the beneficial effects of calorie restriction on metabolism and longevity, and whether the circadian system can be engaged for future medical applications.
28445533	Animals living in the intertidal zone are exposed to prominent temperature changes. To cope with the energetic demands of environmental thermal challenges, ectotherms rely mainly on behavioral responses, which may change depending on the time of the day and seasonally. Here, we analyze how temperature shapes crabs' behavior at 2 different times of the year and show that a transition from constant cold (13.5°C) to constant warm (17.5°C) water temperature leads to increased locomotor activity levels throughout the day in fiddler crabs (Uca pugilator) collected during the summer. In contrast, the same transition in environmental temperature leads to a decrease in the amplitude of the daily locomotor activity rhythm in crabs collected during the winter. In other words, colder temperatures during the cold season favor a more prominent diurnal behavior. We interpret this winter-summer difference in the response of daily locomotor activity to temperature changes within the framework of the circadian thermoenergetics hypothesis, which predicts that a less favorable energetic balance would promote a more diurnal activity pattern. During the winter, when the energetic balance is likely less favorable, crabs would save energy by being more active during the expected high-temperature phase of the day-light phase-and less during the expected low-temperature phase of the day-dark phase. Our results suggest that endogenous rhythms in intertidal ectotherms generate adaptive behavioral programs to cope with thermoregulatory demands of the intertidal habitat.
28444476	This study assessed melatonin levels and the dim light melatonin onset (DLMO) in adults with Autism Spectrum Disorder (ASD) and also investigated the relationships between melatonin and objectively measured sleep parameters. Sixteen adults with ASD (ASD-Only), 12 adults with ASD medicated for comorbid diagnoses of anxiety and/or depression (ASD-Med) and 32 controls participated in the study. Although, the timing of the DLMO did not differ between the two groups, advances and delays of the melatonin rhythm were observed in individual profiles. Overall mean melatonin levels were lower in the ASD-Med group compared to the two other groups. Lastly, greater increases in melatonin in the hour prior to sleep were associated with greater sleep efficiency in the ASD groups.
28444396	Our aim was to evaluate the circadian rhythm of distal skin temperature (DST) in sleep-disordered breathing (SDB), its relation to excessive daytime sleepiness and the effect of continuous positive airway pressure (CPAP) on DST.Eighty SDB patients (53.1 ± 1.2 years old, 27.6% women) and 67 healthy participants (52.3 ± 1.6 years old, 26.9% women) wore a temperature data logger for 1 week. On the last day of that week, SDB patients underwent a polysomnography followed by a Maintenance of Wakefulness Test (MWT), Multiple Sleep Latency Test, and Sustained Attention to Response Task protocol to objectively quantify daytime sleepiness. A subset of 21 moderate to severe SDB patients were treated with CPAP during at least 3 months and revaluated with the same procedure. A nonparametric analysis was performed to characterize DST to assess differences between groups and associations among DST, polysomnography, and daytime sleepiness measures.	SDB patients showed an unstable, fragmented, flattened, phase-advanced, and less robust DST rhythm as compared to healthy participants. The more severe the SDB, the worse the DST pattern was, as indicated by the correlation coefficient. Sleepiness, according to MWT sleep latencies, was also associated with the higher fragmentation, lower amplitude, and less robustness of the DST rhythm. Treatment with CPAP improved DST pattern regularity and robustness.	DST is altered in SDB, exhibiting a direct relationship to the severity of this condition, and improves with CPAP treatment. DST independently correlates with sleepiness, thus, its measurement may contribute to the understanding of the pathophysiology of sleepiness in these patients.	
28444394	Shortened or mistimed sleep affects metabolic homeostasis, which may in part be mediated by dysregulation of endogenous circadian clocks. In this study, we assessed the contribution of sleep disruption to metabolic dysregulation by analysing diurnal transcriptome regulation in metabolic tissues of mice subjected to a sleep restriction (SR) paradigm.Male mice were subjected to 2 × 5 days of SR with enforced waking during the first 6 hours of the light phase. SR and control mice were sacrificed at different time points of the day and RNA preparations from the mediobasal hypothalamus (MBH), liver, and epididymal white adipose tissue (eWAT) were subjected to whole-genome microarray hybridization. Transcriptional rhythms were associated with changes in behavioral and physiological parameters such as sleep, body temperature, and food intake. Rhythm detection was performed with CircWave and transcription profiles were compared by 2-way analysis of variance and t-tests with Benjamini-Hochberg corrections.	Clock gene rhythms were blunted in all tissues, while transcriptome regulation was associated with either clock gene expression, sleep patterns, or food intake in a tissue-specific manner. Clock gene expression was associated with apoptosis pathways in the MBH and with tumor necrosis factor alpha signalling in liver. Food intake-associated genes included cilium movement genes in the MBH and lipid metabolism-associated transcripts in liver.	In mice, repeated SR profoundly alters behavioral and molecular diurnal rhythms, disrupting essential signalling pathways in MBH, liver, and eWAT, which may underlie the metabolic and cognitive disturbances observed in sleep-restricted humans such as shift workers.	
28443630	The endogenous circadian clock drives oscillations that are completely synchronized with the environmental day-night rhythms with a period of approximately 24 hours. Temporal misalignment between one's internal circadian clock and the external solar time often occurs in shift workers and long-distance travelers; such misalignments are accompanied by sleep disturbances and gastrointestinal distress. Repeated exposure to jet lag and rotating shift work increases the risk of lifestyle-related diseases, such as cardiovascular complaints and metabolic insufficiencies. However, the mechanism behind the disruption of one's internal clock is not well understood. In this paper, we therefore present a new theoretical concept called "jet lag separatrix" to understand circadian clock disruption and slow recovery from jet lag based on the mathematical model describing the hierarchical structure of the circadian clock. To demonstrate the utility of our theoretical study, we applied it to predict that re-entrainment via a two-step jet lag in which a four-hour shift of the light-dark cycle is given in the span of two successive days requires fewer days than when given as a single eight-hour shift. We experimentally verified the feasibility of our theory in C57BL/6 strain mice, with results indicating that this pre-exposure of jet lag is indeed beneficial.
28442544	Saliva cortisol is a possible marker of noise-induced stress and could then mediate the relation observed between exposure to aircraft or road traffic noise and cardiovascular diseases. However, the association between transportation noise and cortisol levels is still unclear. The objective of the study was to investigate the variability of saliva cortisol concentration as an indicator of disturbed hypothalamus-pituitary-adrenal (HPA) axis regulation in relation to long-term aircraft noise exposure.Saliva samples were taken when awakening and before going to bed for 1244 participants older than 18 years of age. Information about health, socioeconomic and lifestyle factors was also collected by means of a face-to-face questionnaire performed at home by an interviewer. Aircraft noise exposure was assessed for each participant's home address using noise maps. Linear regression models were used to evaluate the effects of aircraft noise exposure on the morning and evening cortisol levels and on the daily variation of cortisol per hour.	This study suggests a modification of the cortisol circadian rhythm in relation to aircraft noise exposure. This exposure was associated with a smaller variation of cortisol levels over the day, with unchanged morning cortisol levels, but higher cortisol levels in the evening.	These findings provide some support for a psychological stress induced by aircraft noise exposure, resulting in HPA dysregulation and a flattened cortisol rhythm, thus contributing to cardiovascular diseases.	
28442402	During dusk and dawn, the ambient illumination undergoes drastic changes in irradiance (or intensity) and spectrum (or color). While the former is a well-studied factor in synchronizing behavior and physiology to the earth's 24-h rotation, color sensitivity in the regulation of circadian rhythms has not been systematically studied. Drawing on the concept of color opponency, a well-known property of image-forming vision in many vertebrates (including humans), we consider how the spectral shifts during twilight are encoded by a color-opponent sensory system for non-image-forming (NIF) visual functions, including phase shifting and melatonin suppression. We review electrophysiological evidence for color sensitivity in the pineal/parietal organs of fish, amphibians and reptiles, color coding in neurons in the circadian pacemaker in mice as well as sporadic evidence for color sensitivity in NIF visual functions in birds and mammals. Together, these studies suggest that color opponency may be an important modulator of light-driven physiological and behavioral responses.
28442311	Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction.We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors.	We recruited 23 female and 22 male adults with CF aged 18 to 46 years and 26 female and 22 male volunteers aged 18 to 45 years. Compared with volunteers without CF, patients with CF had delayed sleep onset (0.612 h; P = .015), midsleep (1.11 h; P < .001), and wake (1.15 h; P < .001) times and prolonged sleep latency (7.21 min; P = .05) and duration (0.489 h; P = .05). Every hour delay in sleep onset was associated with shorter sleep duration by 0.29 h in patients with CF and 0.75 h in subjects without CF (P = .007) and longer sleep latency by 7.51 min in patients with CF and 1.6 min in volunteers without CF (P = .035). Among patients with CF, FEV1 % predicted, prior acute pulmonary exacerbations, and weight were independent of all free-day sleep measurements.	CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.	
28440906	The biological clock, whose function deteriorates with increasing age, determines bodily circadian (i.e. 24h) rhythms, including that of cholesterol metabolism. Dampening of circadian rhythms has been associated with aging and disease. Therefore, we hypothesized that individuals with a familial predisposition for longevity have a higher amplitude circadian serum cholesterol concentration rhythm. The aim of this study was to investigate circadian rhythmicity of serum cholesterol concentrations in offspring of nonagenarian siblings and their partners. Offspring from nonagenarian siblings (n = 19), and their partners as controls (n = 18), were recruited from the Leiden Longevity Study. Participants (mean age 65 years) were studied in a controlled in-hospital setting over a 24-h period, receiving three isocaloric meals at 9:00 h, 12:00 h and 18:00 h. Lights were off between 23:00 h and 8:00 h. Serum total cholesterol (TC), HDL cholesterol (HDL-C), non-HDL-C and triglycerides (TG) were determined every 30 min over a 24-h period. Serum TC concentrations were higher during day than during night in offspring (5.2 vs. 4.7 mm, P < 0.001) and in controls (5.3 vs. 5.0 mm, P < 0.001). The difference in TC concentrations between day and night tended to be greater in offspring than in controls (0.5 vs. 0.3 mm, P = 0.109), reaching statistical significance in females (P = 0.045). Notably, the day-night serum differences in non-HDL-C were twofold greater in offspring than in controls (0.43 vs. 0.21 mm, P = 0.044) and most explicit in females (0.53 vs. 0.22, P = 0.078). We conclude that familial longevity is characterized by a high circadian rhythmicity of non-HDL-C in healthy elderly offspring from nonagenarian siblings.
28440811	We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.
28440582	The circadian (c. 24 h) system has a central role in regulating the timing and coordination of photosynthesis, and in turn photosynthesis and photosynthetic products which are controlled by the circadian clock feedback to affect the circadian oscillator that generates rhythms. However, little is known about the mechanism(s) by which this feedback occurs. One group of likely candidates for signal transduction to the circadian clock are the PHYTOCHROME INTERACTING FACTOR (PIF) family of transcription factors which have been shown to be involved in numerous signaling pathways in Arabidopsis. Yet despite evidence that some PIF genes are under circadian control and bind promoter motifs present in circadian genes, until now PIFs have not been shown to affect the circadian system. Using a range of techniques, we have examined how circadian rhythms are affected in higher order pif mutants and the mechanisms by which PIFs regulate signaling to the circadian clock. We show that PIFs mediate metabolic signals to the circadian oscillator and that sucrose directly affects PIF binding to the promoters of key circadian oscillator genes in vivo that may entrain the oscillator. Our results provide a basis for understanding the mechanism for metabolic signaling to the circadian system in Arabidopsis.
28439991	DNA repair is responsible for maintaining the integrity of the genome. Perturbations in the DNA repair pathways have been identified in several human cancers. Thus, compounds targeting DNA damage response (DDR) hold great promise in cancer therapy. A great deal of effort, in pursuit of new anticancer drugs, has been devoted to understanding the basic mechanisms and functions of the cellular DNA repair machinery. Melatonin, a widely produced indoleamine in all organisms, is associated with a reduced risk of cancer and has multiple regulatory roles on the different aspects of the DDR and DNA repair. Herein, we have mainly discussed how defective components in different DNA repair machineries, including homologous recombination (HR), nonhomologous end-joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER), and finally DNA mismatch repair (MMR), can contribute to the risk of cancer. Melatonin biosynthesis, mode of action, and antioxidant effects are reviewed along with the means by which the indoleamine regulates DDR at the transduction, mediation, and functional levels. Finally, we summarize recent studies that illustrate how melatonin can be combined with DNA-damaging agents to improve their efficacy in cancer therapy.
28439257	Circadian clocks have been developed in evolution as an anticipatory mechanism allowing for adaptation to the constantly changing light environment due to rotation of the Earth. This mechanism is functional in all light-sensitive organisms. There is a considerable body of evidence on the tight connection between the circadian clock and most aspects of physiology and metabolism. Clocks, operative in the pancreatic islets, have caught particular attention in the last years due to recent reports on their critical roles in regulation of insulin secretion and etiology of type 2 diabetes. While β-cell clocks have been extensively studied during the last years, α-cell clocks and their role in islet function and orchestration of glucose metabolism stayed unexplored, largely due to the difficulty to isolate α-cells, which represents a considerable technical challenge. Here, we provide a detailed description of an experimental approach for the isolation of separate mouse α- and β-cell population, culture of isolated primary α- and β-cells, and their subsequent long-term high-resolution circadian bioluminescence recording. For this purpose, a triple reporter ProGlucagon-Venus/RIP-Cherry/Per2:Luciferase mouse line was established, carrying specific fluorescent reporters for α- and β-cells, and luciferase reporter for monitoring the molecular clockwork. Flow cytometry fluorescence-activated cell sorting allowed separating pure α- and β-cell populations from isolated islets. Experimental conditions, developed by us for the culture of functional primary mouse α- and β-cells for at least 10 days, will be highlighted. Importantly, temporal analysis of freshly isolated α- and β-cells around-the-clock revealed preserved rhythmicity of core clock genes expression. Finally, we describe the setting to assess circadian rhythm in cultured α- and β-cells synchronized in vitro. The here-described methodology allows to analyze the functional properties of primary α- and β-cells under physiological or pathophysiological conditions and to assess the islet cellular clock properties.
28439010	Circadian rhythms modulate many aspects of physiology. Knowledge of the molecular basis of these rhythms has exploded in the last 20 years. However, most of these data are from model organisms, and translation to clinical practice has been limited. Here, we present an approach to identify molecular rhythms in humans from thousands of unordered expression measurements. Our algorithm, cyclic ordering by periodic structure (CYCLOPS), uses evolutionary conservation and machine learning to identify elliptical structure in high-dimensional data. From this structure, CYCLOPS estimates the phase of each sample. We validated CYCLOPS using temporally ordered mouse and human data and demonstrated its consistency on human data from two independent research sites. We used this approach to identify rhythmic transcripts in human liver and lung, including hundreds of drug targets and disease genes. Importantly, for many genes, the circadian variation in expression exceeded variation from genetic and other environmental factors. We also analyzed hepatocellular carcinoma samples and show these solid tumors maintain circadian function but with aberrant output. Finally, to show how this method can catalyze medical translation, we show that dosage time can temporally segregate efficacy from dose-limiting toxicity of streptozocin, a chemotherapeutic drug. In sum, these data show the power of CYCLOPS and temporal reconstruction in bridging basic circadian research and clinical medicine.
28438982	The histaminergic system modulates numerous physiological functions such as wakefulness, circadian rhythm, feeding, and thermoregulation. However, it is not yet known if this system is also involved in psychological stress-induced hyperthermia (PSH) and, if so, which histamine (H) receptor subtype mediates the effect. Therefore, we investigated the effects of pretreatments with intraperitoneal injections of mepyramine (an H1 receptor inverse agonist), cimetidine (an H2 receptor antagonist), and ciproxifan (an H3 receptor inverse agonist) on cage-exchange stress-induced hyperthermia (a model of PSH) by monitoring core body temperature (Tc) during both light (10:00 am-12:00 pm) and dark (10:00 pm-12:00 am) phases in conscious, freely moving rats. We also investigated the effects of these drugs on stress-induced changes in locomotor activity (La) to rule out the possibility that effects on Tc are achieved secondary to altered La Cage-exchange stress increased Tc within 20 min followed by a gradual decrease back to baseline Tc during both phases. In the light phase, mepyramine and cimetidine markedly attenuated PSH, whereas ciproxifan did not affect it. In contrast, in the dark phase, mepyramine dropped Tc by 1°C without affecting cage-exchange stress-induced hyperthermia, whereas cimetidine and ciproxifan did not affect both postinjection Tc and PSH Cage-exchange stress induced an increase in La, especially in the light phase, but none of these drugs altered cage-exchange stress-induced La in either circadian rhythm phase. These results suggest that the histaminergic system is involved in the physiological mechanisms underlying PSH, particularly through H1 and H2 receptors, without influencing locomotor activity.
28436325	Light is a necessary environmental factor for production of conidia and pigment, formation of stroma, and development of Cordyceps militaris, a well-known edible and medicinal mushroom. In this study, an obvious rhythm loop was observed in certain strains of C. militaris under conditions of alternating 12-hour intervals of dark and light. A possibly related gene, Cmvvd, the homologue of the blue-light photoreceptor of Neurospora crassa, was cloned from the genome of C. militaris. The protein CmVVD is predicted to be 203 amino acids in length and is characterized by the presence of a light, oxygen, or voltage domain. Analysis of the CmVVD sensor domain (light, oxygen, or voltage) suggested that it is a blue-light receptor. Cysteine 108 is essential for the in vivo function of VIVID (VVD) in N. crassa photoadaptation. However, proline is in this position instead in all of the tested CmVVD proteins, suggesting that CmVVD may have a different function or may function in ways different from VVD in N. crassa. Genetic variation analysis of CmVVD in 6 representative strains indicated that 3 informative sites exist. Cmvvd messenger RNA was able to be induced by light, and the expression level increased over 10 times after irradiation and was maintained at high levels in the nascent fruiting body. The light-induced expression of Cmvvd was abolished in Cmwc-1 mutants, suggesting that the expression of Cmvvd is dependent on the photoreceptor CmWC-1 or on a functional CmWC-1/WC-2 complex. This article will help to open the still-unexplored field of circadian rhythms for this fungus.
28435104	Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism. We examined memory performance and circadian rhythms in flies with loss-of-function mutations in two PD genes: PINK1 and parkin. We found learning and memory abnormalities in both mutant genotypes, as well as a weakening of circadian rhythms that is underpinned by electrophysiological changes in clock neurons. Our study paves the way for further work that may help us understand the mechanisms underlying these neglected aspects of PD, thus identifying new targets for treatments to address these non-motor problems specifically and perhaps even to halt disease progression in its prodromal phase.
28435007	The robustness of stem cells is one of the major factors that directly impacts life quality and life span. Evidence has accumulated that changes in the stem cell compartment affect human mental health and serve as an indicator of psychiatric problems. It is well known that stem cells continuously replace differentiated cells and tissues that are used up during life, although this replacement occurs at a different pace in the various organs. However, the participation of local neural stem cells in regeneration of the central nervous system is controversial. It is known that low numbers of stem cells circulate continuously in peripheral blood (PB) and lymph and undergo a circadian rhythm in their PB level, with the peak occurring early in the morning and the nadir at night, and recent evidence suggests that the number and pattern of circulating stem cells in PB changes in psychotic disorders. On the other hand, progress in the creation of induced pluripotent stem cells (iPSCs) from patient somatic cells provides valuable tools with which to study changes in gene expression in psychotic patients. We will discuss the various potential sources of stem cells that are currently employed in regenerative medicine and the mechanisms that explain some of their beneficial effects as well as the emerging problems with stem cell therapies. However, the main question remains: Will it be possible in the future to modulate the stem cell compartment to reverse psychiatric problems?
28434990	Although sleep is strongly implicated in memory consolidation, the molecular basis for the role of sleep in memory is not known. It has been established that the consolidation of hippocampus-dependent memory depends on the activation of the Erk1,2 MAP kinase (MAPK) pathway which activates de novo CRE-mediated transcription and translation, two processes required for memory consolidation pathway. The activation of MAPK during memory formation and its nuclear translocation both depend upon cAMP signals generated by the calmodulin-stimulated adenylyl cyclases, type 1 and type 8 (AC1 and AC8). This signaling pathway undergoes a circadian oscillation in the hippocampus with maximal activation during REM sleep. This data supports the hypothesis that the persistence of long-term memory traces may depend upon the reactivation and circadian oscillation of the cAMP/MAP kinase/CRE transcriptional pathway in tagged neurons which reaches a maximum during REM sleep.
28433459	Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover, targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurodegeneration rather than simply alleviating symptoms with no curative intent. Further research is required to more comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders to allow for disease modifying treatments to be discovered.
28432961	Patients with epilepsy and those with psychogenic non-epileptic seizures (PNES) experience high levels of stress and stress is one of the most frequently self-identified seizure precipitants. Although stress is a multifaceted phenomenon, few studies have systematically examined its different components in patients with seizures. The aim of this study was therefore to describe diurnal patterns of psychological and physiological measures of stress in patients with epilepsy and patients with PNES, and explore their relationships to each other in order to improve our understanding of the mechanisms underlying stress and seizure occurrence in these patients.A range of stress markers including self-reported stress, salivary cortisol, and heart rate variability (HRV) were explored in adult patients with refractory epilepsy (N=22) and those with PNES (N=23) undergoing three- to five-day video-telemetry.	A diurnal pattern was observed in the physiological measures, characterized by higher levels of physiological arousal in the mornings and lower levels at night in both patients with epilepsy and PNES. The physiological measures (cortisol and HRV) were associated with each other in patients with epilepsy; no close relationship was found with self-reported stress in either of the two patient groups.	The findings contribute to and expand on previous studies of the patterns of stress in patients with seizures. The results also indicate a discrepancy between patients' physiological responses and their subjective stress perceptions, suggesting that simple self-reports cannot be used as a proxy of physiological arousal in patients with seizures and stress. Stress in these patient groups should be studied using a combination of complementary measures.	
28432637	Environmental toxicants are increasingly implicated in the global decline in metabolic health. Focusing on diabetes, herein, the molecular and cellular mechanisms by which metabolism disrupting chemicals (MDCs) impair energy homeostasis are discussed.Emerging data implicate MDC perturbations in a variety of pathways as contributors to metabolic disease pathogenesis, with effects in diverse tissues regulating fuel utilization. Potentiation of traditional metabolic risk factors, such as caloric excess, and emerging threats to metabolism, such as disruptions in circadian rhythms, are important areas of current and future MDC research. Increasing evidence also implicates deleterious effects of MDCs on metabolic programming that occur during vulnerable developmental windows, such as in utero and early post-natal life as well as pregnancy. Recent insights into the mechanisms by which MDCs alter energy homeostasis will advance the field's ability to predict interactions with classical metabolic disease risk factors and empower studies utilizing targeted therapeutics to treat MDC-mediated diabetes.	

28431191	Day-night cycled light improves health outcomes in preterm infants, yet the best time to institute cycled light is unclear. The hypothesis of this study was that extremely preterm infants receiving early cycled light would have better health and developmental outcomes than infants receiving late cycled light. Infants born at ≤28 weeks gestation were randomly assigned to early cycled light (ECL) starting at 28 weeks postmenstrual age [PMA] or late cycled light (LCL), starting at 36 weeks PMA. Daylight was 200-600 lux and night was 5-30 lux. Primary outcomes were weight over time and length of hospitalization. Secondary outcomes were hospital costs, sleep development, and neurodevelopment at 9, 18, and 24 months corrected age. Of 121 infants randomized, 118 were included in analysis. Weight gain in the two groups did not differ significantly but increased across time in both groups. In PMA weeks 36-44, the mean weight gain was 193.8 grams in the ECL group compared to 176.3 grams in the LCL group. Effect sizes for weight were Cohen d = 0.26 and 0.36 for 36 and 44 weeks PMA. Infants in the ECL group went home an average of 5.5 days earlier than the LCL group, but this difference was not statistically significant. There were no group differences on neurodevelopmental outcomes. Although statistically non-significant, clinically important differences of improved weight gain and decreased hospital stay were observed with ECL. The small observed effect sizes on weight during hospitalization should be considered in future cycled light research with extremely preterm infants. © 2017 Wiley Periodicals, Inc.
28430522	Stroke is a major cause of acquired cerebral disability among adults, frequently accompanied by depression, anxiety, cognitive impairment, disrupted sleep and fatigue. New ways of intervention to prevent these complications are therefore needed. The major circadian regulator, the suprachiasmatic nucleus, is mainly controlled by natural daylight, and the blue spectrum is considered the most powerful. During stroke rehabilitation, patients typically are mostly indoors and therefore not exposed to the natural daytime variation in light intensity. Furthermore, several rehabilitation hospitals may be exposed to powerful light in the blue spectrum, but at a time that is adversely related to their endogenous circadian phase, for example in the late evening instead of the daytime.Naturalistic light that mimics the natural daytime spectrum variation will have a positive impact on the health of poststroke patients admitted to rehabilitation. We test specifically for improved sleep and less fatigue (questionnaires, polysomnography, Actiwatch), improved well-being (questionnaires), lessen anxiety and depression (questionnaires), improved cognition (tests), stabilizing of the autonomous nervous system (ECG/HR, blood pressure, temperature) and stabilizing of the diurnal biochemistry (blood markers).	The study is a prospective parallel longitudinal randomized controlled study (quasi randomization). Stroke patients in need of rehabilitation will be included at the acute stroke unit and randomized to either the intervention unit (naturalistic lighting) or the control unit (CU) (standard lighting). The naturalistic light is installed in the entire IU (Cromaviso, Denmark).	This study aims to elucidate the influence of naturalistic light on patients during long-term hospitalization in a real hospital setting. The hypotheses are based on preclinical research, as studies using naturalistic light have never been performed before. Investigating the effects of naturalistic light in a clinical setting is therefore much needed.	
28430154	Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state.
28430105	The transcription factor RpaA is the master regulator of circadian transcription in cyanobacteria, driving genome-wide oscillations in mRNA abundance. Deletion of rpaA has no effect on viability in constant light conditions, but renders cells inviable in cycling conditions when light and dark periods alternate. We investigated the mechanisms underlying this viability defect, and demonstrate that the rpaA- strain cannot maintain appropriate energy status at night, does not accumulate carbon reserves during the day, and is defective in transcription of genes crucial for utilization of carbohydrate stores at night. Reconstruction of carbon utilization pathways combined with provision of an external carbon source restores energy charge and viability of the rpaA- strain in light/dark cycling conditions. Our observations highlight how a circadian output pathway controls and temporally coordinates essential pathways in carbon metabolism to maximize fitness of cells facing periodic energy limitations.
28428956	The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.
28428757	Blood pressure, renal hemodynamics, electrolyte, and water excretion all display diurnal oscillation. Disturbance of these patterns is associated with hypertension and chronic kidney disease. Kidney oxygenation is dependent on oxygen delivery and consumption that in turn are determined by renal hemodynamics and metabolism. We hypothesized that kidney oxygenation also demonstrates 24-h periodicity. Telemetric oxygen-sensitive carbon paste electrodes were implanted in Sprague-Dawley rats (250-300 g), either in renal medulla (n = 9) or cortex (n = 7). Arterial pressure (MAP) and heart rate (HR) were monitored by telemetry in a separate group (n = 8). Data from 5 consecutive days were analyzed for rhythmicity by cosinor analysis. Diurnal electrolyte excretion was assessed by metabolic cages. During lights-off, oxygen levels increased to 105.3 ± 2.1% in cortex and 105.2 ± 3.8% in medulla. MAP was 97.3 ± 1.5 mmHg and HR was 394.0 ± 7.9 bpm during lights-off phase and 93.5 ± 1.3 mmHg and 327.8 ± 8.9 bpm during lights-on. During lights-on, oxygen levels decreased to 94.6 ± 1.4% in cortex and 94.2 ± 8.5% in medulla. There was significant 24-h periodicity in cortex and medulla oxygenation. Potassium excretion (1,737 ± 779 vs. 895 ± 132 μmol/12 h, P = 0.005) and the distal Na+/K+ exchange (0.72 ± 0.02 vs. 0.59 ± 0.02 P < 0.001) were highest in the lights-off phase, this phase difference was not found for sodium excretion (P = 0.4). It seems that oxygen levels in the kidneys follow the pattern of oxygen delivery, which is known to be determined by renal blood flow and peaks in the active phase (lights-off).
28428698	Circadian periodicity of plasma lipid peroxides and serum ascorbic acid and uric acid levels were studied in one hundred renal stone formers (55 women and 45 men; age 20-60 years) and 50 clinically healthy volunteers (21 women and 29 men; age 21-45 years) with diurnal activity from 06:00 to 22:00 and nocturnal rest. A marked circadian variation was demonstrated by population-mean-cosinor for all studied variables in stone formers and healthy subjects. By comparison to the healthy controls, parameter tests indicate that the stone formers had a higher MESOR (±SE) of MDA (2.90 ± 0.03 vs. 2.28 ± 0.06; F = 94.929, p < 0.001), a lower MESOR of serum ascorbic acid (0.722 ± 0.010 vs. 0.839 ± 0.10; F = 32.083, p < 0.001), and a similar MESOR of serum uric acid. Furthermore, the patients also differed from the healthy subjects in terms of their circadian amplitude and acrophase (tested jointly) of all three variables (p < 0.001). The demonstration herein of a circadian rhythm in MDA, serum ascorbic and uric acid suggests that these variables could also serve as markers to optimize the timing of treatment and to assess the patient's response to treatment for further management.
28427145	We previously demonstrated that chemopreventive methylselenocysteine (MSC) prevents N-Nitroso-N-methylurea (NMU)-induced mammary carcinogenesis in the susceptible Fischer 344 (F344) rats by enhancing NAD+-dependent SIRT1 activity, restoring circadian expression of Period 2 (Per2) and circadian controlled genes. Here, we show that compared to the genetically resistant Copenhagen (COP) rat strain, mammary glands of the F344 rats have a 4-hour phase delay in circadian expression of Per2. Consequently, F344 rats failed to increase SIRT1 activity and circadian expression of Per2 and DDRR genes after exposure to NMU. Exposure of COP rats to NMU had the opposite effect, enhancing SIRT1 activity, increasing circadian expression of Per2 and DDRR genes. Significantly, SIRT1 activity and circadian expression of Per2 and DDRR genes in NMU-treated F344 rats on a chemopreventive regimen of MSC approximated those in NMU-treated COP rats. These results indicated that COP rats have an increased capacity to maintain NAD+-dependent SIRT1 activity under genotoxic stress. This contention was supported by increased stability of the period and phase of circadian locomotor activity in COP vs F344 rats exposed to changing light conditions. The increased sensitivity and rapid response of COP to changing light were correlated with the enhanced circadian response of this strain to carcinogen. Disturbance of circadian rhythm by jet lag also disrupted circadian expression of Per2 and DDRR genes, and accelerated mammary tumorigenesis in rodent models. These results suggested that uncoupling of DDRR responses from circadian control by environmental stresses and endogenous factors increases susceptibility to mammary carcinogenesis, possibly by inducing a promutagenic state.
28426765	Allatotropins (AT) are neuropeptides with pleotropic functions on a variety of insect tissues. They affect processes such as juvenile hormone biosynthesis, cardiac rhythm, oviduct and hindgut contractions, nutrient absorption and circadian cycle. The present work provides experimental evidence that AT elicits immune responses in two important mosquito disease vectors, Anopheles albimanus and Aedes aegypti. Hemocytes and an immune-competent mosquito cell line responded to AT by showing strong morphological changes and increasing bacterial phagocytic activity. Phenoloxidase activity in hemolymph was also increased in Ae. aegypti mosquitoes treated with AT but not in An. albimanus, suggesting differences in the AT-dependent immune activation in the two species. In addition, two important insect immune markers, nitric oxide levels and expression of antimicrobial peptide genes, were increased in An. albimanus guts after AT treatment. AT conjugated to quantum dot nanocrystals (QDots) specifically labeled hemocytes in vivo in both mosquito species, implying molecular interactions between AT and hemocytes. The results of our studies suggest a new role for AT in the modulation of the immune response in mosquitoes.
28426389	Among the most co-occurring conditions in autism spectrum disorders (ASD), there are sleep disorders which may exacerbate associated behavioral disorders and lead to intensification of existing autistic symptoms. Several studies investigating the use of melatonin in the treatment of sleep disorders in ASD have shown comparative efficiency in sleep with little or no side effects. Here we report a case of ASD with non-24-hour rhythm and the effect of melatonin in circadian parameters by actigraphy. Visual analysis of the first 10 days recorded and the periodogram suggest that this patient showed a non-24-hour rhythm. This ASD subject showed before melatonin administration an activity/rest rhythm lower than 24 hours. The results show that melatonin increased approximately 4.7 times the regularity of circadian activity rhythm and resting staying on average between 00:00 and 06:00 and showed positive effects in improving the quality of sleep and behavior. So, the actigraphy showed an ASD subject with a non-24-hour activity/rest rhythm which changed this rhythm to a 24-hour rhythm after melatonin administration. This result reinforces the prospect of therapy with melatonin for synchronization (increased regularity) of endogenous rhythms and improve sleep quality and hence behavior and indicates the actigraphy as a choice tool to characterize several parameters of the activity/rest rhythm of ASD individuals.
28425940	As a response to environmental changes driven by the Earth's axial rotation, most organisms evolved an internal biological timer-the so called circadian clock-which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another fundamental rhythmic process, the cell cycle. However, the precise mechanisms of this connection are not fully understood. Disruption of circadian rhythms has a profound impact on cell division and cancer development and, vice versa, malignant transformation causes disturbances of the circadian clock. Conventional knowledge attributes tumor suppressor properties to the circadian clock. However, this implication might be context-dependent, since, under certain conditions, the clock can also promote tumorigenesis. Therefore, a better understanding of the molecular links regulating the physiological balance between the two cycles will have potential significance for the treatment of cancer and associated disorders.
28425198	Circadian (∼24 h) rhythms of cellular network plasticity in the central circadian clock, the suprachiasmatic nucleus (SCN), have been described. The neuronal network in the SCN regulates photic resetting of the circadian clock as well as stability of the circadian system during both entrained and constant conditions. EphA4, a cell adhesion molecule regulating synaptic plasticity by controlling connections of neurons and astrocytes, is expressed in the SCN. To address whether EphA4 plays a role in circadian photoreception and influences the neuronal network of the SCN, we have analyzed circadian wheel-running behavior of EphA4 knockout (EphA4-/- ) mice under different light conditions and upon photic resetting, as well as their light-induced protein response in the SCN. EphA4-/- mice exhibited reduced wheel-running activity, longer endogenous periods under constant darkness and shorter periods under constant light conditions, suggesting an effect of EphA4 on SCN function. Moreover, EphA4-/- mice exhibited suppressed phase delays of their wheel-running activity following a light pulse during the beginning of the subjective night (CT15). Accordingly, light-induced c-FOS (FBJ murine osteosarcoma viral oncogene homolog) expression was diminished. Our results suggest a circadian role for EphA4 in the SCN neuronal network, affecting the circadian system and contributing to the circadian response to light.
28425172	Many studies on sleep deprivation effects lack data regarding the recovery period. We investigated the 2-day homeostatic and circadian sleep recovery response to 24 h of total sleep deprivation (TSD) induced by brief rotation of an activity wheel. Eight mice were implanted with telemetry transmitters (DSI F40-EET) that recorded simultaneously their electroencephalography (EEG), locomotor activity and temperature during 24 h of baseline (BSL), TSD and 2 days of recovery (D1 and D2). In a second experiment, two groups of five non-implanted mice underwent TSD or ad libitum sleep, after which they were killed, adrenal glands were weighed and blood was collected for analysis of corticosterone concentration. During TSD mice were awake at least 97% of the time, with a consecutive sleep rebound during D1 that persisted during D2. This was characterized by increases of non-rapid eye movement (NREM) sleep (44.2 ± 6.9% for D1 and 43.0 ± 7.7% for D2 versus 33.8 ± 9.2% for BSL) and the relative delta band power (179.2 ± 34.4% for D1 and 81.9 ± 11.2% for D2). Greater NREM and REM sleep amounts were observed during the 'light' periods. Temperature and locomotor activity characteristics were unchanged during D1 and D2 versus BSL. In non-implanted mice, corticosterone levels as well as adrenal gland and overall body weights did not differ between TSD and ad libitum sleep groups. In conclusion, 24 h of TSD in an activity wheel without stress responses influence homeostatic sleep regulation with no effect on the circadian regulation over at least 2 days of recovery in mice.
28424614	Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.
28424270	To investigate the relationship between the presence of a circadian body temperature rhythm and behaviorally assessed consciousness levels in patients with disorders of consciousness (DOC; i.e., vegetative state/unresponsive wakefulness syndrome or minimally conscious state).In a cross-sectional study, we investigated the presence of circadian temperature rhythms across 6 to 7 days using external skin temperature sensors in 18 patients with DOC. Beyond this, we examined the relationship between behaviorally assessed consciousness levels and circadian rhythmicity.	Analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3 hours). We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised were closely linked to the integrity of circadian variations in body temperature. Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in 2 out of 8 patients.	The study provides evidence for an association between circadian body temperature rhythms and arousal as a necessary precondition for consciousness. Our findings also make a case for circadian rhythms as a target for treatment as well as the application of diagnostic and therapeutic means at times when cognitive performance is expected to peak.	
28423315	The central circadian pacemaker, the suprachiasmatic nucleus (SCN), encodes day length information by mechanisms that are not well understood. Here, we report that genetic ablation of miR-132/212 alters entrainment to different day lengths and non-24 hr day-night cycles, as well as photoperiodic regulation of Period2 expression in the SCN. SCN neurons from miR-132/212-deficient mice have significantly reduced dendritic spine density, along with altered methyl CpG-binding protein (MeCP2) rhythms. In Syrian hamsters, a model seasonal rodent, day length regulates spine density on SCN neurons in a melatonin-independent manner, as well as expression of miR-132, miR-212, and their direct target, MeCP2. Genetic disruption of Mecp2 fully restores the level of dendritic spines of miR-132/212-deficient SCN neurons. Our results reveal that, by regulating the dendritic structure of SCN neurons through a MeCP2-dependent mechanism, miR-132/212 affects the capacity of the SCN to encode seasonal time.
28422445	Several studies suggest a strong genetic component of attention-deficit/hyperactivity disorder (ADHD), a complex neurodevelopmental disorder characterized by inappropriate levels of hyperactivity, impulsivity and inattention. Determining specific genetic risk variants for each symptom dimension of ADHD may aid in the identification of the biological risk factors of the disorder. In this study, we explored the potential genetic underpinnings of the hyperactive phenotype of ADHD. To this end, we examined differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of SHR/NCrl, an animal model of ADHD, compared with its genetic control, the Wistar Kyoto (WKY/NCrl) rat and the Wistar rat, strain used to represent the 'normal' heterogeneous population. Relative to WKY/NCrl and Wistar controls, SHR/NCrl showed hyperactivity in the open-field test. Treatment with the ADHD drug, amphetamine (AMPH) reduced hyperactivity in SHR/NCrl. Meanwhile, AMPH increased locomotor activity in WKY/NCrl and Wistar rats. Gene expression analysis found 21 common upregulated and 36 downregulated genes in the PFC of drug-naive SHR/NCrl when compared with WKY/NCrl and Wistar rats. Of these DEGs, expression levels of two genes, Atxn7 and Per2, which are involved in transcription and circadian rhythm, respectively, were downregulated following AMPH treatment in SHR/NCrl. Quantitative real-time-polymerase chain reaction analyses verified expression patterns of these genes in the PFC of drug-naïve and AMPH-treated SHR/NCrl. The present findings indicate genetic risk variants that may be associated with the hyperactive phenotype in ADHD. Further studies are warranted to establish the roles of Atxn7 and Per2 in mediating hyperactivity.
28421530	Occurrence of stroke cases displays a time-of-day variation in human. However, the mechanism linking circadian rhythm to the internal response mechanisms against pathophysiological events after ischemic stroke remained largely unknown. To this end, temporal changes in the susceptibility to ischemia/reperfusion (I/R) injury were investigated in mice in which the ischemic stroke induced at four different Zeitgeber time points with 6-h intervals (ZT0, ZT6, ZT12, and ZT18). Besides infarct volume and brain swelling, neuronal survival, apoptosis, ischemia, and circadian rhythm related proteins were examined using immunohistochemistry, Western blot, planar surface immune assay, and liquid chromatography-mass spectrometry tools. Here, we present evidence that midnight (ZT18; 24:00) I/R injury in mice resulted in significantly improved infarct volume, brain swelling, neurological deficit score, neuronal survival, and decreased apoptotic cell death compared with ischemia induced at other time points, which were associated with increased expressions of circadian proteins Bmal1, PerI, and Clock proteins and survival kinases AKT and Erk-1/2. Moreover, ribosomal protein S6, mTOR, and Bad were also significantly increased, while the levels of PRAS40, negative regulator of AKT and mTOR, and phosphorylated p53 were decreased at this time point compared to ZT0 (06:00). Furthermore, detailed proteomic analysis revealed significantly decreased CSKP, HBB-1/2, and HBA levels, while increased GNAZ, NEGR1, IMPCT, and PDE1B at midnight as compared with early morning. Our results indicate that nighttime I/R injury results in less severe neuronal damage, with increased neuronal survival, increased levels of survival kinases and circadian clock proteins, and also alters the circadian-related proteins.
28421465	This review summarizes what has been learned about the interaction between skeletal muscle and bone from mouse models in which BMAL1, a core molecular clock protein has been deleted. Additionally, we highlight several genes which change following loss of BMAL1. The protein products from these genes are secreted from muscle and have a known effect on bone homeostasis.Circadian rhythms have been implicated in regulating systems homeostasis through a series of transcriptional-translational feedback loops termed the molecular clock. Recently, skeletal muscle-specific disruption of the molecular clock has been shown to disrupt skeletal muscle metabolism. Additionally, loss of circadian rhythms only in adult muscle has an effect on other tissue systems including bone. Our finding that the expression of a subset of skeletal muscle-secreted proteins changes following BMAL1 knockout combined with the current knowledge of muscle-bone crosstalk suggests that skeletal muscle circadian rhythms are important for maintenance of musculoskeletal homeostasis. Future research on this topic may be important for understanding the role of the skeletal muscle molecular clock in a number of diseases such as sarcopenia and osteoporosis.	
28420980	In mammals, melanopsin-expressing retinal ganglion cells (mRGCs) are, among other things, involved in several non-image-forming visual functions, including light entrainment of circadian rhythms. Considering the profound impact of aging on visual function and ophthalmic diseases, here we evaluate changes in mRGCs throughout the life span in humans. In 24 post-mortem retinas from anonymous human donors aged 10-81 years, we assessed the distribution, number and morphology of mRGCs by immunostaining vertical retinal sections and whole-mount retinas with antibodies against melanopsin. Human retinas showed melanopsin immunoreactivity in the cell body, axon and dendrites of a subset of ganglion cells at all ages tested. Nearly half of the mRGCs (51%) were located within the ganglion cell layer (GCL), and stratified in the outer (M1, 12%) or inner (M2, 16%) margin of the inner plexiform layer (IPL) or in both plexuses (M3, 23%). M1 and M2 cells conformed fairly irregular mosaics, while M3 cell distribution was slightly more regular. The rest of the mRGCs were more regularly arranged in the inner nuclear layer (INL) and stratified in the outer margin of the IPL (M1d, 49%). The quantity of each cell type decrease after age 70, when the total number of mRGCs was 31% lower than in donors aged 30-50 years. Moreover, in retinas with an age greater than 50 years, mRGCs evidenced a decrease in the dendritic area that was both progressive and age-dependent, as well as fewer branch points and terminal neurite tips per cell and a smaller Sholl area. After 70 years of age, the distribution profile of the mRGCs was closer to a random pattern than was observed in younger retinas. We conclude that advanced age is associated with a loss in density and dendritic arborization of the mRGCs in human retinas, possibly accounting for the more frequent occurrence of circadian rhythm disorders in elderly persons.
28420965	Circadian rhythms are daily rhythms that regulate many biological processes - from gene transcription to behavior - and a disruption of these rhythms can lead to a myriad of health risks. Circadian rhythms are entrained by light, and their 24-h oscillation is maintained by a core molecular feedback loop composed of canonical circadian ("clock") genes and proteins. Different modulators help to maintain the proper rhythmicity of these genes and proteins, and one emerging modulator is dopamine. Dopamine has been shown to have circadian-like activities in the retina, olfactory bulb, striatum, midbrain, and hypothalamus, where it regulates, and is regulated by, clock genes in some of these areas. Thus, it is likely that dopamine is essential to mechanisms that maintain proper rhythmicity of these five brain areas. This review discusses studies that showcase different dopaminergic mechanisms that may be involved with the regulation of these brain areas' circadian rhythms. Mechanisms include how dopamine and dopamine receptor activity directly and indirectly influence clock genes and proteins, how dopamine's interactions with gap junctions influence daily neuronal excitability, and how dopamine's release and effects are gated by low- and high-pass filters. Because the dopamine neurons described in this review also release the inhibitory neurotransmitter GABA which influences clock protein expression in the retina, we discuss articles that explore how GABA may contribute to the actions of dopamine neurons on circadian rhythms. Finally, to understand how the loss of function of dopamine neurons could influence circadian rhythms, we review studies linking the neurodegenerative disease Parkinson's Disease to disruptions of circadian rhythms in these five brain areas. The purpose of this review is to summarize growing evidence that dopamine is involved in regulating circadian rhythms, either directly or indirectly, in the brain areas discussed here. An appreciation of the growing evidence of dopamine's influence on circadian rhythms may lead to new treatments including pharmacological agents directed at alleviating the various symptoms of circadian rhythm disruption.
28418582	Plants adjust their architecture to optimize growth and reproductive success under changing climates. Hypocotyl elongation is a pivotal morphogenic trait that is profoundly influenced by light and temperature conditions. While hypocotyl photomorphogenesis has been well characterized at the molecular level, molecular mechanisms underlying hypocotyl thermomorphogenesis remains elusive. Here, we demonstrate that the E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) conveys warm temperature signals to hypocotyl thermomorphogenesis. To investigate the roles of COP1 and its target ELONGATED HYPOCOTYL 5 (HY5) during hypocotyl thermomorphogenesis, we employed Arabidopsis mutants that are defective in their genes. Transgenic plants overexpressing the genes were also produced. We examined hypocotyl growth and thermoresponsive turnover rate of HY5 protein at warm temperatures under both light and dark conditions. Elevated temperatures trigger the nuclear import of COP1, thereby alleviating the suppression of hypocotyl growth by HY5. While the thermal induction of hypocotyl growth is circadian-gated, the degradation of HY5 by COP1 is uncoupled from light responses and timing information. We propose that thermal activation of COP1 enables coincidence between warm temperature signaling and circadian rhythms, which allows plants to gate hypocotyl thermomorphogenesis at the most profitable time at warm temperatures.
28417351	We evaluate the impact of maternal and post-weaning high-fat (HF) diet on ovarian follicular population, steroidogenesis, and gene expression with a focus on the circadian clock system and insulin-like growth factor 2 (Igf2) in adult offspring ovaries, and to elucidate whether a maternal and post-weaning diet confers similar risks.Virgin Sprague-Dawley rats were fed with normal chow (C) diet or HF diet for 5 weeks before mating, during gestation, and lactation. Female offspring were fed with the C or HF diet from weaning to 6 months of age, resulting in four study groups (n = 6 per group): C/C, C/HF, HF/C, and HF/HF.	Ovaries from offspring exposed to post-weaning HF diet (i.e., the C/HF and HF/HF groups) had a decrease in small follicle numbers, but with similar numbers of antral follicles and corpora lutea. Offspring from HF-fed dams (i.e., the HF/C and HF/HF groups) had increased plasma estradiol concentrations and decreased luteinizing hormone levels at 6 months of age. In addition, Igf2 and each of the circadian rhythm core genes Clock, Per1, Per2, and Per3 were increased in the ovaries of offspring exposed to maternal HF diet (both HF/C and HF/HF groups).	Maternal and post-weaning HF diet programs the reproductive profile of the female offspring in adult life through different manners. Post-weaning HF intake resulted in the reduction of small follicles in adulthood, whereas maternal HF diet had long-term deleterious consequences on female offspring steroidogenesis and coincided with alteration of the upregulation of the imprinted gene Igf2 and changes in ovarian circadian rhythms.	
28416676	The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and found that the rate of phase shifts induced by a single light pulse was different in the two rhythms. The Per1-luc rhythm was phase-delayed instantaneously by the light presented at the subjective evening in parallel with the activity onset of behavioral rhythm, whereas the Bmal1-ELuc rhythm was phase-delayed gradually, similar to the activity offset. The dissociation was confirmed in cultured SCN slices of mice carrying both Per1-luc and Bmal1-ELuc reporters. The two rhythms in a single SCN slice showed significantly different periods in a long-term (3 wk) culture and were internally desynchronized. Regional specificity in the SCN was not detected for the period of Per1-luc and Bmal1-ELuc rhythms. Furthermore, neither is synchronized with circadian intracellular Ca2+ rhythms monitored by a calcium indicator, GCaMP6s, or with firing rhythms monitored on a multielectrode array dish, although the coupling between the circadian firing and Ca2+ rhythms persisted during culture. These findings indicate that the expressions of two key clock genes, Per1 and Bmal1, in the SCN are regulated in such a way that they may adopt different phases and free-running periods relative to each other and are respectively associated with the expression of activity onset and offset.

28416043	During adolescence, internal circadian rhythms and biological sleep drive change to result in later sleep and wake times. As a result of these changes, early middle school and high school start times curtail sleep, hamper a student's preparedness to learn, negatively impact physical and mental health, and impair driving safety. Furthermore, a growing body of evidence shows that delaying school start times positively impacts student achievement, health, and safety. Public awareness of the hazards of early school start times and the benefits of later start times are largely unappreciated. As a result, the American Academy of Sleep Medicine is calling on communities, school boards, and educational institutions to implement start times of 8:30 AM or later for middle schools and high schools to ensure that every student arrives at school healthy, awake, alert, and ready to learn.
28415870	Prospective study designs ideally allow patients to be followed from the first manifestations of the illness or even from an at-risk stage. It can thus provide data on the predictive value of changes in clinical symptomatology, cognition or further biological markers to broaden our understanding of the etiopathology and symptomatic trajectory of bipolar disorders. The scope of this narrative review is to summarize evidence from prospectively collected data on psychopathological and other clinical and biological changes in the early developmental course of bipolar disorders.The narrative review was based on a literature search conducted in February 2016 within the PubMed library for prospective study data of persons in antecedent and early manifest stages of manifest bipolar disorder published within the last 15 years.	A total of 19 prospective studies were included. Regarding psychopathological features; personality, temperament and character traits as well as changes in sleep and circadian rhythm, the evidence suggests that risk factors for the development of bipolar disorder can already be described and should be studied further to understand their interaction, mediation with other factors and timing in the developmental process of bipolar disorder. Apart from the positive family history, childhood anxiety, sleep problems, subthreshold (hypo)manic symptoms and certain character traits/emotionality should be identified and monitored already in clinical practice as their presence likely increases risk of bipolar disorder. Up to date no substantiated evidence was found from prospective studies addressing cognitive features, life events, immunological parameters and morphological central nervous system changes as potential risk factors for bipolar disorder.	For an improved understanding of episodic disorders, longitudinal data collection is essential. Since the etiology of bipolar disorders is complex, a number of potential risk factors have been proposed. Prospective studies addressing this spectrum and resilience factors are critical and will be best conducted within multi-site research networks or initiatives.	
28414715	Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver.
28414048	Light exerts widespread effects on physiology and behaviour. As well as the widely-appreciated role of light in vision, light also plays a critical role in many non-visual responses, including regulating circadian rhythms, sleep, pupil constriction, heart rate, hormone release and learning and memory. In mammals, responses to light are all mediated via retinal photoreceptors, including the classical rods and cones involved in vision as well as the recently identified melanopsin-expressing photoreceptive retinal ganglion cells (pRGCs). Understanding the effects of light on the laboratory mouse therefore depends upon an appreciation of the physiology of these retinal photoreceptors, including their differing sens itivities to absolute light levels and wavelengths. The signals from these photoreceptors are often integrated, with different responses involving distinct retinal projections, making generalisations challenging. Furthermore, many commonly used laboratory mouse strains carry mutations that affect visual or non-visual physiology, ranging from inherited retinal degeneration to genetic differences in sleep and circadian rhythms. Here we provide an overview of the visual and non-visual systems before discussing practical considerations for the use of light for researchers and animal facility staff working with laboratory mice.
28413931	Glucose variations are common throughout sleep and wakefulness in people with type 1 diabetes mellitus (T1DM). The objective of this investigation was to characterize the time-varying coupling between glucose and unstructured physical activity over a 60-hr period in young adults with T1DM. The hypothesis was that coupling would differ during sleep versus wakefulness and would exhibit circadian variations.Young adults with T1DM treated with an insulin pump participated in the study. Glucose variations were monitored with a continuous glucose monitoring system, and activity was assessed using an activity-monitoring band worn on the nondominant wrist. Simultaneous glucose and physical activity data across a continuous 60-hr period were used for analysis. Wavelet coherence analysis was employed to quantify the coupling between physical activity and glucose. Cosinor analysis was used to assess whether glucose/activity coherence exhibited significant circadian variations.	Participants comprised 23 adults, aged 18-30 years, with T1DM. Coherence analysis demonstrated substantial coupling between physical activity and glucose variations during both wakefulness and sleep. For rapid (10-30 min) fluctuations, mean coherence was higher during sleep than wakefulness ( F = 10.86, p = .003). Rapid glucose variations consistently led to changes in activity ( p = .001) during sleep but not during wake. Cosinor analysis revealed significant circadian modulation of glucose/activity coupling, especially for fluctuation periods 2-4 hr.	Unstructured physical activity and glucose variations demonstrated strong time- and frequency-dependent coupling over a 60-hr period in young adults with T1DM, with sleep/wake differences and circadian modulation evident in this relationship.	
28413577	Over the course of the day, the heart is challenged with dramatic fluctuations in energetic demand and nutrient availability. It is therefore not surprising that rhythms in cardiac metabolism have been reported at multiple levels, including the utilization of glucose, fatty acids, and amino acids. Evidence has emerged suggesting that the cardiomyocyte circadian clock is in large part responsible for governing cardiac metabolic rhythms. In doing so, the cardiomyocyte clock temporally partitions ATP generation for increased contractile function during the active period, promotes nutrient storage at the end of the active period, and facilitates protein turnover (synthesis and degradation) during the beginning of the sleep phase. This review highlights the roles of cardiac metabolism rhythms as well as the potential pathological consequences of their impairment.
28412756	Previous animal studies have indicated associations between circadian clock genes and cognitive impairment . In this study, we assessed whether 11 circadian clockgenes are associated with cognitive aging independently and/or through complex interactions in an old Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to evaluate cognitive function. Our data showed associations between cognitive aging and single nucleotide polymorphisms (SNPs) in 4 key circadian clock genes, CLOCK rs3749473 (p = 0.0017), NPAS2 rs17655330 (p = 0.0013), RORA rs13329238 (p = 0.0009), and RORB rs10781247 (p = 7.9 x 10-5). We also found that interactions between CLOCK rs3749473, NPAS2 rs17655330, RORA rs13329238, and RORB rs10781247 affected cognitive aging (p = 0.007). Finally, we investigated the influence of interactions between CLOCK rs3749473, RORA rs13329238, and RORB rs10781247 with environmental factors such as alcohol consumption, smoking status, physical activity, and social support on cognitive aging (p = 0.002 ~ 0.01). Our study indicates that circadian clock genes such as the CLOCK, NPAS2, RORA, and RORB genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-environment interactions.
28412540	Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive RGCs deputed to non-image forming functions of the eye such as synchronization of circadian rhythms to light-dark cycle. These cells are characterized by unique electrophysiological, anatomical and biochemical properties and are usually more resistant than conventional RGCs to different insults, such as axotomy and different paradigms of stress. We also demonstrated that these cells are relatively spared compared to conventional RGCs in mitochondrial optic neuropathies (Leber's hereditary optic neuropathy and Dominant Optic Atrophy). However, these cells are affected in other neurodegenerative conditions, such as glaucoma and Alzheimer's disease. We here review the current evidences that may underlie this dichotomy. We also present our unpublished data on cell experiments demonstrating that melanopsin itself does not explain the robustness of these cells and some preliminary data on immunohistochemical assessment of mitochondria in mRGCs.
28412365	In the eukaryotic circadian clock machinery, negative feedback repression of CLOCK (CLK) and BMAL1 transcriptional activity by PERIOD (PER) and CRYPTOCHROME (CRY) underlies the basis for 24 h rhythmic gene expression. Thus, precise regulation of the time-dependent nuclear entry of circadian repressors is crucial to generating normal circadian rhythms. Here, we sought to identify novel kinase(s) that regulate nuclear entry of mammalian CRY1 (mCRY1) with an unbiased screening using red fluorescent protein (RFP)-tagged human kinome expression plasmids in mammalian cells. Transient expression of human vaccinia-related kinase 3 (hVRK3) reduced the nuclear presence of mCRY1. hVRK3 expression also induced alterations in the subcellular localization of other core clock proteins, including mCRY2, mPER2, and BMAL1. In contrast, the subcellular localization of mCLK was not changed. Given that singly expressed mCLK mostly resides in the cytoplasm and that nuclear localization sequence (NLS) mutation of hVRK3 attenuated the effect of hVRK3 co-expression on subcellular localization, ectopically expressed hVRK3 presumably reduces the retention of proteins in the nucleus. Finally, downregulation of hvrk3 using siRNA reduced the amplitude and lengthened the period of the cellular bioluminescence rhythm. Taken together, these data suggest that VRK3 plays a role in setting the amplitude and period length of circadian rhythms in mammalian cells.
28412321	In response to the daily light-dark (LD) cycle, organisms on Earth have evolved with the approximately 24-h endogenous oscillations to coordinate behavioral and physiological processes, including feeding, sleep, and metabolism homeostasis. Circadian desynchrony triggered by an energy-dense diet rich in fats and fructose is intimately connected with a series of metabolic disorders. Previous studies revealed that (-)-Epigallocatechin-3-gallate (EGCG) could mitigate metabolic misalignment; however, only a few reports have focused on its potential effect on directly manipulating circadian rhythms to ameliorate metabolic syndrome. Our goal was to investigate the regulating effect of EGCG treatment on metabolic misalignment triggered by a high-fat and high-fructose diet (HFFD) associating with the circadian clock. Our results indicated that HFFD treatment partially exhibited poor circadian oscillations of the core clock gene and the clock-controlled gene in the liver and fat relative to the control group. EGCG administration may ameliorate the diet-dependent decline in circadian function by controlling the Sirt1-PGC1αloop, implying the existence of an EGCG-entrainable oscillator. Subsequently, reducing fatty acid synthesis and elevating β-oxidation in the liver coupled with the increasing brown adipose tissue (BAT) energy expenditure observed in the EGCG group of mice prevented the adipocyte hypertrophy and fat accumulations common to BAT and white adipose tissue (WAT) derived from the HFFD mice. This study is the first to provide compelling evidences that EGCG may ameliorate diet-induced metabolic misalignment by regulating the rhythmic expression of the circadian clock genes in the liver and fat.
28412140	It is increasingly recognized that sleep disturbances and Alzheimer's disease (AD) share a bidirectional relationship. AD patients exhibit sleep problems and alterations in the regulation of circadian rhythms; conversely, poor quality of sleep increases the risk of development of AD. The aim of the current study was to determine whether chronic sleep restriction potentiates the brain impact of amyloid-β oligomers (AβOs), toxins that build up in AD brains and are thought to underlie synapse damage and memory impairment. We further investigated whether alterations in levels of pro-inflammatory mediators could play a role in memory impairment in sleep-restricted mice. We found that a single intracerebroventricular (i.c.v.) infusion of AβOs disturbed sleep pattern in mice. Conversely, chronically sleep-restricted mice exhibited higher brain expression of pro-inflammatory mediators, reductions in levels of pre- and post-synaptic marker proteins, and exhibited increased susceptibility to the impact of i.c.v. infusion of a sub-toxic dose of AβOs (1pmol) on performance in the novel object recognition memory task. Sleep-restricted mice further exhibited an increase in brain TNF-α levels in response to AβOs. Interestingly, memory impairment in sleep-restricted AβO-infused mice was prevented by treatment with the TNF-α neutralizing monoclonal antibody, infliximab. Results substantiate the notion of a dual relationship between sleep and AD, whereby AβOs disrupt sleep/wake patterns and chronic sleep restriction increases brain vulnerability to AβOs, and point to a key role of brain inflammation in increased susceptibility to AβOs in sleep-restricted mice.
28411580	Pelteobagrus vachellii, an important freshwater fish in China, shows predominantly nocturnal behavior. To better understand the growth and molecular mechanisms underlying altered feeding times in this species, we studied the growth and liver transcriptome of P. vachellii with shifted feeding times. In this study, a 9-week growth trial was conducted on male P. vachellii (mean weight±S.E.=1.05±0.36g) with commercial feed. Two triplicate groups of fish were fed either at 0800 (day group, control) or at 2000 (night group) with the same amount of feed. After nine weeks, a significant increase in growth was observed in the night group, demonstrated by the specific growth rate (SGR). Using high-throughput RNA-seq, 70,793,844 and 67,930,610 paired-end clean reads were obtained from six cDNA libraries of P. vachellii liver, and 60,069 unigenes were assembled. Gene expression comparison revealed that 122 genes were significantly up-regulated and 59 genes were significantly down-regulated in the night group. Gene pathway and GO enrichment analyses revealed metabolic responses of genes and gene networks related to protein, lipid and carbohydrate metabolism and rhythms. This study indicates that an alternative feeding time can improve growth and create metabolic alterations in the liver of P. vachellii.
28410879	Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is a popular method for the measurement of mRNA expression level and is a critical tool for basic research. The identification of suitable reference genes that are stable and not affected by experimental conditions is a critical step in the accurate normalization of RT-PCR. On the other hand, the levels of numerous transcripts exhibit circadian oscillation in various peripheral tissues and it is thought to be regulated by feeding rhythms in addition to the molecular circadian clock. Here, we investigated the effects of feeding schedule on the temporal expression profiles of 13 common housekeeping genes in metabolic tissues of mice fed during either the sleep or the active phase. The expression of most of these genes fluctuated dependently on feeding rhythms in the liver and WAT, but not in skeletal muscle. Two-way analyses of variance (ANOVA) identified 18S ribosomal RNA (Rn18s) as the only gene that was stably expressed throughout the day independently of feeding schedules in the liver and WAT, although RefFinder software showed that peptidylprolyl isomerase A (Ppia) was the most stably expressed housekeeping gene. Both ANOVA and RefFinder software determined that Actb was the preferred reference gene for skeletal muscle. Furthermore, NormFinder proposed that the optimal pairs of reference genes were beta-2 microglobulin (B2m)-Ppia in the liver, Ppia-TATA box binding protein (Tbp) in WAT, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (Ywhaz)-glyceraldehyde-3-phosphate dehydrogenase (Gapdh) in skeletal muscle, and that their stability value was better than that of a single stable gene. The appropriate reference gene pairs for normalizing genes of interest in mouse circadian studies are B2m-Ppia in the liver, Ppia-Tbp in WAT, and Ywhaz-Gapdh in skeletal muscle.
28409677	This study aims to describe the 24-hour activity rhythm in adults with attention-deficit/hyperactivity disorder (ADHD). A total of 18 ADHD patients and 37 healthy controls (HCs) wore an actigraph for 7 days. ADHD patients showed higher motor activity than HCs at 4:00, 6:00, 15:00 and 16:00 hour. Within the theoretical framework of the two-process model of sleep regulation, the observed data may be explained by lower homeostatic sleep pressure in ADHD. This could lead to an increase in motor activity in the second half of the night, when sleep need decreases more rapidly, and in the first half of the afternoon, when patients do not experience the typical post-lunch dip.
28409386	Published research has offered contradictory evidence of the occurrence of nocturnal oviposition by carrion-breeding blowflies, a behavior that can affect the interpretation of forensic estimates of a minimum post mortem interval (minPMI) by up to 12 hours, depending on latitude and season. The majority of published studies are from the northern hemisphere. Field experiments were conducted in South Africa and Australia that extend observations to species of the southern hemisphere. Various vertebrate carrion was exposed at night in summer under different lunar phases and/or artificial lighting, and in woodland and pasture areas. Three laboratory experiments were also conducted. No nocturnal oviposition occurred outdoors in Berry, Australia, but Lucilia cuprina, Lucilia sericata and Chrysomya megacephala laid eggs outdoors at night in Grahamstown and Durban, South Africa. In laboratory experiments L. sericata, L. cuprina, Chrysomya chloropyga and Chrysomya putoria laid eggs and Calliphora augur deposited larvae under nocturnal conditions. Chrysomya albiceps and C. chloropyga laid eggs in darkness with increasing likelihood as ambient temperature increased. This study shows that nocturnal ovi/larviposition by carrion-breeding blowflies is possible in both South Africa and Australia. The forensic issue is therefore not whether nocturnal oviposition occurs, but rather whether the conditions of a particular case are more or less conducive to it. Circadian rhythms and physiological thresholds (particularly temperature and humidity) appear to act individually and in conjunction to stimulate or inhibit nocturnal laying. The significance of carcass size, freezing and handling of carcasses and comprehensive quantification for experimental design is discussed, and recommendations are made for future laboratory and case scene experiments.
28408291	Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders caused by complex interplay between various genes and environmental factors during embryonic development. Changes at the molecular, cellular and neuroanatomical levels are especially evident in the medial prefrontal cortex (mPFC) of ASD patients and are particularly contributing to social impairments. In the present study we tested the hypothesis that altered neuronal development and plasticity, as seen in the mPFC of ASD individuals, may result from aberrant expression of functionally connected genes. Towards this end, we combined transcriptome sequencing and computational gene ontology analysis to identify the molecular networks impaired in the mPFC of a valproic acid (VPA) rat model of autism. This investigation identified two subsets of genes differentially expressed in the mPFC of VPA rats: one group of genes being functionally involved in the regulation of the circadian rhythm, while the second group encompasses a set of differentially expressed collagen genes acting within the extracellular matrix. Ultimately, our integrated transcriptome analysis identified a distinct subset of altered gene networks in the mPFC of VPA rats, contributing to our understanding of autism at the molecular level, thus providing novel insight into the genetic alterations associated with this neurodevelopmental disorder.

28407113	Circadian clocks are autonomous daily timekeeping mechanisms that allow organisms to adapt to environmental rhythms as well as temporally organize biological functions. Clock-controlled timekeeping involves extensive regulation of rhythmic gene expression. To date, relatively few clock-associated promoter elements have been identified and characterized. In an unbiased search of core clock gene promoters from 12 species of Drosophila, we discovered a 29-bp consensus sequence that we designated as the Clock-Associated Transcriptional Activation Cassette or 'CATAC'. To experimentally address the spatiotemporal expression information associated with this element, we generated constructs with four separate native CATAC elements upstream of a basal promoter driving expression of either the yeast Gal4 or firefly luciferase reporter genes. Reporter assays showed that presence of wild-type, but not mutated CATAC elements, imparted increased expression levels as well as rhythmic regulation. Part of the CATAC consensus sequence resembles the E-box binding site for the core circadian transcription factor CLOCK/CYCLE (CLK/CYC), and CATAC-mediated expression rhythms are lost in the presence of null mutations in either cyc or the gene encoding the CLK/CYC inhibitor, period (per). Nevertheless, our results indicate that CATAC's enhancer function persists in the absence of CLK/CYC. Thus, CATAC represents a novel cis-regulatory element encoding clock-controlled regulation.
28406083	Evaluation of mean blood pressure values, ambulatory arterial stiffness index (AASI), pulse pressure (PP), blood pressure variability (BPV), and circadian blood pressure rhythm using ambulatory blood pressure monitoring (ABPM) in children with IgA nephropathy and Henoch-Schönlein nephropathy (IgAN/HSN).In 48 children (29 with IgAN, 19 with HSN) aged 14.04 ± 3.76 years, we evaluated retrospectively 24-hour systolic and diastolic BP (24hSBP, 24hDBP), AASI, PP, systolic and diastolic BPV, and nocturnal BP dip by ABPM, body mass index (BMI) Z-score, medications, and biochemical parameters. The control group (CG) consisted of 20 healthy children aged 13.36 ± 4.12 years.	AASI was 0.369 ± 0.100 in IgAN, 0.346 ± 0.148 in HSN, and 0.300 ± 0.067 in the CG; AASI was significantly (p = 0.009) higher in IgAN vs. CG. PP was higher (P = 0.04) in IgAN vs. HSN. Based on ABPM data, poorly-controlled hypertension was found in 14 of 22 patients (63.6%) with previously diagnosed hypertension. No differences in BPV or nocturnal BP dip were found between the groups. In all children with IgAN/HSN, 24hDBP correlated significantly with proteinuria, cholesterol, triglycerides, and prednisone dose; BMI Z-score correlated with SBPV, DBPV, and PP.	1. Children with IgAN have higher arterial stiffness compared to healthy peers. 2. In children with IgAN/HSN, proteinuria and hyperlipidemia are risk factors for elevated diastolic blood pressure, while obesity is a risk factor for increased blood pressure variability and pulse pressure. 3. Pediatric patients with IgAN/HSN require regular ABPM evaluation to allow for early detection of poor pharmacological control of hypertension.
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28405929	Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated. In cancer cells, upregulation of the WNT/beta-catenin signaling induces dramatic changes in key metabolic enzymes that modify their thermodynamic behavior. This leads to activation of pyruvate dehydrogenase kinase1 (PDK-1) and monocarboxylate lactate transporter. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-coenzyme A (acetyl-CoA) in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. This leads to aerobic glycolysis in spite of the availability of oxygen. This phenomenon is referred to as the Warburg effect. Cytoplasmic pyruvate is converted into lactate. The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation, i.e., MYC and CYCLIN D1. This ultimately promotes the nucleotide, protein and lipid synthesis necessary for cell growth and multiplication. In cancer, activation of the PI3K-AKT pathway induces an increase of the aerobic glycolysis. Moreover, prostaglandin E2 by activating the canonical WNT pathway plays also a role in cancer. In addition in many cancer cells, PPAR gamma is downregulated. Moreover, PPAR gamma contributes to regulate some key circadian genes. In cancers, abnormalities in the regulation of circadian rhythms (CRs) are observed. CRs are dissipative structures which play a key-role in far-from-equilibrium thermodynamics. In cancers, metabolism, thermodynamics and CRs are intimately interrelated.
28405468	Animals exhibit circadian rhythms with a period of approximately 24 h in various physiological functions, including locomotor activity. This rhythm is controlled by an endogenous oscillatory mechanism, or circadian clock, which consists of cyclically expressed clock genes and their product proteins. cryptochrome (cry) genes are thought to be involved in the clock mechanism, and their functions have been examined extensively in holometabolous insects, but in hemimetabolous insects their role is less well understood.In the present study, the role of cry genes was investigated using RNAi technology in a hemimetabolous insect, the cricket Gryllus bimaculatus. Using a molecular cloning approach, we obtained cDNAs for two cry genes: Drosophila-type cry1 (Gb'cry1) and mammalian-type cry2 (Gb'cry2). Gb'cry2 has six splicing variants, most of which showed rhythmic mRNA expression. Gb'cry1RNAi treatment had only a limited effect at the behavioral and molecular levels, while Gb'cry2RNAi had a significant effect on behavioral rhythms and molecular oscillatory machinery, alone or in combination with Gb'cry1RNAi. In Gb'cry1/Gb'cry2 double-RNAi crickets, most clock genes showed arrhythmic expression, except for timeless, which retained clear rhythmic expression. Molecular analysis revealed that some combination of Gb'cry1 and Gb'cry2 variants suppressed CLK/CYC transcriptional activity in cultured cells.	Based on these results, we propose a new model of the cricket's circadian clock, including a molecular oscillatory loop for Gb'cry2, which can operate independent of the Gb'per/Gb'tim loop.	
28405243	To elucidate the effects of altered dietary carbohydrate and fat balance on liver and adipose tissue transcriptomes, 3-week-old rats were fed three kinds of diets: low-, moderate-, and high-fat diets (L, M, and H) containing a different ratio of carbohydrate-fat (C-F) (65:15, 60:20, and 35:45 in energy percent, respectively).The rats consumed the diets for 9 weeks and were subjected to biochemical and DNA microarray analyses.	The rats in the H-group exhibited lower serum triacylglycerol (TG) levels but higher liver TG and cholesterol content than rats in the L-group. The analysis of differentially expressed genes (DEGs) between each group (L vs M, M vs H, and L vs H) in the liver revealed about 35% of L vs H DEGs that were regulated in the same way as M vs H DEGs, and most of the others were L- vs H-specific. Gene ontology analysis of these L vs H DEGs indicated that those related to fatty acid synthesis and circadian rhythm were enriched. Interestingly, about 30% of L vs M DEGs were regulated in a reverse way compared with L vs H and M vs H DEGs. These reversed liver DEGs included M-up/H-down genes (Sds for gluconeogenesis from amino acids) and M-down/H-up genes (Gpd2 for gluconeogenesis from glycerol, Agpat9 for TG synthesis, and Acot1 for beta-oxidation). We also analyzed L vs H DEGs in white (WAT) and brown (BAT) adipose tissues and found that both oxidation and synthesis of fatty acids were inhibited in these tissues.	These results indicate that the alteration of dietary C-F balance differentially affects the transcriptomes of metabolizing and energy-storing tissues.	
28403234	Rhythmic activation and repression of the frequency (frq) gene are essential for normal function of the Neurospora circadian clock. WHITE COLLAR (WC) complex, the positive element of the Neurospora circadian system, is responsible for stimulation of frq transcription. We report that a C2H2 finger domain-containing protein IEC-1 and its associated chromatin remodeling complex INO80 play important roles in normal Neurospora circadian clock function. In iec-1KO strains, circadian rhythms are abolished, and the frq transcript levels are increased compared to that of the wild-type strain. Similar results are observed in mutant strains of the INO80 subunits. Furthermore, ChIP data show that recruitment of the INO80 complex to the frq promoter is IEC-1-dependent. WC-mediated transcription of frq contributes to the rhythmic binding of the INO80 complex at the frq promoter. As demonstrated by ChIP analysis, the INO80 complex is required for the re-establishment of the dense chromatin environment at the frq promoter. In addition, WC-independent frq transcription is present in ino80 mutants. Altogether, our data indicate that the INO80 complex suppresses frq transcription by re-assembling the suppressive mechanisms at the frq promoter after transcription of frq.
28403080	Diurnal variations in ventricular tachyarrhythmias (VAs) have been demonstrated in idiopathic arrhythmogenic heart disease. The electrophysiological characteristics of diurnal variations in idiopathic right ventricular outflow tract (RVOT) VA have not previously been elucidated. Sixty-two consecutive patients undergoing catheter ablation for idiopathic RVOT VA (mean age: 42.8 ± 12.3 years, 35 females) were enrolled. The diurnal variation type (group 1, n = 36) was defined as those patients who had most ventricular premature contractions (VPCs) during the night hours by preprocedure Holter recordings. Group 2 (n = 26) was defined as those patients who did not have significant VPC variations. The baseline characteristics and electrophysiological properties were collected and analyzed, and the rates of recurrence after catheter ablation were compared between the 2 groups. In this study, heart rate variability analysis demonstrated lower low frequency/high frequency ratios in group 1 than in group 2 (3.95 ± 3.08 vs 6.26 ± 5.33; P = 0.042). There were no significant differences in baseline characteristics, echocardiography and electrophysiological characteristics between the 2 groups. During a mean follow-up period of 13.5 ± 11.0 months, a total of 16 patients had VA recurrences, including 13 patients from group 1 and 3 patients from group 2 (36.1% vs 12.5%, P = 0.039). This study demonstrated the effect of the autonomic nervous system in idiopathic RVOT VAs and that the diurnal variation type leads to a higher recurrence rate after catheter ablation.
28402850	The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.
28402052	A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal ganglion cells project predominately to our biological clock, the suprachiasmatic nucleus (SCN). Light-induced vasopressin release enhances the responses of SCN neurons to light. It also enhances expression of genes involved in photo-entrainment of biological rhythms.In all animals, the transition between night and day engages a host of physiological and behavioural rhythms. These rhythms depend not on the rods and cones of the retina, but on retinal ganglion cells (RGCs) that detect the ambient light level in the environment. These project to the suprachiasmatic nucleus (SCN) of the hypothalamus to entrain circadian rhythms that are generated within the SCN. The neuropeptide vasopressin has an important role in this entrainment. Many SCN neurons express vasopressin, and it has been assumed that the role of vasopressin in the SCN reflects the activity of these cells. Here we show that vasopressin is also expressed in many retinal cells that project to the SCN. Light-evoked vasopressin release contributes to the responses of SCN neurons to light, and enhances expression of the immediate early gene c-fos in the SCN, which is involved in photic entrainment of circadian rhythms.	
28402026	The aim of this study was to evaluate the influence of rider's skill on the plasma cortisol levels of trekking horses on two courses, walking on field and forest courses (about 4.5 to 5.1 km each). Three riders of different skills did horse trekking (HT) in a tandem line under a fixed order: advanced-leading, beginner-second and intermediate-last. A total of six horses were used and they experienced all positions in both courses; a total of 12 experiments were done. Blood samples were obtained before HT, immediately after and 2 h after HT. As a control, additional blood samples were obtained from the same horses on non-riding days. Irrespective of the course and the rider's skill, the cortisol level before HT was higher than that of control (P < 0.05). In both courses, the cortisol levels immediately after HT ridden by the advanced rider were higher than that of control (P < 0.05). However, in every case, the cortisol level 2 h after HT was closely similar to the level of the control. Thus, we concluded the stress of trekking horse was not sufficient to disturb the circadian rhythm of the cortisol level, irrespective of the course and the rider's skill.
28401936	Patients with asthma experience circadian variations in their symptoms. However it remains unclear how specific aspects of this common airway disease relate to clock genes, which are critical to the generation of circadian rhythms in mammals. Here, we used a viral model of acute and chronic airway disease to examine how circadian clock disruption affects asthmatic lung phenotypes. Deletion of the core clock gene bmal1 or environmental disruption of circadian function by jet lag exacerbated acute viral bronchiolitis caused by Sendai virus (SeV) and influenza A virus in mice. Post-natal deletion of bmal1 was sufficient to trigger increased SeV susceptibility and correlated with impaired control of viral replication. Importantly, bmal1-/- mice developed much more extensive asthma-like airway changes post infection, including mucus production and increased airway resistance. In human airway samples from two asthma cohorts, we observed altered expression patterns of multiple clock genes. Our results suggest a role for bmal1 in the development of asthmatic airway disease via the regulation of lung antiviral responses to common viral triggers of asthma.Mucosal Immunology advance online publication, 12 April 2017; doi:10.1038/mi.2017.24.
28401917	The mammalian circadian timing system consists of the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and subsidiary peripheral clocks in other tissues. Glucocorticoids (GCs) are adrenal steroid hormones with widespread physiological effects that undergo daily oscillations. We previously demonstrated that the adrenal peripheral clock plays a pivotal role in circadian GC rhythm by driving cyclic GC biosynthesis. Here, we show that the daily rhythm in circulating GC levels is controlled by bimodal actions of central and adrenal clockwork. When mice were subjected to daytime restricted feeding to uncouple central and peripheral rhythms, adrenal GC contents and steroidogenic acute regulatory protein expression peaked around zeitgeber time 00 (ZT00), consistent with shifted adrenal clock gene expression. However, restricted feeding produced two distinct peaks in plasma GC levels: one related to adrenal GC content and the other around ZT12, which required an intact SCN. Light pulse-evoked activation of the SCN increased circulating GC levels in both wild-type and adrenal clock-disrupted mutant mice without marked induction of GC biosynthesis. In conclusion, we demonstrate that adrenal clock-dependent steroidogenesis and a SCN-driven central mechanism regulating GC release cooperate to produce daily circulatory GC rhythm.
28399169	Maize (Zea mays L.) is one of the major staple food crops of the world. However, high photoperiod sensitivity, especially for tropical germplasms, impedes attempts to improve maize agronomical traits by integration of tropical and temperate maize germplasms. Physiological and phenotypic responses of maize to photoperiod have widely been investigated based on multi-site field observations; however, proteome-based responsive mechanisms under controlled photoperiod regimes, nutrient and moisture soils are not yet well understood. In the present study, we sequenced and analyzed six proteomes of tropically-adapted and photoperiod-sensitive M9 inbred line at the vegetative 3 stage and proteomes from tropically-adapted and photoperiod-sensitive Shuang M9 (SM9) inbred line at the vegetative-tasseling stage. All plants were grown in growth chambers with controlled soil and temperature and three photoperiod regimes, a short photoperiod (SP) of 10 h light/14 h dark, a control neutral photoperiod (NP) of 12 h light/12 h dark, and a long photoperiod (LP) of 16 h light/8 h dark for a daily cycle. We identified 4,395 proteins of which 401 and 425 differentially-expressed proteins (DPs) were found in abundance in M9 leaves and in SM9 leaves as per SP/LP vs. NP, respectively. Some DPs showed responses to both SP and LP while some only responded to either SP or LP, depending on M9 or SM9. Our study showed that the photoperiodic response pathway, circadian clock rhythm, and high light density/intensity crosstalk with each other, but apparently differ from dark signaling routes. Photoperiod response involves light-responsive or dark-responsive proteins or both. The DPs positioned on the signaling routes from photoperiod changes to RNA/DNA responses involve the mago nashi homolog and glycine-rich RNA-binding proteins. Moreover, the cell-to-cell movement of ZCN14 through plasmodesmata is likely blocked under a 16-h-light LP. Here, we propose a photoperiodic model based on our findings and those from previous studies.
28398338	Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.
28397606	The eclosion gate in insect development is controlled by the circadian clock and hormonal cascade. To study mechanisms underlying the eclosion gate, we examined eclosion-timing signals from the circadian clock, and the role of 20-hydroxyecdysone in the eclosion gate of the flesh fly, Sarcophaga crassipalpis. Phase responses of the eclosion rhythm were examined by applying a low-temperature pulse in the day prior to the first eclosion peak. A low-temperature pulse applied about 5.4 h before eclosion advanced an eclosion peak by 0.9 h. This indicates that an interval from the Zeitgeber (external environmental cues) input to the behavioral output by the circadian clock is 4.5 h. Signals released by the circadian clock in the last 4.5 h before eclosion could change eclosion time. In the prothoracic gland, daily changes in immunoreactivity against a circadian clock protein PERIOD were observed in the last two days before eclosion. Hemolymph titers of 20-hydroxyecdysone were very low in the last two days of the pupal period. 20-hydroxyecdysone injections caused a delay, not an advancement, in eclosion time in a time dependent manner: pharate adults were sensitive to 20-hydroxyecdysone about 20 and 16 h before eclosion, whereas no significant effects were observed about 12 and 8 h before eclosion. These results suggest that 20-hydroxyecdysone is not a timing signal submitted by the circadian clock but an indicator to suppress premature eclosion. The circadian clock in the prothoracic gland presumably sends a signal distinct from ecdysteroids from several hours before eclosion to time the onset of eclosion.
28397310	Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders.
28396906	Studies focusing on the offspring of affected parents utilize the well-established familial aggregation of mood disorders as a powerful tool for the identification of risk factors, early clinical manifestations, and prodromes of mood disorders in these offspring. The major goals of the Lausanne-Geneva mood cohort study are to: (1) assess the familial aggregation of bipolar and unipolar mood disorders; (2) prospectively identify risk factors for mood disorders as well as their early signs and prodromes; (3) identify their endophenotypes including cognitive features, alterations in brain structure, HPA-axis dysregulation, and abnormalities of the circadian rhythm of activity.Probands with bipolar disorders, major depressive disorder, and controls with at least one child aged from 4 to 17.9 years at study intake, their offspring, as well as their spouses are invited to take part in follow-up assessments at predetermined ages of the offspring. Direct semi-structured diagnostic interviews have been used for all participants. Probands, spouses, and adult offspring also undergo neurocognitive testing, anthropomorphic measures and biochemical exams, structural Magnetic Resonance Imaging, as well as objective assessments of physical activity using accelerometers in combination with ecological momentary assessments.	Currently, our study has up to seven follow-up assessments extending over a period of 20 years. There are 214 probands and 389 offspring with one direct interview before age 18 as well as a second assessment over follow-up. Data on 236 co-parents are also available from whom 55% have been directly interviewed. First publications support the specificity of the familial aggregation of BPD and the strong influence of an early onset of the parental BPD, which amplifies the risk of developing this disorder in offspring.	Information from clinical, biological, cognitive, and behavioral measures, based on contemporary knowledge, should further enhance our understanding of mood disorder psychopathology, its consequences, and underlying mechanisms.	
28395871	Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD.We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice.	We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice.	We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.	
28391254	Cushing's syndrome is rare in childhood and is usually caused by a pituitary adenoma. Primary hyperfunction of adrenal glands is less frequent, particularly primary pigmented nodular adrenocortical disease (PPNAD). It occurs usually in children and adolescents, with female preponderance, while Cushing's disease has increased frequency in prepubertal males. A case of a 6-year-old boy is presented with isolated non-familiar PPNAD. The clinical pattern involved Cushingoid appearance, hypertension, virilization and depressive mood. Laboratory analyses showed loss of circadian rhythm of cortisol, undetectable adrenocorticotropic hormone (ACTH) level, impaired fasting glucose, polycythemia and elevated white blood count (WBC). Radiology investigation revealed a slightly enlarged medial branch of the left adrenal gland and a normal right one, so a unilateral adrenalectomy was performed. Pathohistology described multiple dark brownish pigmented nodules of various sizes confined to the cortex. Contralateral adrenalectomy was done 3 months later. Follow-up of 3 years was uneventful, except for one adrenal crisis during an intercurrent respiratory illness.
28391049	Most cyanobacteria are obligate oxygenic photoautotrophs, and thus their growth and survival is highly dependent on effective utilization of incident light. Cyanobacteria have evolved a diverse set of phytochromes and cyanobacteriochromes (CBCRs) that allow cells to respond to light in the range from ∼300nm to ∼750nm. Together with associated response regulators, these photosensory proteins control many aspects of cyanobacterial physiology and metabolism. These include far-red light photoacclimation (FaRLiP), complementary chromatic acclimation (CCA), low-light photoacclimation (LoLiP), photosystem content and stoichiometry (long-term adaptation), short-term acclimation (state transitions), circadian rhythm, phototaxis, photomorphogenesis/development, and cellular aggregation. This minireview highlights some discoveries concerning phytochromes and CBCRs as well as two acclimation processes that improve light harvesting and energy conversion under specific irradiance conditions: FaRLiP and CCA.
28390292	A possible mechanism of disrupted circadian rhythms in delirium was identified using resting-state functional connectivity. Thirty-four delirious patients and 38 non-delirious controls were scanned for resting-state functional MRI. Seed-based connectivity of the suprachiasmatic nucleus was compared between the groups. In delirious patients functional connectivity from the circadian clock was increased to the dorsal anterior cingulate cortex and decreased to the posterior cingulate cortex, parahippocampal gyrus, cerebellum, and thalamus. A dysregulation of the default mode network and mental coordination processing areas by the circadian clock may be the underlying pathophysiology of sleep-wake cycle disturbance and symptom fluctuation in delirium.
28389273	A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment.
28389048	Neuromedin S (NMS) has been identified as an endogenous ligand for FM-3/GPR66 and FM-4/TGR-1 which are NMU receptors NMUR1 and NMUR2, respectively. The NMS molecule is present in some peripheral tissues and the central nervous system (CNS), and it had been documented that NMS has fundamental and important roles in multiple physiological functions and processes such as circadian rhythm, energy balance, feeding behavior, stress responses and reproduction. The possible role of NMS in sexual development postnatally, however, is still obscure. This study aims to determine the change of NMS and its receptor gene expression in the reproductive axis of male Xiaomeishan pigs, postnatally. Firstly, the cDNA of the NMS and its receptors was cloned and sequenced. The results showed that there was a lack of 12 amino acids in the C-terminal of the male Xiaomeishan pig NMS amino-acid sequences compared with other animal species, but the main protein structure of prepro-NMS was high in homology. In addition, the nucleotide sequence and amino acids of the male Xiaomeishan pig's NMUR1 and NMUR2 had high homology. The NMS and NMUR2 mRNA in the male Xiaomeishan pig was detected in the reproductive axis at postnatal development stages, including postnatal day 3, 30, 60, 90 and 120, using real-time PCR and immunohistochemistry. The data showed that there were developmental changes in NMS and NMUR2 in the reproductive axis of the male Xiaomeishan pigs, postnatally, which suggested that NMS and NMUR2 might have a role in the development of the boar reproductive axis, but its regulatory mechanism remains to be elucidated.
28388556	Cancers adversely affect organismal physiology. To date, the genes within a patient responsible for systemically spreading cancer-induced physiological disruption remain elusive. To identify host genes responsible for transmitting disruptive, cancer-driven signals, we thoroughly analyzed the transcriptome of a suite of host organs from mice bearing 4T1 breast cancer, and discovered complexly rewired patterns of circadian gene expression in the liver. Our data revealed that 7 core clock transcription factors, represented by Rev-erba and Rorg, exhibited abnormal daily expression rhythm in the liver of 4T1-bearing mice. Accordingly, expression patterns of specific set of downstream circadian genes were compromised. Osgin1, a marker for oxidative stress, was an example. Specific downstream genes, including E2f8, a transcriptional repressor that controls cellular polyploidy, displayed a striking pattern of disruption, "day-night reversal." Meanwhile, we found that the liver of 4T1-bearing mice suffered from increased oxidative stress. The tetraploid hepatocytes population was concomitantly increased in 4T1-bearing mice, which has not been previously appreciated as a cancer-induced phenotype. In summary, the current study provides a comprehensive characterization of the 4T1-affected hepatic circadian transcriptome that possibly underlies cancer-induced physiological alteration in the liver.
28388457	Background Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation strategy for treatment-refractory OCD. However, a substantial group still fails to respond. Sleep disorders, e.g. circadian rhythm sleep disorders (CRSD), are highly prevalent in OCD and might mediate treatment response. The aims of the current study were to compare sleep disturbances between OCD patients and healthy subjects as well as between rTMS responders and non-responders, and most importantly to determine sleep-related predictors of rTMS non-response. Methods 22 OCD patients received at least 10 sessions rTMS combined with psychotherapy. Sleep disturbances were measured using questionnaires and actigraphy. Sleep in patients was compared to healthy subjects. Treatment response was defined as >35% reduction on YBOCS. Treatment response prediction models were based on measures of CRSD and insomnia. Results Sleep disturbances were more prevalent in OCD patients than healthy subjects. The OCD group consisted of 12 responders and 10 non-responders. The CRSD model could accurately predict non-response with 83% sensitivity and 63% specificity, whereas the insomnia model could not. Conclusions CRSD is more prevalent in OCD patients than healthy subjects, specifically in rTMS non-responders. Therefore, CRSD may serve as a biomarker for different subtypes of OCD corresponding with response to specific treatment approaches.
28388438	ATAXIN-2 (ATX2) has been implicated in human neurodegenerative diseases, yet it remains elusive how ATX2 assembles specific protein complexes to execute its physiological roles. Here we employ the posttranscriptional co-activator function of Drosophila ATX2 to demonstrate that LSM12 and ME31B/DDX6 are two ATX2-associating factors crucial for sustaining circadian rhythms. LSM12 acts as a molecular adaptor for the recruitment of TWENTY-FOUR (TYF) to ATX2. The ATX2-LSM12-TYF complex thereby stimulates TYF-dependent translation of the rate-limiting clock gene period (per) to maintain 24 hr periodicity in circadian behaviors. In contrast, ATX2 contributes to NOT1-mediated gene silencing and associates with NOT1 in a ME31B/DDX6-dependent manner. The ME31B/DDX6-NOT1 complex does not affect PER translation but supports high-amplitude behavioral rhythms along with ATX2, indicating a PER-independent clock function of ATX2. Taken together, these data suggest that the ATX2 complex may switch distinct modes of posttranscriptional regulation through its associating factors to control circadian clocks and ATX2-related physiology.
28388406	Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.
28386434	Repeatable between-individual differences in the behavioural manifestation of underlying circadian rhythms determine chronotypes in humans and terrestrial animals. Here, we have repeatedly measured three circadian behaviours, awakening time, rest onset and rest duration, in the free-ranging pearly razorfish, Xyrithchys novacula, facilitated by acoustic tracking technology and hidden Markov models. In addition, daily travelled distance, a standard measure of daily activity as fish personality trait, was repeatedly assessed using a State-Space Model. We have decomposed the variance of these four behavioural traits using linear mixed models and estimated repeatability scores (R) while controlling for environmental co-variates: year of experimentation, spatial location of the activity, fish size and gender and their interactions. Between- and within-individual variance decomposition revealed significant Rs in all traits suggesting high predictability of individual circadian behavioural variation and the existence of chronotypes. The decomposition of the correlations among chronotypes and the personality trait studied here into between- and within-individual correlations did not reveal any significant correlation at between-individual level. We therefore propose circadian behavioural variation as an independent axis of the fish personality, and the study of chronotypes and their consequences as a novel dimension in understanding within-species fish behavioural diversity.
28386121	Living systems exhibit non-randomly organized biochemical, physiological, and behavioral processes that follow distinctive patterns. In particular, animal behavior displays both fractal dynamics and periodic rhythms yet the relationship between these two dynamic regimens remain unexplored. Herein we studied locomotor time series of visually isolated Japanese quails sampled every 0.5 s during 6.5 days (>106 data points). These high-resolution, week-long, time series enabled simultaneous evaluation of ultradian rhythms as well as fractal organization according to six different analytical methods that included Power Spectrum, Enright, Empirical Mode Decomposition, Wavelet, and Detrended Fluctuation analyses. Time series analyses showed that all birds exhibit circadian rhythms. Although interindividual differences were detected, animals presented ultradian behavioral rhythms of 12, 8, 6, 4.8, 4 h and/or lower and, irrespective of visual isolation, synchronization between these ultradian rhythms was observed. Moreover, all birds presented similar overall fractal dynamics (for scales ∼30 s to >4.4 h). This is the first demonstration that avian behavior presents fractal organization that predominates at shorter time scales and coexists with synchronized ultradian rhythms. This chronobiological pattern is advantageous for keeping the organism's endogenous rhythms in phase with internal and environmental periodicities, notably the feeding, light-dark and sleep-wake cycles.
28384423	Interest in the ecology of stress in wild populations has triggered the development of noninvasive methods for quantifying stress hormones. Measurement of fecal corticosteroid metabolites (FCMs) is one such method, but it is still unclear whether FCMs can be a reliable proxy of free plasma glucocorticoids. To assess the validity of this assumption, we carried out a robust assessment on brown lemmings (Lemmus trimucronatus) from Bylot Island, Nunavut, Canada, that were hand captured and anesthetized and related plasma glucocorticoid levels to fecal metabolite glucocorticoid levels. We examined endogenous factors that could explain interindividual variability. Blood corticosterone was measured from samples obtained on capture and 30 min later, and FCM levels were measured from animals kept in captivity for 72 h. Plasma free corticosterone increased 135-fold over baseline values 30 min after capture, which confirmed that initial handling was perceived as a stressor. We found that FCM levels were highly related with free (marginal [Formula: see text] = 0.53) but not with total ([Formula: see text] = 0.02) corticosterone levels, regardless of age, sex, and reproductive condition. FCM levels started increasing 2 h after capture and reached maximum levels 4 h after capture. No circadian rhythm in FCMs was found. Plasma total corticosterone levels were much higher in adult females compared with adult males, but this difference was much smaller when measuring free corticosterone levels and FCM levels. Our results suggest that FCM levels are good measures of stress by being closely related to plasma free corticosterone levels in brown lemmings.
28384165	During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance.To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors.	Healthy young volunteers (5 females, 18 males; mean age +SEM = 23.2 +1.2 years) were evaluated before Ramadan and two weeks into it. Blood samples were collected at 9 am (±1 hour) and twelve hours later for determination of serum lipid profile, high sensitivity CRP (hsCRP), and adiponectin. The expression of CLOCK, DUSP1 and IL-1α was evaluated in circulating leukocytes.	Mean levels of GGT and morning adiponectin decreased, while those of LDL-c/ HDL-c and atherogenic index (AI) increased significantly in Ramadan compared to Shabaan. There was no significant difference between morning and evening adiponectin during Ramadan, while the diurnal rhythm of hsCRP was lost. CLOCK gene expression mean was significantly higher in morning than in evening during Shabaan. Mean morning and evening DUSP1 mRNA levels showed significant increase during Ramadan compared to Shabaan, however, its diurnal rhythm was maintained. Morning IL-1α mRNA expression remained significantly higher than in the evening during Ramadan, but was markedly decreased compared to Shabaan.	Ramadan fasting in Saudi Arabia is associated with improvements in some cardiometabolic risk factors, such as circulating GGT and hsCRP and leukocyte expression of IL-1α mRNA, suggesting that intermittent fasting might have a beneficial component. These benefits may be offset by the previously reported dysregulation in the circadian rhythm, excess glucocorticoid levels and action, and insulin resistance, explaining increased prevalence of cardiometabolic disorders and type 2 diabetes mellitus.	
28382018	The circadian clock is an endogenous oscillator that drives daily rhythms in physiology, behavior, and gene expression. The underlying mechanisms of circadian timekeeping are cell-autonomous and involve oscillatory expression of core clock genes that is driven by interconnecting transcription-translation feedback loops (TTFLs). Circadian clock TTFLs are further regulated by posttranslational modifications, in particular, phosphorylation. The hippocampus plays an important role in spatial memory and the conversion of short- to long-term memory. Several studies have reported the presence of a peripheral oscillator in the hippocampus and have highlighted the importance of circadian regulation in memory formation. Given the general importance of phosphorylation in circadian clock regulation, we performed global quantitative proteome and phosphoproteome analyses of the murine hippocampus across the circadian cycle, applying spiked-in labeled reference and high accuracy mass spectrometry (MS). Of the 3,052 proteins and 2,868 phosphosites on 1,368 proteins that were accurately quantified, 1.7% of proteins and 5.2% of phosphorylation events exhibited time-of-day-dependent expression profiles. The majority of circadian phosphopeptides displayed abrupt fluctuations at mid-to-late day without underlying rhythms of protein abundance. Bioinformatic analysis of cyclic phosphorylation events revealed their diverse distribution in different biological pathways, most notably, cytoskeletal organization and neuronal morphogenesis. This study provides the first large-scale, quantitative MS analysis of the circadian phosphoproteome and proteome of the murine hippocampus and highlights the significance of rhythmic regulation at the posttranslational level in this peripheral oscillator. In addition to providing molecular insights into the hippocampal circadian clock, our results will assist in the understanding of genetic factors that underlie rhythms-associated pathological states of the hippocampus.
28382017	The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer's disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders.
28381314	Isoflurane anesthesia alters the blood levels of several neuroendocrine hormones associated with normal metabolism and physiology and increases stress, but the effect of brief CO2 anesthesia on these parameters is unknown. In this study, we examined the effects of isoflurane (4%) compared with brief CO2 (70% CO2, 30% air) anesthesia on circadian rhythms of plasma measures of physiology and metabolism. Adult male Sprague-Dawley rats (Crl:SD; n = 6 per group) were maintained on a 12:12-h light:dark (300 lx; lights on, 0600) photoperiod. After 1 wk of acclimation, a series of 6 low-volume blood draws were collected by cardiocentesis under anesthesia using isoflurane (10 min or less) compared with CO2 (1 min or less) at a single circadian time point every 4 d (0400, 0800, 1200, 1600, 2000, or 2400) over 3 wk to assess arterial blood glucose, lactic acid, and potassium and plasma melatonin, leptin, insulin, total fatty acids, and corticosterone concentrations. Results revealed that plasma levels (mean ± SEM) of melatonin were low (11 ± 1 pg/mL) during the light phase in both groups but were significantly lower during the dark phase in the isoflurane group (48 ± 6 pg/mL) compared with the CO2 group (162 ± 18 pg/mL). In addition, prominent circadian rhythms of arterial plasma levels of corticosterone, glucose, total fatty acids, lactic acid, and potassium were altered in the isoflurane group compared with the CO2 group. These findings demonstrate that the normal circadian rhythms of endocrine physiology and metabolism observed during brief CO2 anesthesia in rats are markedly disrupted by isoflurane anesthesia.
28380384	The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, ∼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.
28380364	The small ventral lateral neurons (sLNvs) constitute a central circadian pacemaker in the Drosophila brain. They organize daily locomotor activity, partly through the release of the neuropeptide pigment-dispersing factor (PDF), coordinating the action of the remaining clusters required for network synchronization. Despite extensive efforts, the basic principles underlying communication among circadian clusters remain obscure. We identified classical neurotransmitters released by sLNvs through disruption of specific transporters. Adult-specific RNAi-mediated downregulation of the glycine transporter or impairment of glycine synthesis in LNv neurons increased period length by nearly an hour without affecting rhythmicity of locomotor activity. Electrophysiological recordings showed that glycine reduces spiking frequency in circadian neurons. Interestingly, downregulation of glycine receptor subunits in specific sLNv targets impaired rhythmicity, revealing involvement of glycine in information processing within the network. These data identify glycinergic inhibition of specific targets as a cue that contributes to the synchronization of the circadian network.
28379565	Increased evening cortisol levels, observed with aging and psychological stress, have been implicated in bone mineral density (BMD) loss. The effect on bone microarchitecture and fracture risk has never been studied.To study the relationship between salivary cortisol circadian rhythm and: 1) Trabecular Bone Score (TBS), a texture parameter correlated with bone microarchitecture, 2) fracture prevalence.	Cross-sectional study including 608 women >50 years old (mean 65.5) from OsteoLaus cohort. Data included: FRAX© questionnaire, BMD, TBS and vertebral fracture (VFx) assessment by dual X-ray absorptiometry, and measures of salivary cortisol circadian rhythm (awakening, 30 minutes thereafter, 11 AM and 8 PM).	In the multivariate model, participants in the highest tertile of 8PM salivary cortisol (sc-8PM) (mean 5.7±2.5 nmol/l) versus lowest tertile (1.7±0.4 nmol/l) had lower TBS values (1.27 vs. 1.29; p=0.02), more prevalent VFx grades 2 and 3 (OR 5.34; p=0.012), low-trauma fractures (OR 1.80; p=0.036) and major osteoporotic fractures (OR 1.96; p=0.042), without difference in lumbar spine BMD (0.91 vs. 0.92 g/cm2; p=0.431). VFx prevalence was associated with sc-8PM and TBS independently of each other, and of all other risk factors. The cut point for sc-8PM correlating with the presence of >1 VFx was 3.62 nmol/l (sensitivity 0.74, specificity 0.66).	High sc-8PM is associated with low TBS and an increased prevalence of radiologic VFx independently of other risk factors. Measurement of salivary cortisol at 8PM may add relevant information in the assessment of fracture risk.	
28377415	Since the publication of the International Agency for Research on Cancer Monograph in 2007 classifying night shift work leading to a disruption of circadian rhythm as probably carcinogenic to humans, there is an increasingly growing interest in understanding how circadian disruption may play a role in cancer development.This systematic review provides a comprehensive update on epidemiologic evidences on circadian disruption and prostate cancer since the last review published in 2012. We identified 12 new studies evaluating the effects of several circadian disruptors such as night shift work, sleep patterns, and circadian genes in prostate cancer risk. In contrast, no new studies have focused on exposure to light at night.Several convincing and biologically plausible hypotheses have been proposed to understand how circadian disruption may be related to cancer. However, the current difficulty of concluding on the role of circadian disruption on prostate cancer risk requires further studies including a better characterization of the different night shift systems, data on sleep patterns and chronotype, measurement of biomarkers, and investigations of polymorphisms in the genes regulating the biological clock. Cancer Epidemiol Biomarkers Prev; 26(7); 985-91. ©2017 AACR.
28376115	Recent studies support plasticity in adult brain white matter structure and myelination in response to various experiential factors. One possible contributor to this plasticity may be activity-dependent modulation of serum- and glucocorticoid-inducible kinase 1 (Sgk1) expression in oligodendrocytes. We examined whether Sgk1 expression in adult rat brain white matter is increased by acute stress-induced elevations in endogenous corticosterone and whether it fluctuates with diurnal variations in corticosterone. We observed rapid increases (within 30 min) in Sgk1 mRNA in the corpus callosum in response to acute stress, as well as large increases at the beginning of the rat's active period (the time of peak corticosterone secretion). These increases were absent in adrenalectomized rats. Corticosterone treatment of adrenalectomized rats also rapidly increased corpus callosum Sgk1 mRNA. The majority of Sgk1 mRNA in corpus callosum was co-localized with myelin basic protein mRNA, suggesting that mature oligodendrocytes respond dynamically to acute stress and circadian rhythms. The regulation of Sgk1 expression by acute stress and time of day was selective for white matter, with limited alteration of Sgk1 expression by these factors in hippocampus and somatosensory cortex. These results indicate a unique sensitivity of oligodendrocyte Sgk1 expression to activity-dependent fluctuations in corticosterone hormone secretion, and raises the prospect that hypothalamic-pituitary-adrenal axis dysregulation or glucocorticoid pharmacotherapy may compromise the normal activity-dependent interactions between oligodendrocytes and neurons.
28375324	There are several wearable products specially developed or marketed for studying sleep, circadian rhythms, and light levels. However, new recommendations relating to human physiological responses to light have changed what measurements researchers may demand. The performances of 11 light-logging dosimeters from eight manufacturers were compared. The directional and spectral sensitivities, linearity, dynamic range, and resolution were tested for seven models, and compared along with other published data. The sample mainly comprised light-logging actigraphy dosimeters wearable as badges, in accordance with measurement protocols for larger-scale field studies. A proposed standard for optical performance assessments is set out.
28374011	The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.
28373831	Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the "control" of the "master biological clock" reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.
28373805	Restless legs syndrome (RLS) is associated with dysfunction of the dopaminergic systems in the pathways that specifically link the sensory input and motor output. Keeping in mind that clinical symptomatology in RLS and cerebrospinal fluid dopamine concentrations in healthy individuals show changes throughout the day, we hypothesized that excitability of the related pathways increases during the night in RLS, and in the present study, we aimed to analyze our hypothesis by the assessment of blink reflex (BR) recovery.Eleven patients with primary RLS and eight age- and gender-matched healthy subjects were included in the study. All participants underwent detailed interviews and neurological examinations. BR responses were recorded after single and paired supraorbital stimulation during the early afternoon and late at night. For double stimulation, interstimulus intervals (ISI) of 100, 300, and 500 ms were used. Daytime and nighttime investigations were separately compared between the patient and control groups (between-group analyses). In-group analyses were conducted between daytime and nighttime investigations of the patient and control groups.	BR responses to single stimuli were normal in all participants at all sessions. R2 recovery was the highest in the patient group during nighttime investigations. In-group analysis showed a reduction of R2 recovery during the night in healthy subjects. R2 recoveries at ISIs of 300 and 500 ms at nighttime were higher in RLS patients but did not reach statistical significance.	The BR circuit is less excitable during the night in healthy individuals, whereas the reduction of excitability is lost in RLS. Despite the limited number of included subjects, we suggest that the normal circadian modulation of the BR circuit is lost in RLS.	
28373692	Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.54.
28371363	The vertebrate retina contains a circadian clock participating in adaptations to day and night vision. This peripheral clock is independent of the master clock in the suprachiasmatic nucleus (SCN). The retinal clock is located in several cell types, including the photoreceptors. To investigate the role of the circadian clock of the photoreceptor cells in regulation of retinal protein rhythms, we analysed diurnal protein expression in the photoreceptor-deficient cone-rod homeobox knockout mouse (Crx-/- ) and the 129/Sv mouse.2D gels were made from retinal homogenates of 129/Sv and Crx-/- mice killed at midday and midnight. Stained gels were analysed by use of PDQuest 2D gel analysis software. After trypsin digestion of differential expressed spots, the proteins were identified by LC-MS/MS using a nano-liquid chromatograph connected to a Q-TOF Premier mass spectrometer. These data were used to search the SWISS-PROT database.	Both the retinae of the control and the Crx-/- mice exhibited diurnal proteins rhythms. As expected, proteins involved in phototransduction were not detected in the Crx-/- mouse; in this phenotype, however, proteins from spots showing diurnal rhythms were specifically identified as enzymes involved in glucose metabolism, Krebs cycle, and mitochondrial enzymes. Data are available via ProteomeXchange with identifier PXD005556.	We show diurnal protein rhythms in the retina of a mouse lacking the rods and cones. The diurnal protein rhythms in this genotype, lacking the circadian clock of the photoreceptors, might be caused by a circadian clock in other retinal cell types or a direct light input to the retina.	
28370506	Food intake during the rest phase promotes circadian desynchrony, which has been associated with metabolic diseases. However, the link between circadian rhythm and metabolic alterations is not well understood. To investigate this issue, we explored the circadian rhythm of c-Fos immunoreactivity (IR) in rats fed during the day, during the night or with free access to food for 3 weeks. The analysis was focused on the hypothalamic nuclei, which are interconnected and involved in the control of energy homeostasis and/or arousal: lateral hypothalamus (LH), perifornical area, arcuate, ventrolateral pre-optic (VLPO) and tuberomammillary nuclei. The results show that food intake during the rest phase flattened the circadian c-Fos expression in the LH and perifornical area, and induced a phase shift in the VLPO area. In addition, c-Fos expression was analyzed in the orexin and melanin-concentrating hormone (MCH) neurons of the LH, which are involved in the control of food intake and arousal, and in α-melanin-stimulating hormone and neuropeptide Y (NPY) cells in the arcuate nucleus, all of which are involved in feeding-fasting cycles, energy homeostasis and sending projections to the LH. The results indicate that feeding during the rest phase decreased orexin neuron activation in the light in comparison with the other groups. Feeding during this phase also flattened the activity rhythm of MCH and α-melanin-stimulating hormone neurons and increased NPY IR when the light was turned on. This evidence indicates that mealtime differentially affected the hypothalamic nuclei under investigation leading to a circadian conflict that might account for metabolic impairment.
28369217	Comparative genomics studies typically limit their focus to single nucleotide variants (SNVs) and that was the case for previous comparisons of woolly mammoth genomes. We extended the analysis to systematically identify not only SNVs but also larger structural variants (SVs) and indels and found multiple mammoth-specific deletions and duplications affecting exons or even complete genes. The most prominent SV found was an amplification of RNase L (with different copy numbers in different mammoth genomes, up to 9-fold), involved in antiviral defense and inflammasome function. This amplification was accompanied by mutations affecting several domains of the protein including the active site and produced different sets of RNase L paralogs in four mammoth genomes likely contributing to adaptations to environmental threats. In addition to immunity and defense, we found many other unique genetic changes in woolly mammoths that suggest adaptations to life in harsh Arctic conditions, including variants involving lipid metabolism, circadian rhythms, and skeletal and body features. Together, these variants paint a complex picture of evolution of the mammoth species and may be relevant in the studies of their population history and extinction.
28368352	In this study, the aim was to test the biochemical effects of melatonin supplementation in Intensive Care Unit (ICU) patients, since their blood levels are decreased. Sixty-four patients were enrolled in the study. From the evening of the 3rd ICU day, patients were randomized to receive oral melatonin (3 mg, group M) or placebo (group P) twice daily, at 20:00 and 24:00, until discharged. Blood was taken (at 00:00 and 14:00), on the 3rd ICU day to assess basal nocturnal melatonin values, and then during the treatment period on the 4th and 8th ICU days. Melatonin, total antioxidant capacity, and oxidative stress were evaluated in serum. Melatonin circadian rhythm before treatment was similar in the two groups, with a partial preservation of the cycle. Four hours from the 1st administration (4th ICU day, 00:00), melatonin levels increased to 2514 (982.3; 7148) pg·mL-1 in group M vs. 20.3 (14.7; 62.3) pg·mL-1 in group P (p < 0.001). After five treatment days (8th ICU day), melatonin absorption showed a repetitive trend in group M, while in group P nocturnal secretion (00:00) was impaired: 20 (11.5; 34.5) pg·mL-1 vs. 33.8 (25.0; 62.2) on the 3rd day (p = 0.029). Immediately from the beginning of treatment, the total antioxidant capacity was significantly higher in melatonin treated subjects at 00:00; a significant correlation was found between total antioxidant capacity and blood melatonin values (ρ = 0.328; p < 0.001). The proposed enteral administration protocol was adequate, even in the early phase, to enhance melatonin blood levels and to protect the patients from oxidative stress. The antioxidant effect of melatonin could play a meaningful role in the care and well-being of these patients.
28368307	Melatonin is a molecule which has gained a great deal of interest in many areas of science; its synthesis was classically known to be in the pineal gland. However, many organs synthesize melatonin, such as several ocular structures. Melatonin is known to participate in many functions apart from its main action regulating the circadian rhythm. It is synthesized from serotonin in two steps, with a rate-limiting step carried out by arylalkymine N-acetyltransferase (AANAT). In this report, the role of TRPV4 channel present in human ciliary body epithelial cells in AANAT production was studied. Several experiments were undertaken to verify the adequate time to reach the maximal effect by using the TRPV4 agonist GSK1016790A, together with a dose-response study. An increase of 2.4 folds in AANAT was seen after 18 h of incubation with 10 nM of GSK1016790A (p < 0.001, n = 6). This increment was verified by antagonist assays. In summary, AANAT levels and therefore melatonin synthesis change after TRPV4 channel stimulation. Using this cell model together with human ciliary body tissue it is possible to suggest that AANAT plays an important role in pathologies related to intraocular pressure.
28368004	Circadian and seasonal rhythms are seen in many species, modulate several aspects of human physiology, including brain functions such as mood and cognition, and influence many neurological and psychiatric illnesses. However, there are few data regarding the genome-scale molecular correlates underlying these rhythms, especially in the human brain. Here, we report widespread, site-specific and interrelated diurnal and seasonal rhythms of gene expression in the human brain, and show their relationship with parallel rhythms of epigenetic modification including histone acetylation, and DNA methylation. We also identify transcription factor-binding sites that may drive these effects. Further, we demonstrate that Alzheimer's disease pathology disrupts these rhythms. These data suggest that interrelated diurnal and seasonal epigenetic and transcriptional rhythms may be an important feature of human brain biology, and perhaps human biology more broadly, and that changes in such rhythms may be consequences of, or contributors to, diseases such as Alzheimer's disease.
28367676	Within the human population, there is large interindividual variability in the timing of sleep and circadian rhythms. This variability has been attributed to individual differences in sleep physiology, circadian physiology, and/or light exposure. Recent experimental evidence suggests that the latter is necessary to evoke large interindividual differences in sleep and circadian timing. We used a validated model of human sleep and circadian physiology to test the hypothesis that intrinsic differences in sleep and circadian timing are amplified by self-selected use of artificial light sources. We tested the model under 2 conditions motivated by an experimental study (Wright et al., 2013): (1) a "natural" light cycle, and (2) a "realistic" light cycle that included attenuation of light due to living indoors when natural light levels are high and use of electric light when natural light levels are low. Within these conditions, we determined the relationship between intrinsic circadian period (within the range of 23.7-24.6 h) and timing of sleep onset, sleep offset, and circadian rhythms. In addition, we simulated a work week, with fixed wake time for 5 days and free sleep times on weekends. Under both conditions, a longer intrinsic period resulted in later sleep and circadian timing. Compared to the natural condition, the realistic condition evoked more than double the variation in sleep timing across the physiological range of intrinsic circadian periods. Model predictions closely matched data from the experimental study. We found that if the intrinsic circadian period was long (>24.2 h) under the realistic condition, there was significant mismatch in sleep timing between weekdays and weekends, which is known as social jetlag. These findings indicate that individual tendencies to have very delayed schedules can be greatly amplified by self-selected modifications to the natural light/dark cycle. This has important implications for therapeutic treatment of advanced or delayed sleep phase disorders.
28367108	Ageing is an inevitable biological process that results in a progressive structural and functional decline, as well as biochemical alterations that altogether lead to reduced ability to adapt to environmental changes. As clock oscillations and clock-controlled rhythms are not resilient to the aging process, aging of the circadian system may also increase susceptibility to age-related pathologies such as Alzheimer's disease (AD). Besides the amyloid-beta protein (Aβ)-induced metabolic decline and neuronal toxicity in AD, numerous studies have demonstrated that the disruption of sleep and circadian rhythms is one of the common and earliest signs of the disease. In this study, we addressed the questions of whether Aβ contributes to an abnormal molecular circadian clock leading to a bioenergetic imbalance. For this purpose, we used different oscillator cellular models: human skin fibroblasts, human glioma cells, as well as mouse primary cortical and hippocampal neurons. We first evaluated the circadian period length, a molecular clock property, in the presence of different Aβ species. We report here that physiologically relevant Aβ1-42 concentrations ranging from 10 to 500 nM induced an increase of the period length in human skin fibroblasts, human A172 glioma cells as well as in mouse primary neurons whereas the reverse control peptide Aβ42-1, which is devoid of toxic action, did not influence the circadian period length within the same concentration range. To better understand the underlying mechanisms that are involved in the Aβ-related alterations of the circadian clock, we examined the cellular metabolic state in the human primary skin fibroblast model. Notably, under normal conditions, ATP levels displayed circadian oscillations, which correspond to the respective circadian pattern of mitochondrial respiration. In contrast, Aβ1-42 treatment provoked a strong dampening in the metabolic oscillations of ATP levels as well as mitochondrial respiration and in addition, induced an increased oxidized state. Overall, we gain here new insights into the deleterious cycle involved in Aβ-induced decay of the circadian rhythms leading to metabolic deficits, which may contribute to the failure in mitochondrial energy metabolism associated with the pathogenesis of AD.
28366864	Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.
28366622	Circadian clocks have evolved to synchronize physiology, metabolism and behaviour to the 24-h geophysical cycles of the Earth. Understanding the circadian clock mechanism could play an important role in forensic entomology because it temporally gates behaviour such as locomotor activities, feeding, mating, egg laying and adult emergence which could provide useful information for crime reconstruction. The scuttle fly Megaselia scalaris colonises both exposed and buried bodies, whether indoors or outdoors. Locomotor activity, oviposition and adult emergence of this species have been investigated using technologies employed in many previous Drosophila circadian studies. The results reported here clearly highlight the underlying role of the circadian clock in regulating the behaviour of males and females of M. scalaris, and show the role of light as a "zeitgeber" for clock resetting. In contrast to Calliphoridae, M. scalaris can reach the oviposition site and lay eggs in darkness both during the day and the night, although the number of ovipositing females is lower under subjective darkness. The number of eggs laid shows a clear circadian rhythm with much higher numbers laid during the day than during night or subjective night. In conclusion, locomotor activity and oviposition rate of M. scalaris is under circadian clock control with significant forensic implications.
28366537	Two decades of research into functions of the ubiquitous transcription factor HIF have revealed pervasive roles in development, oxygen homeostasis, metabolism, cancer and responses to ischemia. Unsurprisingly, HIF activities impinge on many pathologies, for which underlying molecular mechanisms are actively sought. HIF is a member of the heterodimeric bHLH/PAS family of transcription factors, a set of proteins that commonly function in developmental pathways and adaptive responses to environmental or physiological stress. Similarities in the mechanisms that regulate gene targeting by these transcription factors create opportunities for extensive crosstalk between family members. Data supporting pathway interactions between HIF1a and other bHLH/PAS factors, both collaborative and antagonistic, is beginning to surface in the areas of cancer, circadian rhythm, and immune responses. This review summarises the status of HIF1a-bHLH/PAS protein crosstalk and is dedicated to the memory of Lorenz Poellinger, a pioneer investigator into the molecular mechanisms of HIF, AHR, and ARNT bHLH/PAS factors.
28364486	Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research.We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype.	A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified.	GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed.	
28364473	To examine the prevalence of circadian misalignment in clinically diagnosed delayed sleep phase disorder (DSPD) and to compare mood and daytime functioning in those with and without a circadian basis for the disorder.One hundred and eighty-two DSPD patients aged 16-64 years, engaged in regular employment or school, underwent sleep-wake monitoring in the home, followed by a sleep laboratory visit for assessment of salivary dim light melatonin onset (DLMO). Based on the DLMO assessments, patients were classified into two groups: circadian DSPD, defined as DLMO occurring at or after desired bedtime (DBT), or non-circadian DSPD, defined as DLMO occurring before DBT.	One hundred and three patients (57%) were classified as circadian DSPD and 79 (43%) as non-circadian DSPD. DLMO occurred 1.66 hours later in circadian DSPD compared to non-circadian DSPD (p < .001). Moderate-severe depressive symptoms (Beck Depression Inventory-II) were more prevalent in circadian DSPD (14.0%) than in non-circadian DSPD (3.8%; p < .05). Relative to non-circadian DSPD patients, circadian DSPD patients had 4.31 times increased odds of at least mild depressive symptoms (95% CI 1.75 to 10.64; p < .01). No group differences were found for daytime sleepiness or function, but DSPD symptoms were rated by clinicians to be more severe in those with circadian DSPD.	Almost half of patients clinically diagnosed with DSPD did not show misalignment between the circadian pacemaker and the DBT, suggesting that the reported difficulties initiating sleep at the DBT are unlikely to be explained by the (mis)timing of the circadian rhythm of sleep propensity. Circadian misalignment in DSPD is associated with increased depressive symptoms and DSPD symptom severity.	
28364446	Firefighters' schedules include extended shifts and long work weeks which cause sleep deficiency and circadian rhythm disruption. Many firefighters also suffer from undiagnosed sleep disorders, exacerbating fatigue. We tested the hypothesis that a workplace-based Sleep Health Program (SHP) incorporating sleep health education and sleep disorders screening would improve firefighter health and safety compared to standard practice.Prospective station-level randomized, field-based intervention.	US fire department.	1189 firefighters.	Sleep health education, questionnaire-based sleep disorders screening, and sleep clinic referrals for respondents who screened positive for a sleep disorder.	Firefighters were randomized by station. Using departmental records, in an intention-to-treat analysis, firefighters assigned to intervention stations which participated in education sessions and had the opportunity to complete sleep disorders screening reported 46% fewer disability days than those assigned to control stations (1.4 ± 5.9 vs. 2.6 ± 8.5 days/firefighter, respectively; p = .003). There were no significant differences in departmental injury or motor vehicle crash rates between the groups. In post hoc analysis accounting for intervention exposure, firefighters who attended education sessions were 24% less likely to file at least one injury report during the study than those who did not attend, regardless of randomization (OR [95% CI] 0.76 [0.60, 0.98]; χ2 = 4.56; p = .033). There were no significant changes pre- versus post-study in self-reported sleep or sleepiness in those who participated in the intervention.	A firefighter workplace-based SHP providing sleep health education and sleep disorders screening opportunity can reduce injuries and work loss due to disability in firefighters.	
28364421	To better understand the development of sleep, we characterized the development of circadian rhythms in sleep and wakefulness in the artificially-reared, isolated rat pup using an experimental design that minimized the effects of maternal separation.Neonatal rats were reared in constant conditions (dim red light) while electroencephalographic and electromyographic signals were continuously recorded for up to 3 weeks. This time period spanned the preweaned and weaned ages. The distribution of sleep-wake states was analyzed to estimate the emergence of circadian rhythms.	Overt ~24-hour rhythms in time spent awake and asleep appear by postnatal day (P)17. A marked bi-modal sleep-wake pattern was also observed, evidenced by the appearance of a pronounced ~12-hour component in the periodogram over the subsequent 3 days (P17-P21). This suggested the presence of two ~24-hour components consistent with the dual-oscillator concept. During this 3-day time window, waking bouts became longer resulting in a repartition of the duration of intervals without non-rapid-eye movement (NREM) sleep into short (<30 minutes) and longer inter-NREM sleep episodes. These longer waking bouts did not immediately result in an increase in NREM sleep delta (0.5-4.0 Hz) power, which is an index of sleep homeostasis in adult mammals. The sleep homeostatic response did not fully mature until P25.	These results demonstrate that the maturation of circadian organization of sleep-wake behavior precedes the expression of mature sleep homeostasis.	
28363189	Kiwifruit (Actinidia chinensis var. deliciosa (A. Chev) A. Chev.) is a dioecious vine highly dependent on pollination, which is limited by a lack of synchrony of flowering time between male and female plants. In many plant species, the regulation of the timing of flowering depends largely on seasonal cues such as photoperiod, which is detected by photoreceptors. In this report, we determined the full sequences of the PHYB (AcPHYB) and PHYA (AcPHYA) genes and a partial sequence of the CRY2 (AcCRY2) gene in kiwifruit. Next, we monitored the expression patterns of these photoreceptor genes (AcPHYA, AcPHYB and AcCRY2) as well as other genes involved in flowering regulation (AcCO-like and AcFT) in the leaves of kiwifruit plants grown under natural photoperiods in the field. The annual expression patterns of AcPHYB, AcPHYA and AcCRY2 genes showed that they were significantly highly expressed from late flower development until full bloom and fitting with floral evocation, closely matching the peaks of expression detected for the AcFT and AcCO-like genes. In addition, the daily expression patterns of AcPHYB, AcPHYA and AcCRY2 were analyzed in leaves collected under different daylength conditions. Under long-day (LD) conditions, maximum expression levels were detected in the middle of the day in April (before full bloom), while their expression lost their daily rhythmic patterns in June (after full bloom) and were consistently expressed at low levels. Under short-day (SD) conditions, AcPHYB, AcPHYA and AcCRY2 gene expression patterns were the opposite of those observed in April. With respect to AcFT, no expression was detected in SD conditions. In contrast, the AcCO-like gene oscillated for all daylength conditions with the same daily rhythm. Our results seem to indicate the involvement of photoreceptor genes in kiwifruit flowering regulation. The different daily expression patterns detected for AcPHYA, AcPHYB, AcCRY2 and AcFT under different daylength conditions suggest that photoperiod regulates their expression, while the uniform expression of the AcCO-like gene is in agreement with its reported regulation by the circadian clock.
28363112	Protein synthesis is an energy-demanding cellular process. Consequently, a well-timed, fine-tuned and plastic regulation of translation is needed to adjust and maintain cell states under dynamically changing environments. Genome-wide monitoring of translation was recently facilitated by ribosome profiling, which uncovered key features of translation regulation. In this review, we summarize recent ribosome profiling studies in mammals providing novel insight in dynamic translation regulation, notably related to circadian rhythms, diurnal feeding/fasting cycles, cell cycle progression, stress responses, and tRNA landscapes. In particular, recent results show that regulating translation initiation and elongation represent important mechanisms used in mammalian cells to rapidly modulate protein expression in dynamically changing environments.
28361901	Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues.
28361573	The aim of this study was to investigate the effect of time-of-day on oxidative stress, cardiovascular parameters, muscle damage parameters, and hormonal responses following the level-1 Yo-Yo intermittent recovery test (YYIRT). A total of 11 healthy subjects performed an intermittent test (YYIRT) at two times-of-day (i.e., 07:00 h and 17:00 h), with a recovery period of ≥36 h in-between, in a randomized order. Blood samples were taken at the rest (baseline) and immediately (post-YYIRT) after the YYIRT for measuring oxidative stress, biochemical markers, and hormonal response. Data were statistically analyzed using one-way and two-way repeated measures ANOVA and Bonferroni test at p < 0.05. Observed power (α = 0.05) and partial eta-squared were used. Our results showed that oxygen uptake (VO2max), maximal aerobic speed, and the total distance covered tended to be higher in the evening (17:00 h). There was also a main effect of time-of-day for cortisol and testosterone concentration, which were higher after the YYIRT in the morning (p < 0.05). The heart rate peak and the rating of perceived exertion scales were lower in the morning (p < 0.05). However, the plasma glucose (p < 0.01), malondialdehyde, creatine kinase (p < 0.01), lactate dehydrogenase (p < 0.05), high-density lipoprotein (p < 0.01), total cholesterol (p < 0.01), and triglycerides (p < 0.05) were higher after the YYIRT in the evening. Low-density lipoprotein, systolic blood pressure, diastolic blood pressure, and lactate levels (p > 0.05) were similar for the morning and evening test. In conclusion, our findings suggest that aerobic performance presents diurnal variation with great result observed in the evening accompanied by an improvement of hormonal, metabolic, and oxidative responses. These data may help to guide athletes and coaches and contribute to public health recommendations on exercise and muscle damage particularly in the competitive periods.
28360885	Circadian rhythm (CR) plays a critical role in the treatment of several diseases. However, the role of CR in the treatment of peripheral nerve defects has not been studied. It is also known that the pulsed electromagnetic fields (PEMF) can provide a beneficial microenvironment to quicken the process of nerve regeneration and to enhance the quality of reconstruction. In this study, we evaluate the impact of CR on the promoting effect of PEMF on peripheral nerve regeneration in rats. We used the self-made "collagen-chitosan" nerve conduits to bridge the 15-mm nerve gaps in Sprague-Dawley rats. Our results show that PEMF stimulation at daytime (DPEMF) has most effective outcome on nerve regeneration and rats with DPEMF treatment achieve quickly functional recovery after 12 weeks. These findings indicate that CR is an important factor that determines the promoting effect of PEMF on peripheral nerve regeneration. PEMF exposure in the daytime enhances the functional recovery of rats. Our study provides a helpful guideline for the effective use of PEMF mediations experimentally and clinically.
28360884	Normal physiological functions require a robust biological timer called the circadian clock. When clocks are dysregulated, misaligned, or dampened, pathological consequences ensue, leading to chronic diseases and accelerated aging. An emerging research area is the development of clock-targeting compounds that may serve as drug candidates to correct dysregulated rhythms and hence mitigate disease symptoms and age-related decline. In this review, we first present a concise view of the circadian oscillator, physiological networks, and regulatory mechanisms of circadian amplitude. Given a close association of circadian amplitude dampening and disease progression, clock-enhancing small molecules (CEMs) are of particular interest as candidate chronotherapeutics. A recent proof-of-principle study illustrated that the natural polymethoxylated flavonoid nobiletin directly targets the circadian oscillator and elicits robust metabolic improvements in mice. We describe mood disorders and aging as potential therapeutic targets of CEMs. Future studies of CEMs will shed important insight into the regulation and disease relevance of circadian clocks.

28360399	Allelic combinations of major photoperiodic (E1, E3, E4) and maturity (E2) genes have extended the adaptation of quantitative photoperiod sensitive soybean crop from its origin (China ∼35◦N latitude) to both north (up to ∼50◦N) and south (up to 40◦S) latitudes, but their allelic status and role in India (6-35◦N) are unknown. Loss of function and hypoactive alleles of these genes are known to confer photoinsensitivity to long days and early maturity. Early maturity has helped to adapt soybean to short growing season of India. We had earlier found that all the Indian cultivars are sensitive to incandescent long day (ILD) and could identify six insensitive accessions through screening 2071 accessions under ILD. Available models for ILD insensitivity suggested that identified insensitive genotypes should be either e3/e4 or e1 (e1-nl or e1-fs) with either e3 or e4. We found that one of the insensitive accessions (EC 390977) was of e3/e4 genotype and hybridized it with four ILD sensitive cultivars JS 335, JS 95-60, JS 93-05, NRC 37 and an accession EC 538828. Inheritance studies and marker-based cosegregation analyses confirmed the segregation of E3 and E4 genes and identified JS 93-05 and NRC 37 as E3E3E4E4 and EC 538828 as e3e3E4E4. Further, genotyping through sequencing, derived cleaved amplified polymorphic sequences (dCAPS) and cleaved amplified polymorphic sequences (CAPS) markers identified JS 95-60 with hypoactive e1-as and JS 335 with loss of function e3-fs alleles. Presence of photoperiodic recessive alleles in these two most popular Indian cultivars suggested for their role in conferring early flowering and maturity. This observation could be confirmed in F2 population derived from the cross JS 95-60 × EC 390977, where individuals with e1-as e1-as and e4e4 genotypes could flower 7 and 2.4 days earlier, respectively. Possibility of identification of new alleles ormechanism for ILD insensitivity and use of photoinsensitivity in Indian conditions have been discussed.
28360128	The advantages of the model organism Drosophila melanogaster, including low genetic redundancy, functional simplicity, and the ability to conduct large-scale genetic screens, have been essential for understanding the molecular nature of circadian (∼24 hr) rhythms, and continue to be valuable in discovering novel regulators of circadian rhythms and sleep. In this review, we discuss the current understanding of these interrelated biological processes in Drosophila and the wider implications of this research. Clock genes period and timeless were first discovered in large-scale Drosophila genetic screens developed in the 1970s. Feedback of period and timeless on their own transcription forms the core of the molecular clock, and accurately timed expression, localization, post-transcriptional modification, and function of these genes is thought to be critical for maintaining the circadian cycle. Regulators, including several phosphatases and kinases, act on different steps of this feedback loop to ensure strong and accurately timed rhythms. Approximately 150 neurons in the fly brain that contain the core components of the molecular clock act together to translate this intracellular cycling into rhythmic behavior. We discuss how different groups of clock neurons serve different functions in allowing clocks to entrain to environmental cues, driving behavioral outputs at different times of day, and allowing flexible behavioral responses in different environmental conditions. The neuropeptide PDF provides an important signal thought to synchronize clock neurons, although the details of how PDF accomplishes this function are still being explored. Secreted signals from clock neurons also influence rhythms in other tissues. SLEEP is, in part, regulated by the circadian clock, which ensures appropriate timing of sleep, but the amount and quality of sleep are also determined by other mechanisms that ensure a homeostatic balance between sleep and wake. Flies have been useful for identifying a large set of genes, molecules, and neuroanatomic loci important for regulating sleep amount. Conserved aspects of sleep regulation in flies and mammals include wake-promoting roles for catecholamine neurotransmitters and involvement of hypothalamus-like regions, although other neuroanatomic regions implicated in sleep in flies have less clear parallels. Sleep is also subject to regulation by factors such as food availability, stress, and social environment. We are beginning to understand how the identified molecules and neurons interact with each other, and with the environment, to regulate sleep. Drosophila researchers can also take advantage of increasing mechanistic understanding of other behaviors, such as learning and memory, courtship, and aggression, to understand how sleep loss impacts these behaviors. Flies thus remain a valuable tool for both discovery of novel molecules and deep mechanistic understanding of sleep and circadian rhythms.
28358954	In mammalian corneal epithelium, mitosis shows a distinct circadian pattern. However, how this circadian pattern is maintained, and how it or its disruption influence renewal and regeneration remain unclear.C57BL/6 mice were maintained under 12-hour light/12-hour dark (LD), 12-hour light/12-hour light (LL), 12-hour dark/12-hour dark (DD), or reversed LD (DL, 12-hour dark/12-hour light; jet-lag defined as a shift of 12 hours) conditions. Mitotic cells in corneal epithelium were enumerated and analyzed via immunofluorescence at different zeitgeber times (ZTs). Expression of core clock genes (Clock, Bmal1, Period2, Cry1, and Rev-erbα) was qualified via quantitative RT-PCR. The rate and quality of healing at different ZT times and after administration of two small-molecule modifiers of the circadian clock, KL001 and SR8278, was evaluated.	In this study, photic cues were found to influence the 24-hour rhythm of corneal clock gene expression and epithelial cell mitosis in mice. Disruption of the circadian clock by exposure to constant light, constant dark, or jet-lag conditions modified the normal 24-hour patterns of corneal epithelial mitosis and corneal clock gene expression. The time of day of wound occurrence affected the rate and quality of corneal healing, with both of these parameters peaking during the more mitotically active hours of the morning. The two small-molecule modifiers of the circadian clock, KL001 and SR8278, had negative and positive effects on corneal wound healing, respectively.	Circadian rhythms significantly influence corneal epithelium renewal and repair in mice. Our findings reveal possible opportunities for biological rhythm-based interventional strategies to control corneal healing and restore corneal homeostasis.	
28357830	A single-handed transatlantic rowing race was organised between Senegal and French Guyana (2600 nautical miles). During the race, rowers adjust their lifestyle to maintain an optimal level of performance. Nutrition, circadian rhythm disturbance, psychological state, pain and other medical problems impact on physical abilities and increase the occurrence of accidents. We surveyed the prevalence of medical complications during this race and the preparation that we could suggest for this kind of activity.This is a descriptive, retrospective case series study. Follow-up consisted of sending out a questionnaire and performing individual interviews.	A total of 23 participants including 1 woman and 22 men; mean age of 46.5 years (range: 35-59) entered the race. The race lasted for 39 to 52 days with participants rowing between 10 and 12 h/day. Nine participants dropped out. Energy intake was 4500 to 6000 kcal/day and fluid intake was 4 to 5.5 L/day. Mean weight loss was 13.3 kg. The resting period was 6 ± 1 h/24 h divided into 1.5 to 2 h periods essentially during darkness. A total of 92% of the racers required medical care for dermatological problems; other conditions requiring medical care were: tendinitis in 10 cases, diarrhoea in 4, moderate to severe seasickness in 4, hallucinations in 3, panic attacks in 2, burns in 2, and disembarkation syndrome ("land sickness") lasting from 45 min to 6 h in 13.	Physiological and psychological impact of this type of event is still unclear. The most common medical problems are dermatological, rheumatological complications and minor trauma. Medical and psychological preparation should be offered to candidates for these competitions.	
28356031	Since more than 50 years glucocorticoids represent the milestone in the treatment of inflammatory diseases, including rheumatoid arthritis (RA). However, many patients with RA present a circadian rhythm in symptoms severity, with a significant worsening in the morning, that correlates with cyclic changes in circulating hormones and cytokines. Classical steroids therapy given in the morning fails to intercept this pathophysiological phenomenon. In the last years, a novel formulation of prednisone has been developed in order to better fit these variations, improve efficacy and minimize adverse events (chronotherapy). This modified-release (MR) prednisone is administered in the evening at 10.00 p.m. and absorbed after about 4 hours. In the present article we reviewed the evidence supporting a role for MR prednisone in the treatment of RA patients.
28353643	Plasma 25-hydroxyvitamin D (25OHD) deficiency, poor sleep quality, and night-time eating, have been independently associated with adverse pregnancy outcomes, but their inter-relationships are yet to be evaluated. We aimed to investigate the associations between maternal plasma 25OHD status and sleep quality and circadian eating patterns during pregnancy. Data on pregnant women (n = 890) from a prospective cohort (Growing Up in Singapore Towards healthy Outcomes) were analyzed. Plasma 25OHD concentration was measured, while the Pittsburgh sleep quality index (PSQI) and 24-h dietary recall were administered to women at 26-28 weeks' gestation. Plasma 25OHD status was defined as sufficient (>75 nmol/L), insufficient (50-75 nmol/L), or deficient (<50 nmol/L). Poor sleep quality was defined by a total global PSQI score >5. Predominantly day-time (pDT) and predominantly night-time (pNT) were defined according to consumption of greater proportion of calories (i.e., >50%) from 07:00-18:59 and from 19:00-06:59, respectively. After adjustment for confounders, women with plasma 25OHD deficiency had higher odds of poor sleep quality (odds ratio (OR) 3.49; 95% confidence interval (CI) 1.84-6.63) and pNT eating (OR: 1.85; 95% CI 1.00-3.41) than those who were 25OHD sufficient. Our findings show the association of maternal plasma 25OHD deficiency with poor sleep quality and pNT eating at mid-pregnancy.
28352249	Obesity in women is increased by the loss of circulating estrogen after menopause. Shift work, which disrupts circadian rhythms, also increases the risk for obesity. It is not known whether ovarian hormones interact with the circadian system to protect females from obesity. During high-fat feeding, male C57BL/6J mice develop profound obesity and disruption of daily rhythms. Since C57BL/6J female mice did not develop diet-induced obesity (during 8 weeks of high-fat feeding), we first determined if daily rhythms in female mice were resistant to disruption from high-fat diet. We fed female PERIOD2:LUCIFERASE mice 45% high-fat diet for 1 week and measured daily rhythms. Female mice retained robust rhythms of eating behavior and locomotor activity during high-fat feeding that were similar to chow-fed females. In addition, the phase of the liver molecular timekeeping (PER2:LUC) rhythm was not altered by high-fat feeding in females. To determine if ovarian hormones protected daily rhythms in female mice from high-fat feeding, we analyzed rhythms in ovariectomized mice. During high-fat feeding, the amplitudes of the eating behavior and locomotor activity rhythms were reduced in ovariectomized females. Liver PER2:LUC rhythms were also advanced by ~4 h by high-fat feeding, but not chow, in ovariectomized females. Together these data show circulating ovarian hormones protect the integrity of daily rhythms in female mice during high-fat feeding.
28351863	Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes.
28349079	Charles Darwin noted that natural selection applies even to the hourly organization of daily life. Indeed, in many species, the day is segmented into active periods when the animal searches for food, and inactive periods when the animal digests and rests. This episodic temporal patterning is conventionally referred to as ultradian (<24 hours) rhythmicity. The average time between ultradian events is approximately 1-2 hours, but the interval is highly variable. The ultradian pattern is stochastic, jaggy rather than smooth, so that although the next event is likely to occur within 1-2 hours, it is not possible to predict the precise timing. When models of circadian timing are applied to the ultradian temporal pattern, the underlying assumption of true periodicity (stationarity) has distorted the analyses, so that the ultradian pattern is frequently averaged away and ignored. Each active ultradian episode commences with an increase in hippocampal theta rhythm, indicating the switch of attention to the external environment. During each active episode, behavioral and physiological processes, including changes in body and brain temperature, occur in an integrated temporal order, confirming organization by programs endogenous to the central nervous system. We describe methods for analyzing episodic ultradian events, including the use of wavelet mathematics to determine their timing and amplitude, and the use of fractal-based procedures to determine their complexity.
28348112	The endocrine body rhythms including the hypothalamic-pituitary-thyroid axis seem to be regulated by the circadian timing system, and daily rhythmicity of circulating thyroid-stimulating hormone (TSH) is well established. The circadian rhythms are generated by endogenous clocks in the central brain oscillator located in the hypothalamic suprachiasmatic nucleus (SCN) as well as multiple peripheral clocks, but information on the existence and function of a thyroid clock is limited. The molecular machinery in all clock cells is composed of a number of clock genes and their gene products are connected by autoregulatory feedback loops. Here, we provide evidence for a thyroid clock in the rat by demonstrating 24-h antiphase oscillations for the mRNA of the canonical clock genes Per1 and Bmal1, which was unaffected by hypophysectomy. By immunostaining, we supported the existence of a core oscillator in the individual thyroid cells by demonstrating a daily cytoplasmatic-nuclear shuttling of PER1 protein. In normal rats, we found a significant daily rhythmicity in the circulating thyroid hormones preceded by a peak in TSH. In hypophysectomised rats, although the thyroid clock was not affected, the oscillations in circulating thyroid hormones were abolished and the levels were markedly lowered. No daily oscillations in the expression of TSH receptor mRNA were observed in neither control rats nor hypophysectomised rats. Our findings indicate that the daily rhythm of thyroid hormone secretion is governed by SCN signalling via the rhythmic TSH secretion rather than by the local thyroid clock, which was still ticking after hypophysectomy.
28347188	Shift work is a risk factor for inflammation, hypertension, and cardiovascular disease. This increased risk cannot be fully explained by classical risk factors. Shift workers' behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in shift workers, independent of differences in work stress, food quality, and other factors that are likely to differ between night and day shifts. Thus, our objectives were to determine the independent effect of circadian misalignment on 24-h high-sensitivity C-reactive protein (hs-CRP; a marker of systemic inflammation) and blood pressure levels-cardiovascular disease risk factors-in chronic shift workers. Chronic shift workers undertook two 3-day laboratory protocols that simulated night work, comprising 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment), using a randomized, crossover design. Circadian misalignment increased 24-h hs-CRP by 11% ( p < 0.0001). Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 1.4 mmHg and 0.8 mmHg, respectively (both p ≤ 0.038). The misalignment-mediated increase in 24-h SBP was primarily explained by an increase in SBP during the wake period (+1.7 mmHg; p = 0.017), whereas the misalignment-mediated increase in 24-h DBP was primarily explained by an increase in DBP during the sleep opportunity (+1.8 mmHg; p = 0.005). Circadian misalignment per se increases hs-CRP and blood pressure in shift workers. This may help explain the increased inflammation, hypertension, and cardiovascular disease risk in shift workers.
28347186	PAS domain-containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude.
28345624	Why do we go to sleep late and struggle to wake up on time? Historically, light-dark cycles were dictated by the solar day, but now humans can extend light exposure by switching on artificial lights. We use a mathematical model incorporating effects of light, circadian rhythmicity and sleep homeostasis to provide a quantitative theoretical framework to understand effects of modern patterns of light consumption on the human circadian system. The model shows that without artificial light humans wakeup at dawn. Artificial light delays circadian rhythmicity and preferred sleep timing and compromises synchronisation to the solar day when wake-times are not enforced. When wake-times are enforced by social constraints, such as work or school, artificial light induces a mismatch between sleep timing and circadian rhythmicity ('social jet-lag'). The model implies that developmental changes in sleep homeostasis and circadian amplitude make adolescents particularly sensitive to effects of light consumption. The model predicts that ameliorating social jet-lag is more effectively achieved by reducing evening light consumption than by delaying social constraints, particularly in individuals with slow circadian clocks or when imposed wake-times occur after sunrise. These theory-informed predictions may aid design of interventions to prevent and treat circadian rhythm-sleep disorders and social jet-lag.
28345615	Light is an important environmental signal for most insects. The Oriental Armyworm, Mythimna separata, is a serious pest of cereal crops worldwide, and is highly sensitive to light signals during its developmental and reproductive stages. However, molecular biological studies of its response to light stress are scarce, and related genomic information is not available. In this study, we sequenced and de novo assembled the transcriptomes of M. separata exposed to four different light conditions: dark, white light (WL), UV light (UVL) and yellow light (YL). A total of 46,327 unigenes with an average size of 571 base pairs (bp) were obtained, among which 24,344 (52.55%) matched to public databases. The numbers of genes differentially expressed between dark vs WL, dark vs UVL, dark vs YL, and UVL vs YL were 12,012, 12,950, 14,855, and 13,504, respectively. These results suggest that light exposure altered gene expression patterns in M. separata. Putative genes involved in phototransduction-fly, phototransduction, circadian rhythm-fly, olfactory transduction, and taste transduction were identified. This study thus identified a series of candidate genes and pathways potentially related to light stress in M. separata.
28344052	Circadian clocks harmonize processes ranging from intracellular biochemistry to whole-body physiology in accordance with the Earth's 24h rotation. These intrinsic oscillators are based on an interlocked transcriptional-translational feedback loop comprised from a set of core clock factors. In addition to maintaining rhythmicity in nearly every cell of the body, these clock factors also mediate tissue specific metabolic functions. In this review, we will explore how the molecular clock shapes the unique features of different adipose depots.
28343966	Astrocytes are active partners in neural information processing [1, 2]. However, the roles of astrocytes in regulating behavior remain unclear [3, 4]. Because astrocytes have persistent circadian clock gene expression and ATP release in vitro [5-8], we hypothesized that they regulate daily rhythms in neurons and behavior. Here, we demonstrated that daily rhythms in astrocytes within the mammalian master circadian pacemaker, the suprachiasmatic nucleus (SCN), determine the period of wheel-running activity. Ablating the essential clock gene Bmal1 specifically in SCN astrocytes lengthened the circadian period of clock gene expression in the SCN and in locomotor behavior. Similarly, excision of the short-period CK1ε tau mutation specifically from SCN astrocytes resulted in lengthened rhythms in the SCN and behavior. These results indicate that astrocytes within the SCN communicate to neurons to determine circadian rhythms in physiology and in rest activity.
28338745	The human microbiomes across the body evidently interact with various signals in response to biogeographical physiological conditions. To understand such interactions in detail, we investigated how the salivary microbiome in the oral cavity would be regulated by host-related signals. Here, we show that the microbial abundance and gene participating in keeping the human salivary microbiome exhibit global circadian rhythm. Analysis of the 16S rRNA sequences of salivary microbial samples of six healthy adults collected at 4-h intervals for three days revealed that the microbial genera accounting for 68.4-89.6% of the total abundance were observed to significantly oscillate with the periodicity of ∼24 h. These oscillation patterns showed high variations amongst individuals, and the extent of circadian variations in individuals was generally lower than that of interindividual variations. Of the microbial categories oscillated, those classified by aerobic/anaerobic growth and Gram staining, Firmicutes including Streptococcus and Gemella, and Bacteroidetes including Prevotella showed high association with the circadian oscillation. The circadian oscillation was completely abolished by incubating the saliva in vitro, suggesting that host's physiological changes mostly contributed to the microbial oscillation. Further metagenomic analysis showed that circadian oscillation enriched the functions of environmental responses such as various transporters and two-component regulatory systems in the evening, and those of metabolisms such as the biosynthesis of vitamins and fatty acids in the morning.
28338525	Oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus play an important role in food intake regulation. It has been shown that the secretion of oxytocin from the hypothalamus shows a diurnal circadian rhythmic pattern and disturbance of this pattern leads to the development of obesity. However, whether oxytocin secretion from the PVN has a diurnal pattern remains unknown. Here, we show that oxytocin secretion from the PVN does have a diurnal pattern and that the terminals of orexin neurons, the neuropeptide responsible for regulating the sleep-wake rhythm, are synapsed with PVN oxytocin neurons. Using transgenic rats selectively expressing monomeric red fluorescent protein 1 in oxytocin neurons, we found that orexin-A inhibits the activities of PVN oxytocin neurons by inhibiting glutamatergic excitatory synaptic input. These data suggest that orexin is a possible candidate to regulate the circadian rhythm of PVN oxytocin neurons. The circadian rhythmic secretion of oxytocin is considered to play an important role in maintaining homeostasis, including body weight regulation. Our present data indicate a possible contribution of orexin toward the development of circadian rhythm in PVN oxytocin neurons.
28337980	Yeast lacks dedicated photoreceptors; however, blue light still causes pronounced oscillations of the transcription factor Msn2 into and out of the nucleus. Here we show that this poorly understood phenomenon is initiated by a peroxisomal oxidase, which converts light into a hydrogen peroxide (H2O2) signal that is sensed by the peroxiredoxin Tsa1 and transduced to thioredoxin, to counteract PKA-dependent Msn2 phosphorylation. Upon H2O2, the nuclear retention of PKA catalytic subunits, which contributes to delayed Msn2 nuclear concentration, is antagonized in a Tsa1-dependent manner. Conversely, peroxiredoxin hyperoxidation interrupts the H2O2 signal and drives Msn2 oscillations by superimposing on PKA feedback regulation. Our data identify a mechanism by which light could be sensed in all cells lacking dedicated photoreceptors. In particular, the use of H2O2 as a second messenger in signalling is common to Msn2 oscillations and to light-induced entrainment of circadian rhythms and suggests conserved roles for peroxiredoxins in endogenous rhythms.
28337897	Exhaled breath temperature (EBT) is an expression of airway inflammation, an event that drives several lung diseases. The measurement of the exhaled breath temperature has recently been proposed as a popular tool in the diagnosis and monitoring of inflammatory lung diseases due to the fact that it is a non-invasive method. The influence of external factors on EBT, its reproducibility, and its sensitivity to treatment have already been explored. However, to reach clinical practice, EBT requires a complete validation that is still lacking. The aim of this study was to analyse the possible influence of an important internal variable, i.e the circadian rhythm on EBT values in a group of 24 healthy adult volunteers. We repeated measurement of EBT at different hours of the day: 8.00 AM, 12.00 AM, 4.00 PM, 8.00 PM and analysed the correlation with axillary temperature measurement at these times. The EBT resulted significantly different during daily measurements (8.00 AM vs 12.00 AM vs 4.00 PM vs 8.00 PM: 28.01±1.64°C vs 28.8±1.82°C vs 29.34±1.79°C vs 28.06±1.34°C). The highest EBT was reported at 4.00 PM and the lowest at 8.00 AM. For the first time we found an influence of the circadian rhythm on EBT. These data support the validation of the EBT necessary for its promotion in clinical practice.
28337174	Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases.
28336811	Our body clock drives rhythms in the expression of genes that have a 24-h periodicity. The transcription factor BMAL1 is a crucial component of the molecular clock. A number of physiological processes, including immune function, are modulated by the circadian clock. Asthma, a disease with very strong clinical evidence demonstrating regulation by circadian variation, is of particular relevance to circadian control of immunity. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown, and there is no model of asthma in animals with genetic distortion of the molecular clock. We used mice lacking BMAL1 in myeloid cells (BMAL1-LysM-/-) to determine the role of BMAL1 in allergic asthma. Using the ovalbumin model of allergic asthma, we demonstrated markedly increased asthma features, such as increased lung inflammation, demonstrated by drastically higher numbers of eosinophils and increased IL-5 levels in the lung and serum, in BMAL1-LysM-/- mice. In vitro studies demonstrated increased proinflammatory chemokine and mannose receptor expression in IL-4- as well as LPS-treated macrophages from BMAL1-LysM-/- mice compared with wild-type controls. This suggests that Bmal1 is a potent negative regulator in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night, when BMAL1 expression is low.
28335007	Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERBα. These circadian lncRNAs showed similar circadian phases with their nearby genes. The extent of their nuclear localization is higher than protein coding genes but less than enhancer RNAs. The association between enhancer and circadian lncRNAs is also observed in tissues other than liver. Comparative analysis between mouse and rat circadian liver transcriptomes showed that circadian transcription at lncRNA loci tends to be conserved despite of low sequence conservation of lncRNAs. One such circadian lncRNA termed lnc-Crot led us to identify a super-enhancer region interacting with a cluster of genes involved in circadian regulation of metabolism through long-range interactions. Further experiments showed that lnc-Crot locus has enhancer function independent of lnc-Crot's transcription. Our results suggest that the enhancer-associated circadian lncRNAs mark the genomic loci modulating long-range circadian gene regulation and shed new lights on the evolutionary origin of lncRNAs.
28333924	The green alga Chlamydomonas reinhardtii shows various light responses in behavior and physiology. One such photoresponse is the circadian clock, which can be reset by external light signals to entrain its oscillation to daily environmental cycles. In a previous report, we suggested that a light-induced degradation of the clock protein ROC15 is a trigger to reset the circadian clock in Chlamydomonas. However, light signaling pathways of this process remained unclear. Here, we screened for mutants that show abnormal ROC15 diurnal rhythms, including the light-induced protein degradation at dawn, using a luciferase fusion reporter. In one mutant, ROC15 degradation and phase resetting of the circadian clock by light were impaired. Interestingly, the impairments were observed in response to red and violet light, but not to blue light. We revealed that an uncharacterized gene encoding a protein similar to RAS-signaling-related leucine-rich repeat (LRR) proteins is responsible for the mutant phenotypes. Our results indicate that a previously uncharacterized red/violet light signaling pathway is involved in the phase resetting of circadian clock in Chlamydomonas.
28333377	The different types of adipose tissues fulfill a wide range of biological functions-from energy storage to hormone secretion and thermogenesis-many of which show pronounced variations over the course of the day. Such 24-h rhythms in physiology and behavior are coordinated by endogenous circadian clocks found in all tissues and cells, including adipocytes. At the molecular level, these clocks are based on interlocked transcriptional-translational feedback loops comprised of a set of clock genes/proteins. Tissue-specific clock-controlled transcriptional programs translate time-of-day information into physiologically relevant signals. In adipose tissues, clock gene control has been documented for adipocyte proliferation and differentiation, lipid metabolism as well as endocrine function and other adipose oscillations are under control of systemic signals tied to endocrine, neuronal, or behavioral rhythms. Circadian rhythm disruption, for example, by night shift work or through genetic alterations, is associated with changes in adipocyte metabolism and hormone secretion. At the same time, adipose metabolic state feeds back to central and peripheral clocks, adjusting behavioral and physiological rhythms. In this overview article, we summarize our current knowledge about the crosstalk between circadian clocks and energy metabolism with a focus on adipose physiology. © 2017 American Physiological Society. Compr Physiol 7:383-427, 2017.
28333141	Emerging evidences show that disruption of the circadian rhythm is associated with tumor initiation and progression. Neuronal PAS domain protein 2 (NPAS2), one of the core circadian molecules, has been proved to be a potential prognostic biomarker in colorectal and breast cancers. However, to date, the potential functional roles and molecular mechanisms by which NPAS2 affects cancer cell survival are greatly unclear, especially in hepatocellular carcinoma (HCC). We first investigated the expression of NPAS2 and its clinical significance in HCC. We then systematically explored the role of NPAS2 in HCC cell survival both in vitro and in vivo and the underlying mechanism. NPAS2 was frequently upregulated in HCC, which significantly facilitated cell survival both in vitro and in vivo mainly by promoting cell proliferation and inhibiting mitochondria-dependent intrinsic apoptosis, and thus contributed to poor prognosis of HCC patients. Mechanistically, the survival-promoting role of NPAS2 was mediated by transcriptional upregulation of the CDC25A phosphatase and subsequent dephosphorylation of CDK2/4/6 and Bcl-2, which induced cell proliferation and inhibited cell apoptosis in HCC, respectively. Moreover, BMAL1, another core clock transcription factor, was identified to heterodimerize with NPAS2 to bind to the E-box element in the promoter of CDC25A and be associated with the NPAS2-mediated tumor cell survival in HCC. Our findings demonstrate that NPAS2 has a critical role in HCC cell survival and tumor growth, which is mainly mediated by transcriptional upregulation of CDC25A. Thereby, NPAS2 may serve as a potential therapeutic target in HCC patients.
28332253	The endogenous, free-running circadian period (τ) determines the phase relationship that an organism assumes when entrained to the 24-h day. We found a shorter circadian period in African Americans compared to non-Hispanic European Americans (24.07 versus 24.33 h). We speculate that a short circadian period, closer to 24 h, was advantageous to humans living around the equator, but when humans migrated North out of Africa, where the photoperiod changes with seasons, natural selection favoured people with longer circadian periods. Recently, in evolutionary terms, immigrants came from Europe and Africa to America ('the New World'). The Europeans were descendents of people who had lived in Europe for thousands of years with changing photoperiods (and presumably longer periods), whereas Africans had ancestors who had always lived around the equator (with shorter periods). It may have been advantageous to have a longer circadian period while living in Europe early in the evolution of humans. In our modern world, however, it is better to have a shorter period, because it helps make our circadian rhythms earlier, which is adaptive in our early-bird-dominated society. European American women had a shorter circadian period than men (24.24 versus 24.41), but there was no sex difference in African Americans (24.07 for both men and women). We speculate that selection pressures in Europe made men develop a slightly longer period than women to help them track dawn which could be useful for hunters, but less important for women as gatherers.
28332018	Circadian clocks are near universal among organisms and play a key role in coordinating physiological and metabolic functions to anticipate or coincide with predictable daily changes in the physical and social environment. However, whether circadian rhythms persist and are functionally important during hibernation in all mammals is currently unclear. We examined whether circadian rhythms of body temperature (T b) persist during multi-day, steady-state torpor and investigated the association between timing of animal emergence, exposure to light, and resumption of activity and T b rhythms in free-living and captive male arctic ground squirrels. High-resolution (0.02 °C) temperature loggers revealed that circadian rhythms of T b were not present during deep torpor in free-living arctic ground squirrels. Significant circadian rhythms of T b resumed, however, following the resumption of euthermia, but prior to emergence, though rhythms became much more robust coincident with aboveground emergence. Additionally, squirrels maintained in captivity under conditions of constant darkness spontaneously developed significant circadian rhythms of T b and activity soon after ending torpor. Exposing animals to a 5-s pulse of light within a week when they ended torpor increased the strength of rhythms. Our results are consistent with the hypothesis that circadian clock function is inhibited during hibernation in arctic ground squirrels, and we postulate that exposure to external stimuli, such as light in free-living animals, and meals or acute disturbance for captive squirrels, may enhance T b rhythmicity by synchronizing loosely coupled circadian oscillators within the suprachiasmatic nucleus.
28331994	Suprachiasmatic nucleus (SCN) in synchronization with the peripheral clocks regulates the temporal oscillations leading to overt rhythms. Aging leads to attenuation of such circadian regulation, accompanied by increased inflammatory mediators prevalently the cytokines. Suppressors of cytokine signaling (SOCS) family of proteins such as SOCS 1, 3 and cytokine-inducible SH2-containing protein (CIS) negatively regulate the cytokine signaling pathway. The role of SOCS1 in aging and circadian system is obscure. We therefore studied the daily rhythms of rSocs1 mRNA expression at Zeitgeber time (ZT) -0, 6, 12 and 18 in peripheral clocks such as liver, kidney, intestine and heart of 3, 12 and 24 months (m) old male Wistar rats. Interestingly the peripheral clocks studied displayed a rhythmic rSocs1 gene expression in 3 months. In 12 months group, 12 h phase advance in liver and 12 h phase delay in kidney and heart was observed with abolition of rhythms in intestine. Aging (24 months group) resulted in a phase advance by 6 h in liver and heart with abolition of rhythms in intestine in 24 months group. Kidney was also significantly affected upon aging with significant decrease in the rSocs1 levels and abolition of rhythms. The decrease in melatonin levels with aging is associated with decreased immunity and increased oxidative stress. The exogenous administration of melatonin has been linked to play a role in re-synchronization of circadian rhythms, reducing oxidative stress and enhancing immune properties. We therefore had studied the effect of exogenous melatonin upon age induced changes in daily rSocs1 gene expression patterns. Melatonin treatment partially restored the rhythms and daily pulse (ratio of maximum:minimum levels) in liver and intestine in 12 months group. Melatonin administration resulted in a significant increase in mean 24 h rSocs1 expression in intestine and heart of 24 months group compared to that of 3 months. The melatonin administration resulted in differential restoration of rSocs1 rhythms and levels in various tissues of 24 months old group. The sensitivity of 24 months old animals to melatonin found in the present study is a step towards endorsing melatonin as an important anti-aging therapeutic drug.
28331201	Individual cells in a plant can work independently as circadian clocks, and their properties are the basis of various circadian phenomena. The behaviour of individual cellular clocks in Lemna gibba was orderly under 24-h light/dark cycles despite their heterogeneous free-running periods (FRPs). Here, we reveal the entrainment habits of heterogeneous cellular clocks using non-24-h light/dark cycles (T-cycles). The cellular rhythms of AtCCA1::LUC under T = 16 h cycles showed heterogeneous entrainment that was associated with their heterogeneous FRPs. Under T = 12 h cycles, most cells showed rhythms having ~24-h periods. This suggested that the lower limit of entrainment to the light/dark cycles of heterogeneous cellular circadian clocks is set to a period longer than 12 h, which enables them to be synchronous under ~24-h daily cycles without being perturbed by short light/dark cycles. The entrainment habits of individual cellular clocks are likely to be the basis of the circadian behaviour of plant under the natural day-night cycle with noisy environmental fluctuations. We further suggest that modifications of EARLY FLOWERING3 (ELF3) in individual cells deviate the entrainability to shorter T-cycles possibly by altering both the FRPs and light responsiveness.
28330876	Postinjury epilepsy (PIE) is a devastating sequela of various brain insults. While recent studies offer novel insights into the mechanisms underlying epileptogenesis and discover potential preventive treatments, the lack of PIE biomarkers hinders the clinical implementation of such treatments. Here we explored the biomarker potential of different electrographic features in five models of PIE. Electrocorticographic or intrahippocampal recordings of epileptogenesis (from the insult to the first spontaneous seizure) from two laboratories were analyzed in three mouse and two rat PIE models. Time, frequency, and fractal and nonlinear properties of the signals were examined, in addition to the daily rate of epileptiform spikes, the relative power of five frequency bands (theta, alpha, beta, low gamma, and high gamma) and the dynamics of these features over time. During the latent pre-seizure period, epileptiform spikes were more frequent in epileptic compared with nonepileptic rodents; however, this feature showed limited predictive power due to high inter- and intra-animal variability. While nondynamic rhythmic representation failed to predict epilepsy, the dynamics of the theta band were found to predict PIE with a sensitivity and specificity of >90%. Moreover, theta dynamics were found to be inversely correlated with the latency period (and thus predict the onset of seizures) and with the power change of the high-gamma rhythm. In addition, changes in theta band power during epileptogenesis were associated with altered locomotor activity and distorted circadian rhythm. These results suggest that changes in theta band during the epileptogenic period may serve as a diagnostic biomarker for epileptogenesis, able to predict the future onset of spontaneous seizures.SIGNIFICANCE STATEMENT Postinjury epilepsy is an unpreventable and devastating disorder that develops following brain injuries, such as traumatic brain injury and stroke, and is often associated with neuropsychiatric comorbidities. As PIE affects as many as 20% of brain-injured patients, reliable biomarkers are imperative before any preclinical therapeutics can find clinical translation. We demonstrate the capacity to predict the epileptic outcome in five different models of PIE, highlighting theta rhythm dynamics as a promising biomarker for epilepsy. Our findings prompt the exploration of theta dynamics (using repeated electroencephalographic recordings) as an epilepsy biomarker in brain injury patients.
28330768	In the present study, the ventral tail base surface temperature (ST) was monitored using a wearable wireless sensor for estrus detection in cattle. Relationships among ST, behavioral estrus expression, ovulation, and changes in hormone profiles during the estrous cycle were examined. Holstein Friesian or Japanese Black female cattle were used in summer (August-September), autumn (October-November) and winter (January-February; three animals per season). On Day 11 of the estrous cycle (Day 0=the day of ovulation), the sensor was attached to the surface of the ventral tail base and ST was measured every 2min until Day 11 of the next estrous cycle. Hourly maximum ST values were used for analysis. To exclude circadian rhythm and seasonal effects, ST changes were expressed as residual temperatures (RT=actual ST - mean ST for the same hour on the previous 3days). Obvious circadian rhythms of the ST were observed and daily changes in the ST significantly differed among seasons. There was no significant seasonal difference, however, in the RT. The mean RT increased significantly ∼24 compared with ∼48h before ovulation. The mean maximum RT was 1.27±0.30°C, which was observed 5.6±2.4h after the onset of estrus, 2.4±1.3h before LH peak, and 26.9±1.2h before ovulation. The ST of the ventral tail base could be monitored throughout the estrous cycle and could detect a substantial change around the time of expression of behavioral estrus. Calculation and analysis of the RT could be useful for automatic estrous detection.
28330645	The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE® as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry®, 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that enteric-coated bilayer tablets were stable during 3 month under the accelerated condition of 40°C/75% RH. The delayed drug release and bedtime dosage regimen using enteric-coated bilayer tablet containing TEL and PRA, matching the circadian rhythms of hypertension and hyperlipidemia can provide therapeutic benefits for elderly patients in terms of maximizing the therapeutic effects.
28329207	The growing embrace of patient-centered outcomes research (PCOR) in sleep medicine is a significant step forward for the field. In engaging and incorporating the unique perspectives of people with sleep disorders, PCOR enhances the relevance of findings and facilitates the uptake of research into practice. While centering research design around what matters most to people with sleep disorders is critical, research communication must be similarly people-centered. One approach is using "people-centered language" in both professional and public communications. People-centered language is rooted in sociolinguistic research demonstrating that language both reflects and shapes attitudes. People-centered language puts people first, is precise and neutral, and respects autonomy. By adhering to the language guidelines described in this article, sleep researchers will better serve the field's most important stakeholders.
28329091	Recent studies implicate inadequate sleep duration and quality in metabolic disease. Fewer studies have examined the timing of sleep, which may be important because of its potential impact on circadian rhythms of metabolic function. We examined the association between sleep timing and metabolic risk among Hispanic/Latino adults.Cross-sectional data from community-based study of 13429 participants aged 18-74 years. People taking diabetic medications were excluded. Sleep timing was determined from self-reported bedtimes and wake times. Chronotype was defined as the midpoint of sleep on weekends adjusted for sleep duration on weekdays. Other measurements included body mass index (BMI), fasting glucose levels, estimated insulin resistance (HOMA-IR), glucose levels 2 hours post oral glucose ingestion, and hemoglobin A1c. Survey linear regression models tested associations between sleep timing and metabolic measures. Analyses were stratified by diabetes status and age-group when significant interactions were observed.	Among participants with diabetes, fasting glucose levels were positively associated with bedtime (approximately +3%/hour later, p < .01) and midpoint of sleep (approximately +2%/hour later, p < .05). In participants with and without diabetes combined, HOMA-IR was positively associated with midpoint of sleep (+1.5%/hr later, p < .05), and chronotype (+1.2%/hour later, p < .05). Associations differed by age-group. Among those < 36 years, later sleep timing was associated with lower BMI, lower fasting glucose, and lower HbA1c, but the opposite association was observed among older participants.	Later sleep timing was associated with higher estimated insulin resistance across all groups. Some associations between sleep timing and metabolic measures may be age-dependent.	
28328790	The aim of this study was to evaluate the effects of quetiapine XR and lithium on actigraphy-measured circadian parameters in patients with bipolar II depression.This was an 8-week, open-label, prospective, randomized comparative study. The assessments included the 17-item Hamilton Depression Rating Scale score and actigraphic measures concerning the previous 7 days, collected at each visit (weeks 0 [baseline], 1, 2, 4, 6, and 8); the actigraphic data were analyzed with a cosinor analysis.	Medication, time, and the interaction between medication and time were significantly associated with acrophase for the entire group (Ps = 0.003, 0.020, and 0.042, respectively). More specifically, acrophase was significantly delayed at weeks 1 and 6 (Ps = 0.004 and 0.039, respectively) in the quetiapine XR group. The F statistics significantly increased over time for the entire group (P < 0.001), and there was a significant increase in F statistics on weeks 4 and 6 in the quetiapine XR group (Ps = 0.016 and 0.020, respectively) and on weeks 4 and 8 in the lithium group (Ps = 0.001 and 0.016, respectively). In addition, scores on the 17-item Hamilton Depression Rating Scale were significantly associated with the F statistics during 8 weeks for the entire group (P = 0.008).	Both quetiapine XR and lithium affected several circadian parameters, including peak activity time and robustness of circadian rhythm, but exerted different effects on acrophase in patients with bipolar II depression. In particular, clinical depressive symptoms were associated with robustness of circadian rhythm during the course of the 8-week treatment.	
28328532	Adenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome.A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values.	A rare case of ectopic ACTH syndrome causing Cushing's syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing's syndrome.	
28327443	Attention-deficit/hyperactivity disorder (ADHD) is a common condition with comorbid insomnia reported in >70% of children and adults. These patients demonstrate delays in sleep-wake rhythms, nocturnal rise in melatonin, and early morning rise in cortisol. Given that standard psychopharmacologic treatments for ADHD often do not completely control symptoms in participants with circadian rhythm delay, we sought to test whether bright light therapy (BLT) advances circadian rhythms and further reduces ADHD symptoms over standard treatments. In addition to standard of care, participants with ADHD diagnosis underwent 1 week of baseline assessment followed by 2-weeks of 30-min morning 10,000-lux BLT beginning 3 h after mid-sleep time. Participants minimized overhead light after 4 p.m., wore an actigraphy watch, and recorded BLT time on daily sleep logs. Dim Light Melatonin Onset (DLMO) was assessed at baseline and after 2-week treatment. ADHD symptoms were measured by the ADHD-Rating Scales (ADHD-RS). BLT significantly advanced the phase of DLMO by 31 min [mean time (SEM), 20:36 (0:21) advanced to 20:05 (0:20)] and mid-sleep time by 57 min [4:37 (0:22) advanced to 3:40 (0:16); paired t-tests, p = 0.002 and 0.004, respectively). Phase advances (in DLMO or mid-sleep time) were significantly correlated with decreased ADHD-RS total scores (p = 0.027 and 0.044) and Hyperactive-Impulsive sub-scores (p = 0.014 and 0.013, respectively). Actigraphy analysis for a subset of 8 participants with significant DLMO phase advance revealed no significant changes in total sleep time, sleep efficiency, wake after sleep onset, or percent wake during sleep interval. This is the first successful use of BLT for advancing melatonin phase and improving ADHD symptoms in adults. BLT may be a complementary treatment for both delayed sleep timing and ADHD symptoms in adults.
28326910	The measurement of circulating levels of brain-derived neurotrophic factor (BDNF) has been proposed to be a marker of disease and an indicator of recovery. Thus, knowing the temporal pattern and influence of potential circadian rhythms is important. Although several studies have measured BDNF at different times of day, no studies have done so while controlling for potential masking influences such as sleep and activity. Further, no previous study has examined circadian rhythms within individuals. We examined circadian rhythms in plasma BDNF while minimizing masking from behavioral and environmental factors using a 30-h constant routine (CR) protocol. In a sample of 39 healthy adults, we found significant circadian rhythms in 75% of women and 52% of men. The timing of the acrophase of the BDNF rhythm, however, was unrelated to clock time in women, while it was related to clock time in men. These results indicate that the use of single-sample measures of plasma BDNF as a marker of disease will be unreliable, especially in women. Repeated plasma BDNF samples over a 24-h period within individuals would be needed to reveal abnormalities related to disease states.
28326909	Although the suprachiasmatic nucleus (SCN) has long been considered the master circadian clock in mammals, the topology of the connections that synchronize daily rhythms among SCN cells is not well understood. We combined experimental and computational methods to infer the directed interactions that mediate circadian synchrony between regions of the SCN. We analyzed PERIOD2 (PER2) expression from SCN slices during and after treatment with tetrodotoxin, allowing us to map connections as cells resynchronized their daily cycling following blockade and restoration of cell-cell communication. Using automated analyses, we found that cells in the dorsal SCN stabilized their periods slower than those in the ventral SCN. A phase-amplitude computational model of the SCN revealed that, to reproduce the experimental results: (1) the ventral SCN had to be more densely connected than the dorsal SCN and (2) the ventral SCN needed strong connections to the dorsal SCN. Taken together, these results provide direct evidence that the ventral SCN entrains the dorsal SCN in constant conditions.
28326116	The purpose of this study was to evaluate the applicability of data obtained from a wearable activity tracker (Fitbit Charge HR) to medical research. This was performed by comparing the wearable activity tracker (Fitbit Charge HR) with actigraphy (Actiwatch 2) for sleep evaluation and circadian rest-activity rhythm measurement.Sixteen healthy young adults (female participants, 62.5%; mean age, 22.8 years) wore the Fitbit Charge HR and the Actiwatch 2 on the same wrist; a sleep log was recorded over a 14-day period. We compared the sleep variables and circadian rest-activity rhythm measures with Wilcoxon signed-rank tests and Spearman's correlations.	The periods and acrophases of the circadian rest-activity rhythms and the sleep start times did not differ and correlated significantly between the Fitbit Charge HR and the Actiwatch 2. The Fitbit Charge HR tended to overestimate the sleep durations compared with the Actiwatch 2. However, the sleep durations showed high correlation between the two devices for all days.	We found that the Fitbit Charge HR showed high accuracy in sleep evaluation and circadian rest-activity rhythm measurement when compared with actigraphy for healthy young adults. The results suggest that the Fitbit Charge HR could be applicable on medical research as an alternative tool to actigraphy for sleep evaluation and measurement of the circadian rest-activity rhythm.	
28325554	In the Drosophila larval brain, type I and type II neuroblasts (NBs) undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors (INPs) exist only in type II NB lineages. In this study, we reveal a novel function of Inscuteable (Insc) that acts to maintain type I NB lineage identity. In insc type I NB clones of mosaic analyses with a repressible cell marker (MARCM), the formation of extra Deadpan (Dpn)+ NB-like and GMC-like cells is observed. The lack of Insc leads to the defective localization and segregation of Numb during asymmetric cell division. By the end of cytokinesis, this results in insufficient Numb in ganglion mother cells (GMCs). The formation of extra Deadpan (Dpn)+ cells in insc clones is prevented by the attenuation of Notch activity. This suggests that Insc functions through the Numb/Notch signaling pathway. We also show that in the absence of Insc in type I NB lineages, the cellular identity of GMCs is altered where they adopt an INP-like cell fate as indicated by the initiation of Dpn expression accompanied by a transient presence of Earmuff (Erm). These INP-like cells have the capacity to divide multiple times. We conclude that Insc is necessary for the maintenance of type I NB lineage identity. Genetic manipulations to eliminate most type I NBs with overproliferating type II NBs in the larval brain lead to altered circadian rhythms and defective phototaxis in adult flies. This indicates that the homeogenesis of NB lineages is important for the adult's brain function.
28324298	Alzheimer's disease (AD) is increasing in prevalence and has a significant impact on caregivers and the healthcare system. One of the many physiologic process affected by AD is the circadian system, with disruption reflected in abnormalities of the sleep-wake cycle. This interaction is bidirectional, with circadian and sleep disruption influencing disease progression. Understanding the bidirectional relationship between AD and circadian disruption may allow for earlier recognition of the potential to develop dementia as well as improved targeted approaches for therapy. Therapies including melatonin and bright light therapy may be advantageous in improving sleep and circadian rhythms and preventing the progression of disease. However, unfortunately, these modalities are not curative, and additional research is needed to improve treatment options for these individuals.
28324186	Smartphones are prevalently used among adolescents; however, nighttime exposure to blue-enriched light, through electric devices, is known to induce delays of the circadian rhythm phases and poor morning somatic conditions. We therefore investigated whether evening smartphone use may affect sleep-wake cycle and cardiac autonomic nervous system (ANS) activity after awaking in dormitory students.The participants were high school students, living under dormitory rules regarding the curfew, study, meals, lights-out, and wake-up times. The students were forbidden from the use of both television and personal computer in their private rooms, and only the use of a smartphone was permitted. According to prior assessment of smartphone use, we chose age-, sex-, exercise time-matched long (n = 22, >120 min) and short (n = 14, ≤60 min) groups and compared sleep-wake cycle and physiological parameters, such as cardiac ANS activity, blood pressure, and intra-aural temperature. All measurements were performed during 6:30 to 7:00 a.m. in the dormitories.	Compared with the short group, the long group showed a significantly lower cardiac ANS activity (2727 ± 308 vs. 4455 ± 667 ms2, p = 0.030) with a tendency toward a high heart rate, in addition to later bedtimes during weekdays and more delayed wake-up times over the weekend. Blood pressure and intra-aural temperature did not differ between the groups.	In this population, evening smartphone use may be associated with altered sleep-wake cycle and a diminished cardiac ANS activity after awakening could be affecting daytime activities.	
28324069	Most organisms, including humans, have developed an intrinsic system of circadian oscillators, allowing the anticipation of events related to the rotation of the Earth around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behavior. Together with systemic signals, emanating from the central clock which resides in the hypothalamus, peripheral oscillators orchestrate tissue-specific fluctuations in gene expression, protein synthesis, and posttranslational modifications, driving overt rhythms in physiology and behavior. There is increasing evidence on the essential roles of the peripheral oscillators operative in metabolically active organs in the regulation of body glucose homeostasis. Here, we review some recent findings on the molecular and cellular makeup of the circadian timing system and its implications in the temporal coordination of metabolism in health and disease.
28324022	The postnatal synchronization of the circadian variation of the adrenal clock genes in mammals remains unknown. We evaluated the postnatal ontogeny of daily variation of clock genes (Clock/Bmal1/Per1/Per2/Per3/Cry1/Cry2/Rorα/Rev-Erbα) and steroidogenesis-related genes (Star and Mc2r) in rat adrenals and its relationship with the emergence of plasma corticosterone rhythm using Cosinor analysis. Plasma corticosterone circadian rhythm was detected from postnatal day (P) P1, with morning acrophase, between zeitgeber time (ZT) ZT0 and ZT2. From P14, there was a nocturnal acrophase of corticosterone at ZT20, which was associated with pups' eye opening. Since P3 there was a circadian variation of the mRNA expression of Bmal1, Per2, Per3, Cry1 genes with morning acrophase whereas Rev-Erbα had nocturnal acrophase. From P14, Bmal1, Per2, Per3, Cry1 acrophases advanced by approximately 10h, as compared to early neonatal days, becoming vespertine-nocturnal. In all postnatal ages, Per2 and Cry1 circadian profiles were synchronized in phase while Bmal1 was in antiphase with the circadian rhythm of plasma corticosterone. Adult-like Star circadian rhythm profile was observed only from P21. In conclusion, our original data demonstrated a progressive postnatal maturation of the circadian variation of the adrenal clock genes in synchrony with the development of the corticosterone circadian rhythm in rats.
28324017	Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a novel selective BRS-3 agonist (Compound-A) and evaluated its anti-obesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced obese (DIO)-F344 rats. Moreover, repeated oral administration of Compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated Compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of Compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the mRNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Since SCN also controls the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of Compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. Based on this, the energy expenditure enhancement by Compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism and to the stimulation of sympathetic nervous system. Furthermore, the blood pressure increase by Compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through the activation of the HPA axis.
28322186	Isoflurane anesthesia alters the blood levels of several neuroendocrine hormones associated with normal metabolism andphysiology and increases stress, but the effect of brief CO2 anesthesia on these parameters is unknown. In this study, we examined the effects of isoflurane (4%) compared with brief CO2 (70% CO2, 30% air) anesthesia on circadian rhythms of plasma measures of physiology and metabolism. Adult male Sprague-Dawley rats (Crl:SD; n = 6 per group) were maintained on a 12:12-h light:dark(300 lx; lights on, 0600) photoperiod. After 1 wk of acclimation, a series of 6 low-volume blood draws were collected by cardiocentesis under anesthesia using isoflurane (10 min or less) compared with CO2 (1 min or less) at a single circadian time point every 4 d (0400, 0800, 1200, 1600, 2000, or 2400) over 3 wk to assess arterial blood glucose, lactic acid, and potassium and plasma melatonin,leptin, insulin, total fatty acids, and corticosterone concentrations. Results revealed that plasma levels (mean ± SEM) of melatonin were low (11 ± 1 pg/mL) during the light phase in both groups but were significantly lower during the dark phase in the isoflurane group (48 ± 6 pg/mL) compared with the CO2 group (162 ± 18 pg/mL). In addition, prominent circadian rhythms of arterial plasma levels of corticosterone, glucose, total fatty acids, lactic acid, and potassium were altered in the isoflurane group compared withthe CO2 group. These findings demonstrate that the normal circadian rhythms of endocrine physiology and metabolism observedduring brief CO2 anesthesia in rats are markedly disrupted by isoflurane anesthesia.
28322083	Melanin-concentrating hormone (MCH), the neuropeptide produced mainly in the hypothalamus, plays an operative role in regulating food intake and the sleep/wake cycle. Considering that these physiological functions pursue diurnal variations, we checked whether the total hypothalamic MCH level depends on the time of the day. The aggregated MCH peptide content of the whole MCH neuron population was significantly higher at the end of the sleeping period (lights on), than at the end of the active period (lights off). This result, together with earlier observations, indicates that in contrast to the MCH gene expression, the level of MCH peptide is object of circadian variation in the hypothalamus.
28321642	We review recent evidence for circadian rhythm dysregulation in bipolar spectrum disorders (BSDs). We examine evidence for endogenous abnormalities in the biological clock and disruptions in the external entrainment of circadian rhythms in BSDs. We also address whether circadian dysregulation provides vulnerability to onset of BSD and evidence for a new integration of reward and circadian dysregulation in BSD.Relative circadian phase delay (e.g., later melatonin peak, evening chronotype) is associated with BSD, particularly in the depressive phase. More consistent evidence supports irregularity of social rhythms, sleep/wake and activity patterns, and disruptions of social rhythms by life events, as stable trait markers of BSD and potential vulnerabilities for BSD onset. Growing research supports an integrative reward/circadian model. Both endogenous abnormalities in the biological clock pacemaking function and disruptions in the external entrainment of circadian rhythms by physical and social cues are involved in BSDs. Circadian dysregulation may provide vulnerability to BSD onset.	
28320839	Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect.SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic entrainment in nocturnal animals. How these stimuli act in diurnal species remains to be established. Our study in a diurnal rodent, the Grass rat, indicates that sleep deprivation in the early rest period induces phase delays of circadian locomotor activity rhythm. Contrary to nocturnal rodents, both sleep deprivation and caffeine-induced arousal potentiate the photic entrainment in a diurnal rodent. Such enhanced light-induced circadian responses could be relevant for developing chronotherapeutic strategies.
28319944	The impact of time-of-day on the cognitive performance of older patients with limited cognitive reserve after a transient ischemic attack (TIA) or stroke, and on short cognitive tests, such as the Montreal Cognitive Assessment (MoCA), is unknown. We retrospectively studied whether morning versus afternoon assessment might affect the classification of patients aged 70 or older as severe (SCI), mild (MCI), and no (NCI) cognitive impairment by the MoCA.Morning (12 p.m. or earlier) versus afternoon (later than 12 p.m.) proportions of SCI (MoCA score <20), MCI (MoCA score 25-20) and NCI (MoCA score ≥26) were compared in a cohort of patients aged ≥70, attending a rapid-access TIA/stroke clinic.	Of 278 patients, 113 (40.6%) were tested in the morning and 165 (59.4%) in the afternoon. The proportion with SCI was greater in the afternoon than in the morning (10.9 vs. 1.8%, respectively, p = 0.004), with no difference in age, education, diagnosis, disability, or vascular risk factors.	Time-of-day appears to affect cognitive performance of older patients after they undergo TIA and minor stroke. If our cross-sectional findings are confirmed in cross-over studies with repeated testing, timing of assessments should be considered in clinical practice and in research studies.	
28318584	Biological rhythms are an essential regulator of life. There is evidence that circadian rhythm of activity is disrupted under chronic stress in animals and humans, and it may also be less marked during diseases. Here we investigated whether a detectable circadian rhythm of activity exists in dairy cows in commercial settings using a real-time positioning system. We used CowView (GEA Farm Technologies) to regularly record the individual positions of 350 cows in a Danish dairy farm over 5 mo and to infer the cows' activity (resting, feeding, in alley). We ran a factorial correspondence analysis on the cows' activities and used the first component of this analysis to express the variations in activity. On this axis, the activities obtained the following weights: resting = -0.15; in alleys = +0.12; feeding = +0.34. By applying these weights to the proportions of time each cow spent on each of the 3 activities, we were able to chart a circadian rhythm of activity. We found that average level of activity of a cow on a given day and its variations during that day varied with specific states (i.e., estrus, lameness, mastitis). More specifically, circadian variations in activity appeared to be particularly sensitive and to vary 1 to 2 d before the farmer detected a disorder. These findings offer promising avenues for further research to design models to predict physiological or pathological states of cows from real-time positioning data.
28318412	The aim of this study was to investigate lithium and 2,4-dichlorophenol (2,4-DCP)-induced circadian rhythm disorder and their genome-wide effects in zebrafish. Zebrafish larvae were exposed to 250 ppm LiCl (n = 40) or 20 ppm 2,4-DCP. RNA was subsequently extracted and determined quantitatively. The mRNA levels of circadian clock-related genes, including clock1a, bmal1b, per2, and per1b, were determined. Microarray datasets were generated and the differentially expressed genes (DEGs) were identified. The mRNA levels of some upregulated and downregulated DEGs were examined by quantitative real-time polymerase chain reaction (RT-PCR). Finally, gene ontology (GO) enrichment analysis was applied to determine the roles of the DEGs. The mRNA expression levels of circadian rhythm-related genes in the daily cycle were significantly affected after incubation of zebrafish with LiCl and 2,4-DCP. Many genes were differentially expressed during the light phase (97 h) and RT-PCR validation tests revealed that the expression patterns of DEGs were in accordance with those obtained by microarray analysis. GO functional enrichment analysis showed that the DEGs in LiCl- and 2,4-DCP-treated groups were associated with signal transduction and development. Collectively, our findings indicate that LiCl and 2,4-DCP could affect signal transduction pathways and immune response, thereby inducing circadian rhythm disorder.
28317486	In addition to cognitive decline, Alzheimer's Disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and have been referred to as 'sundowning'. They are especially difficult for carers and there are no specific drug treatments. There is increasing evidence that these symptoms reflect pathology of circadian rhythm generation and transmission.We investigated whether a transgenic mouse model relevant to AD (APPswe/PS1dE9) exhibits circadian alterations in locomotor activity in their home cage and whether expression of clock genes involved in the regulation of the circadian cycle is abnormal in the hippocampus and medulla-pons brain regions isolated from these mice.	In 2month old female mice the APPswe/PS1dE9 transgene alters levels and patterns in circadian rhythm of locomotor activity. Expression of the clock genes Per1, Per2, Cry1 and Cry2 was found to increase at night compared to day in wild-type control mice in the medulla/pons. This effect was blunted for Cry1 and Cry2 gene expression in APPswe/PS1dE9.	This study suggests altered circadian regulation of locomotor activity is abnormal in female APPswe/ PS1dE9 mice and that this alteration has biomolecular analogies in a widely available model of AD. The early age at which these effects are manifest suggests that these circadian effects may precede plaque development. The APPswe/PS1dE9 mouse genetic model may have potential to serve as a tool in understanding the neuropathology of circadian abnormalities in AD and as a model system to test novel therapeutic agents for these symptoms.	
28314944	Genome-wide association studies have detected an association between type 2 diabetes risk and a non-coding SNP located in MTNR1B, the gene encoding melatonin receptor 2 (MT2). Melatonin regulates circadian rhythms and sleep and associates with metabolic disorders. However, the mechanisms underlying these actions are still unclear. Functional genomic, animal and clinical studies have not reached the same conclusions: while some studies have reported that decreased melatonin signalling increases type 2 diabetes risk, others have found the opposite. In this commentary, we have tried to provide an explanation for these contradictions and we suggest how the community may progress to reach a unified picture of the effect of melatonin and its signalling on type 2 diabetes.
28314850	The occurrence of ventricular tachyarrhythmias seems to follow circadian, daily, and seasonal distributions. Our aim is to identify potential temporal patterns of electrical storm (ES), in which a cluster of ventricular tachycardias or ventricular fibrillation, negatively affects short- and long-term survival.The TEMPEST study (Circannual Pattern and Temperature-Related Incidence of Electrical Storm) is a patient-level, pooled analysis of previously published data sets. Study selection criteria included diagnosis of ES, absence of acute coronary syndrome as the arrhythmic trigger, and ≥10 patients included. At the end of the selection and collection processes, 5 centers had the data set from their article pooled into the present registry. Temperature data and sunrise and sunset hours were retrieved from Weather Underground, the largest weather database available online. Total sample included 246 patients presenting with ES (221 men; age: 65±9 years). Each ES episode included a median of 7 ventricular tachycardia/ventricular fibrillation episodes. Fifty-nine percent of patients experienced ES during daytime hours (P<0.001). The prevalence of ES was significantly higher during workdays, with Saturdays and Sundays registering the lowest rates of ES (10.4% and 7.2%, respectively, versus 16.5% daily mean from Monday to Friday; P<0.001). ES occurrence was significantly associated with increased monthly temperature range when compared with the month before (P=0.003).	ES incidence is not homogenous over time but seems to have a clustered pattern, with a higher incidence during daytime hours and working days. ES is associated with an increase in monthly temperature variation.	https://www.crd.york.ac.uk. Unique identifier: CRD42013003744.	
28303945	Human sleep-wake cycles are entrained by both natural and artificial light-dark cycles. However, little is known regarding when and how the photoperiod changes entrain the biological clock after conception. To investigate the dependence of sleep patterns in young infants on the natural and artificial light-dark cycles, 1,302 pairs of one-month-old infants and their mothers were asked to answer a questionnaire. Birth in spring, longer daytime sleep duration, early/regular light-off times, and longer maternal nighttime sleep duration were identified as independent variables for longer infant nighttime sleep duration in both univariate and multivariate analyses. Longer maternal nighttime sleep duration was dependent on shorter naps and early/regular bed times but not on the season. We found that nighttime sleep duration depended on both natural and artificial diurnal photoperiod changes in one-month-old infants. Although sleep patterns of infants mimicked those of their mothers, nighttime sleep duration depended on the season, and was positively associated with daytime sleep duration, only in the infants. These specific variables, which render sleep patterns of the infants different from those of their mothers, might be a clue to reveal the covert acquisition process of mature circadian rhythms after birth.
28302851	Circadian clocks are ubiquitous timing systems that induce rhythms of biological activities in synchrony with night and day. In cyanobacteria, timing is generated by a posttranslational clock consisting of KaiA, KaiB, and KaiC proteins and a set of output signaling proteins, SasA and CikA, which transduce this rhythm to control gene expression. Here, we describe crystal and nuclear magnetic resonance structures of KaiB-KaiC,KaiA-KaiB-KaiC, and CikA-KaiB complexes. They reveal how the metamorphic properties of KaiB, a protein that adopts two distinct folds, and the post-adenosine triphosphate hydrolysis state of KaiC create a hub around which nighttime signaling events revolve, including inactivation of KaiA and reciprocal regulation of the mutually antagonistic signaling proteins, SasA and CikA.

28296079	MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome (PWS)-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild-type (WT) allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three-chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general.
28295807	Circadian cycles and photoperiod are known to influence reproductive physiology in several animals. Neuropeptides, such as gonadotropin-inhibitory hormone (GNIH) and gonadotropin-releasing hormone (GNRH), are influenced by melatonin in birds and mammals. The present study demonstrates the role of melatonin in oocyte maturation in the zebrafish (Danio rerio), via the brain-pituitary-reproductive axis, under different photic conditions. Melatonin was significantly higher both in the whole brain and ovary under continuous dark (DD) compared to continuous light (LL) conditions. Transcription of gnih in the brain was high in LL, but low in DD; similarly, melatonin exogenous treatment reduced gnih in cultured brain in a dose-dependent manner. Expression of gnrh3, however, was high in both continuous photic conditions (DD and LL), whereas fshb and lhb were high only during DD. kiss2, another neuropeptide, was high in LL, but kiss1 remain unchanged among the conditions. At the gonad level, expression of fshr, lhcgr, mtnr1aa, and mtnr1ab tracked with the expression of their respective ligand in DD and LL. The expression of mprb is high in DD ovary, although intra-ovarian growth factors (tgfb1a and bmp15) were low. The measured increased percentages of germinal vesicle breakdown, expression of Cyclin B1, and reduced Cdc2p34 phosphorylation are consistent with increased maturation in the dark. Our study thus links melatonin to the inhibition of gnih in the brain-pituitary-reproductive axis of zebrafish in response to photic conditions.
28295415	Nicotinamide adenine dinucleotide (NAD+ ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+ -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology.
28295377	The soaring prevalence of obesity and diabetes is associated with an increase in comorbidities, including elevated risk for cardiovascular diseases (CVDs). CVDs continue to be among the leading causes of death and disability in the United States. While increased nutritional intake from an energy-dense diet is known to disrupt metabolic homeostasis and contributes to the disease risk, circadian rhythm disruption is emerging as a new risk factor for CVD. Circadian rhythms coordinate cardiovascular health via temporal control of organismal metabolism and physiology. Thus, interventions that improve circadian rhythms are prospective entry points to mitigate cardiometabolic disease risk. Although light is a strong modulator of the neural circadian clock, time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs. We discovered that imposing a time-restricted feeding (TRF) regimen in which all caloric intakes occur consistently within ≤ 12 h every day exerts many cardiometabolic benefits. TRF prevents excessive body weight gain, improves sleep, and attenuates age- and diet-induced deterioration in cardiac performance. Using an integrative approach that combines Drosophila melanogaster (fruit fly) genetics with transcriptome analyses it was found that the beneficial effects of TRF are mediated by circadian clock, ATP-dependent TCP/TRiC/CCT chaperonin and mitochondrial electron transport chain components. Parallel studies in rodents have shown TRF reduces metabolic disease risks by maintaining metabolic homeostasis. As modern humans continue to live under extended periods of wakefulness and ingestion events, daily eating pattern offers a new potential target for lifestyle intervention to reduce CVD risk.
28293860	The oxidative status is associated with animal lifespan, metabolism, activity and circadian rhythms. The objective of this work is to study the time course of the oxidative status over a daily cycle in the plasma, liver and brain, and the changes in the plasma cortisol levels of sturgeon and trout. The knowledge of daily oxidative status will provide a better understanding of the trout and sturgeon physiology and adequate maintenance and food supply of farmed fish in relation to photoperiod. Superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase, DT-diaphorase activities, lipid peroxidation and cortisol were measured. Our results showed that the antioxidative enzyme activities and lipid peroxidation in the liver of trout and sturgeon changed through the day, with increased levels in lipid peroxidation of liver in the dark period for sturgeon. This could be related to the different activity time in both species, an issue to be taken into account when designing the guidelines of the maintenance of these species in fish farms. On the contrary, there was not clear influence of the daily rhythms on brain oxidative status. The higher efficiency of the antioxidant defences in the brain of sturgeon, which displays less lipid peroxidation and higher antioxidative activity, could be related to its longer life expectancy. The absence of any apparent daily rhythm in the plasma cortisol levels in sturgeon could indicate a lower susceptibility to stress, and that mechanisms involved in cortisol secretion in chondrosteans could be different from that described for teleosteans.
28292665	We sought to characterize ambient light exposure in the intensive care unit (ICU) environment to identify patterns of light exposure relevant to circadian regulation.A light monitor was affixed to subjects' bed at eye level in a modern intensive care unit and continuously recorded illuminescence for at least 24h per subject. Blood was sampled hourly and measured for plasma melatonin. Subjects underwent hourly vital sign and bedside neurologic assessments. Care protocols and the ICU environment were not modified for the study.	A total of 67,324 30-second epochs of light data were collected from 17 subjects. Light intensity peaked in the late morning, median 64.1 (interquartile range 19.7-138.7) lux. The 75th percentile of light intensity exceeded 100lx only between 9AM and noon, and never exceeded 150lx. There was no correlation between melatonin amplitude and daytime, nighttime or total light exposure (Spearman's correlation coefficients all <0.2 and p>0.5).	Patients' environmental light exposure in the intensive care unit is consistently low and follows a diurnal pattern. No effect of nighttime light exposure was observed on melatonin secretion. Inadequate daytime light exposure in the ICU may contribute to abnormal circadian rhythms.	
28291597	This study investigated the diel emission of volatile organic compounds (VOCs) from intact apple (Malus x domestica Borkh., cv. Golden Delicious) and grape (Vitis vinifera L., cv. Pinot Noir) foliage. Volatiles were monitored continuously for 48 h by proton transfer reaction - time of flight - mass spectrometry (PTR-ToF-MS). In addition, volatiles were collected by closed-loop-stripping-analysis (CLSA) and characterized by gas chromatography-mass spectrometry (GC-MS) after 1 h and again 24 and 48 h later. Fourteen and ten volatiles were characterized by GC-MS in apple and grape, respectively. The majority of these were terpenes, followed by green leaf volatiles, and aromatic compounds. The PTR-ToF-MS identified 10 additional compounds and established their diel emission rhythms. The most abundant volatiles displaying a diel rhythm included methanol and dimethyl sulfide in both plants, acetone in grape, and mono-, homo- and sesquiterpenes in apple. The majority of volatiles were released from both plants during the photophase; whereas methanol, CO2, methyl-butenol and benzeneacetaldehyde were released at significantly higher levels during the scotophase. Acetaldehyde, ethanol, and some green leaf volatiles showed distinct emission bursts in both plants following the daily light switch-off. These new results obtained with a combined analytical approach broaden our understanding of the rhythms of constitutive volatile release from two important horticultural crops. In particular, diel emission of sulfur and nitrogen-containing volatiles are reported here for the first time in these two crops.
28288095	The Earth's rotation forced life to evolve under cyclic day and night environmental changes. To anticipate such daily cycles, prokaryote and eukaryote free-living organisms evolved intrinsic clocks that regulate physiological and behavioural processes. Daily rhythms have been observed in organisms living within hosts, such as parasites. Whether parasites have intrinsic molecular clocks or whether they simply respond to host rhythmic physiological cues remains unknown. Here, we show that Trypanosoma brucei, the causative agent of human sleeping sickness, has an intrinsic circadian clock that regulates its metabolism in two different stages of the life cycle. We found that, in vitro, ∼10% of genes in T. brucei are expressed with a circadian rhythm. The maximum expression of these genes occurs at two different phases of the day and may depend on a post-transcriptional mechanism. Circadian genes are enriched in cellular metabolic pathways and coincide with two peaks of intracellular adenosine triphosphate concentration. Moreover, daily changes in the parasite population lead to differences in suramin sensitivity, a drug commonly used to treat this infection. These results demonstrate that parasites have an intrinsic circadian clock that is independent of the host, and which regulates parasite biology throughout the day.
28287879	Only a few studies have evaluated the abnormalities of ambulatory blood pressure (ABP) in patients with nephrotic syndrome (NS).The 24-h ABPs were measured in primary NS patients with acute onset of disease and analyzed in relation to the clinical variables.	Our subjects comprised 21 patients: 17 with minimal change disease and 4 with focal segmental glomerulosclerosis. Of these patients, 8 (38%) had daytime hypertension, 13 (62%) had nighttime hypertension, and 13 (62%) were non-dippers (nighttime-to-daytime ratio of ABP: NDR > 0.9). The serum sodium level was correlated with the average 24-h ABP and NDR, after adjustment for other clinical variables, such as the increase in body weight, serum albumin level, and urinary protein excretion. The data from repeated ABP measurements, before and after the achievement of remission, showed a marked decrease in the average 24-h ABP after remission. Furthermore, change in the serum sodium level was significantly correlated with the change in NDR.	These results suggest that alteration in renal handling of sodium and water, which might be reflected in serum sodium level, is involved in the abnormality of circadian blood pressure in primary NS patients.	
28287684	Adequate sleep can easily become compromised as student-athletes try to balance the multiple demands on their time. People with sleep deficiency are at increased risk for acute illnesses, traumatic sports injuries, and development of chronic diseases. Training sessions or competitions during extremely early or late hours can interfere with circadian and homeostatic rhythms. Adjusting the training schedule to improve sleep duration has a significantly positive impact on several aspects of athletic performance. Pediatricians should increase the time dedicated in well-child visits for sleep hygiene and evaluate for sleep disorders at all ages. Parents, coaching staff, teachers, and pediatricians should advocate for improved education on the importance of sleep during adolescence. Future sleep research specific to adolescent athletes can further delineate requirements specific to sport, gender, training times, and surrounding competitions. [Pediatr Ann. 2017;46(3):e106-e111.].
28286126	In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the main circadian clock, synchronized by the light-dark cycle, which generates behavioral rhythms like feeding, drinking and activity. Notwithstanding, the main role of the SCN clock on the control of all circadian rhythms has been questioned due to the presence of clock activity in many brain areas, including those implicated in the regulation of feeding and reward. Moreover, whether circadian rhythms of particular motivated behaviors exist is unknown. Here, we evaluated the spontaneous daily and circadian behavior of consumption of a sweet caloric solution (5-10% sucrose), and the effects of sucrose intake on the expression of clock genes in the mouse brain. Mice showed a daily (in a light-dark cycle) and a circadian (in constant darkness conditions) rhythm in the intake and sucrose preference with a rise for both parameters at night (or subjective night). In addition, we observed changes in the circadian day-night expression of the clock gene Per2 in the SCN, cortex and striatum of animals ingesting sucrose compared to control mice on pure water. Finally, daily rhythms of sucrose intake and preference were abolished in Per2Brdm1- and double Per1-/-Per2Brdm1-mutant animals. These data indicate that the expression of circadian rhythms of hedonic feeding behaviors may be controlled by brain circadian clocks and Per gene expression.
28285822	The suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms of physiology and behavior in mammals. Its circadian (∼24 hr) oscillations of gene expression and electrical activity are generated intrinsically and can persist indefinitely in temporal isolation. This robust and resilient timekeeping is generally regarded as a product of the intrinsic connectivity of its neurons. Here we show that neurons constitute only one "half" of the SCN clock, the one metabolically active during circadian daytime. In contrast, SCN astrocytes are active during circadian nighttime, when they suppress the activity of SCN neurons by regulating extracellular glutamate levels. This glutamatergic gliotransmission is sensed by neurons of the dorsal SCN via specific pre-synaptic NMDA receptor assemblies containing NR2C subunits. Remarkably, somatic genetic re-programming of intracellular clocks in SCN astrocytes was capable of remodeling circadian behavioral rhythms in adult mice. Thus, SCN circuit-level timekeeping arises from interdependent and mutually supportive astrocytic-neuronal signaling.
28285255	Few studies have examined relationships between circadian rhythms and unipolar major depressive disorder. Further, no study to date has examined circadian markers as predictors of response to depression treatment. In the present study, we examined associations between circadian timing and its alignment with sleep and depression severity in 30 adults with major depressive disorder who completed a randomized controlled trial of two weeks of time in bed (TIB) restriction administered adjunctive to fluoxetine, with a focus on sex differences. Thirty adults with major depressive disorder received 8 weeks of fluoxetine 20-40 mgs and were randomized to 8h TIB or 6h TIB for the first 2 weeks. Participants in the 6h TIB condition were further randomized to a delayed bedtime or advanced risetime group. Circadian measures included dim light melatonin onset (DLMO) and the difference between DLMO and midsleep point (i.e., phase angle difference). Depression was assessed using the Hamilton Rating Scale for Depression. For females, a phase delay after 2 weeks of fluoxetine and the experimental TIB manipulation was associated with a poorer response to fluoxetine, and depression severity was negatively correlated with phase angle difference, whereas males showed a positive correlation between depression severity and phase angle difference.
28284990	The circadian clock is an endogenous 24 hour rhythm that helps organisms anticipate and adapt to daily and seasonal variations in environment, such as the day/night cycle or changing temperatures. The plant clock is a complex network of transcription factors that regulate each other, forming interlocked feedback loops. Most of its components are light-regulated in some way, making the system highly sensitive to changes in light conditions. Here, we explore the mechanisms by which the plant clock adapts to changing day length. We first present some experimental data illustrating the variety of behaviors found in seedlings exposed to external day/night cycles different from 24h. We then use a mathematical model to characterize the response of the clock to a wide range of external cycle lengths and photoperiods. We show the existence of several domains of periodic entrainment with different ratios between the external cycle length and the period of the clock, and the presence of quasiperiodic and chaotic behaviors outside of the entrainment range. We simulate knockout mutants with impaired clock function and theoretical variants with diminished light sensitivity to highlight the role of a complex network and multiple light inputs in keeping the clock entrained over a wide range of conditions.
28284911	The aim of this study was to determine the association of sleep quality and sleep quantity with metabolic syndrome in Qazvin, Iran.this cross sectional study was conducted in 1079 residents of Qazvin selected by multistage cluster random sampling method in 2011. Metabolic syndrome was defined according to the criteria proposed by the national cholesterol education program third Adult treatment panel. Sleep was assessed using the Pittsburgh sleep quality index (PSQI). A logistic regression analysis was used to examine the association of sleep status and metabolic syndrome.	Mean age was 40.08±10.33years. Of 1079, 578 (52.2%) were female, and 30.6% had metabolic syndrome. The total global PSQI score in the subjects with metabolic syndrome was significantly higher than subjects without metabolic syndrome (6.30±3.20 vs. 5.83±2.76, P=0.013). In logistic regression analysis, sleep disturbances was associated with 1.388 fold increased risk of metabolic syndrome after adjustment for age, gender, and body mass index.	Sleep disturbances component was a predictor of metabolic syndrome in the present study. More longitudinal studies are necessary to understand the association of sleep quality and its components with metabolic syndrome.	
28279595	Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.
28277424	Time of day is a key factor that influences the optimization of athletic performance. Intercollegiate coaches oftentimes hold early morning strength training sessions for a variety of factors including convenience. However, few studies have specifically investigated the effect of early morning vs. late afternoon strength training on performance indices of fatigue. This is athletically important because circadian/ultradian rhythms and alterations in sleep patterns can impact training ability. Therefore, the purpose of the present study was to examine the effects of morning vs. afternoon strength training on an acute performance index of fatigue (countermovement jump height, CMJ), player readiness (Omegawave), and self-reported sleep quantity. We hypothesized afternoon training sessions would be associated with increased levels of performance, readiness, and self-reported sleep. A retrospective analysis was performed on data collected over the course of the pre-season on 10 elite NCAA Division 1 male basketball players. All basketball related activities were performed in the afternoon with strength and conditioning activities performed either in the morning of afternoon. The average values for CMJ, Power output (Power), self-reported sleep quantity (sleep), and player readiness were examined. When player load and duration were matched CMJ (58.8±1.3 vs. 61.9±1.6cm, p = 0.009), power (6378.0±131.2 vs. 6622.1±172.0 W, p = 0.009) and self-reported sleep duration (6.6 + 0.4 vs 7.4 + 0.25 p = 0.016) were significantly higher with afternoon strength and conditioning training, with no differences observed in player readiness values. We conclude that performance is suppressed with morning training and is associated with a decrease in self-reported quantity of sleep.
28276854	The aim of the present study was to investigate the impact of endogenous and exogenous factors for the expression of the daily rhythms of body temperature (BT), blood pressure (BP) and heart rate (HR). One hundred and seventy-three young adults (YA), 17-24 years old (y.o.), of both genders were studied under a modified constant-routine (CR) protocol for 26 h. Participants were assigned randomly to groups with different lighting regimens: CR-LD, n = 77, lights (>400 l×) on from 09:00 to 17:00 h and off (<10 l×) from 17:00 to 09:00 next morning; CR-LL, n = 81, lights on (>400 l×) during the whole experimental session; CR-DD, n = 15, constant dim light (<10 l×) during the whole experiment. Systolic (SBP) and diastolic (DBP) BP, HR and BT were measured every 2 h. For comparison, the results of the former studies performed under conditions of regular life with an activity period from 07:00 to 23:00 h and sleep from 23:00 till 07:00 h (Control) were reanalyzed. Seven-day Ambulatory Blood Pressure Monitoring (ABPM) records from 27 YA (16-38 y.o.) and BT self-measurement data from 70 YA (17-30 y.o.) taken on ≥ 3 successive days at 08:00, 11:00, 14:00, 17:00, 20:00, 23:00 and 03:00 were available. The obtained daily patterns were different between Control and CR-DD groups, due to effects of activity, sleep and light. The comparison of Control and CR-LD groups allowed the effects of sleep and activity to be estimated since the lighting conditions were similar. The activity level substantially elevated SBP, but not DBP. Sleep, on the other hand, lowered the nighttime DBP, but has no effect on SBP. HR was affected both by activity and sleep. In accordance with previous studies, these results confirm that the steep BP increase in the morning is not driven by the circadian clock, but rather by sympathoadrenal factors related to awakening and corresponding anticipatory mechanisms. The effect on BT was not significant. To investigate the impact of light during the former dark time and darkness during the former light time, the CR-LL and CR-DD groups were each compared with the CR-LD group. Light delayed the evening decrease of BT, most likely via a suppression of the melatonin rise. Besides, it had a prominent arousal effect on SBP both in the former light and dark phases, a moderate effect on DBP and no effect on HR. Darkness induced decline in BT. BP values were decreased during the former light time. No effects on HR were found. Altogether, the results of the present paper show that BT, BP and HR are affected by exogenous factors differently. Moreover, the effect was gender-specific. Especially, the response of BT and BP to ambient light was evident only in females. We suppose that the distinct, gender-specific responses of SBP, DBP and HR to activity, sleep and ambient light do reflect fundamental differences in the circadian control of various cardiovascular functions. Furthermore, the presented data are important for the elaboration of updated reference standards, the interpretation of rhythm disorders and for personalized chronotherapeutic approaches to prevent adverse cardiovascular events more effectively.
28276853	Chemotherapy and its associated side effects can induce the disruption of circadian rest-activity rhythm and may have negative consequences on health-related quality of life (HRQoL) of cancer patients. In the current study, repeated-measures cross-sectional design was implemented to determine the status of circadian rest-activity rhythm and to assess the HRQoL of newly diagnosed female breast cancer patients those were planned to receive six cycles of chemotherapy. Rest activity and HRQoL were assessed in twenty-five patients during chemotherapy cycles 1st (C1), 3rd (C3), and 6th (C6) immediately after they reported to the outdoor ward of the Regional Cancer Center, Pt. J.N.M. Medical College, Dr. B.R. Ambedkar Memorial Hospital, Raipur, India. Wrist actigraphs for consecutive spans of 3-4 days were used to record the rest-activity rhythm, and its parameters were computed with the help of Cosinor Rhythmometry. Quality of life (QoL) parameters were assessed using EORTC QLQ-C30 and QLQ-BR23. Results revealed that average scores of all rhythm parameters, such as MESOR, amplitude, acrophase, rhythm quotient, circadian quotient, peak activity, dichotomy index, and autocorrelation coefficient; and all functional scales of QLQ-C30, such as physical, role, emotional, cognitive, and social, and global quality of life statistically significantly decreased with the increasing number of chemotherapy cycles (C1 to C3 and C6). Scores of symptom scales of QLQ-C30, such as fatigue, pain, dyspnoea, insomnia, appetite loss, and diarrhea increased significantly from C1 to C6. Among the QLQ-BR23 scales, scores of sexual functioning, sexual enjoyment, breast symptoms, and arm symptoms significantly decreased, whereas scores of systemic therapy side effects, and upset by hair loss significantly increased across the chemotherapy cycles. We conclude that rest-activity rhythm disrupted and HRQoL of breast cancer patients worsened along the increasing number of chemotherapy cycles. We suggest that along with the treatment protocol, level of disruption of these parameters should be assessed and managed with the proper interventions that prominently include timing of the chemotherapy administration. The latter is pivotal for maintenance of these parameters, which are likely to enhance the physiological ability of patients for better treatment responses and may improve the overall QoL and survival of the patients.
28276851	Actigraphy is the reference objective method to measure circadian rhythmicity. One simpler subjective approach to assess the circadian typology is the Morningness-Eveningness Questionnaire (MEQ) by Horne and Ostberg. In this study, we compared the MEQ score against the actigraphy-based circadian parameters MESOR, amplitude and acrophase in a sample of 54 students of the University of Milan in Northern Italy. MEQ and the acrophase resulted strongly and inversely associated (r = -0.84, p < 0.0001), and their relationship exhibited a clear-cut linear trend. We thus used linear regression to develop an equation enabling us to predict the value of the acrophase from the MEQ score. The parameters of the regression model were precisely estimated, with the slope of the regression line being significantly different from 0 (p < 0.0001). The best-fit linear equation was: acrophase (min) = 1238.7-5.49·MEQ, indicating that each additional point in the MEQ score corresponded to a shortening of the acrophase of approximately 5 min. The coefficient of determination, R2, was 0.70. The residuals were evenly distributed and did not show any systematic pattern, thus indicating that the linear model yielded a good, balanced prediction of the acrophase throughout the range of the MEQ score. In particular, the model was able to accurately predict the mean values of the acrophase in the three chronotypes (Morning-, Neither-, and Evening-types) in which the study subjects were categorized. Both the confidence and prediction limits associated to the regression line were calculated, thus providing an assessment of the uncertainty associated with the prediction of the model. In particular, the size of the two-sided prediction limits for the acrophase was about ±100 min in the midrange of the MEQ score. Finally, k-fold cross-validation showed that both the model's predictive ability on new data and the model's stability to changes in the data set used for parameter estimation were good. In conclusion, the actigraphy-based acrophase can be predicted using the MEQ score in a population of college students of North Italy.
28276850	A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.
28276525	Vertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). The hRPE-YC cells demonstrated circadian rhythms in Bmal1 transcription. Also, these cells represented circadian rhythms in Ca2+-spiking frequencies, which were canceled by dominant-negative Bmal1 transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted Bmal1 transcriptional rhythms with a type-1 phase response curve. This is consistent with significant M3 muscarinic receptor expression and little photo-sensor (Cry2 and Opn4) expression in these cells. Moreover, forskolin phase-shifted Bmal1 transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative Bmal1 transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca2+ signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks.
28276426	Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability. In addition, mir-92a levels within PDF cells respond to light pulses and also affect the phase shift response. Translating ribosome affinity purification (TRAP) and in vitro luciferase reporter assay indicate that mir-92a suppresses expression of sirt2, which is homologous to human sir2 and sirt3. sirt2 RNAi also phenocopies mir-92a overexpression. These experiments indicate that sirt2 is a functional mir-92a target and that mir-92a modulates PDF neuronal excitability via suppressing SIRT2 levels in a rhythmic manner.
28275212	Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs) have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA) microarrays were conducted in an NAFLD rodent model. Potential target genes of significantly changed lncRNA were predicted using cis/trans-regulatory algorithms. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to explore their function. In the current analysis, 89 upregulated and 177 downregulated mRNAs were identified, together with 291 deregulated lncRNAs. Bioinformatic analysis of these RNAs has categorized these RNAs into pathways including arachidonic acid metabolism, circadian rhythm, linoleic acid metabolism, peroxisome proliferator-activated receptor (PPAR) signaling pathway, sphingolipid metabolism, steroid biosynthesis, tryptophan metabolism and tyrosine metabolism were compromised. Quantitative polymerase chain reaction (qPCR) of representative nine mRNAs and eight lncRNAs (named fatty liver-related lncRNA, FLRL) was conducted and this verified previous microarray results. Several lncRNAs, such as FLRL1, FLRL6 and FLRL2 demonstrated to be involved in circadian rhythm targeting period circadian clock 3 (Per3), Per2 and aryl hydrocarbon receptor nuclear translocator-like (Arntl), respectively. While FLRL8, FLRL3 and FLRL7 showed a potential role in PPAR signaling pathway through interaction with fatty acid binding protein 5 (Fabp5), lipoprotein lipase (Lpl) and fatty acid desaturase 2 (Fads2). Functional experiments showed that interfering of lncRNA FLRL2 expression affected the expression of predicted target, circadian rhythm gene Arntl. Moreover, both FLRL2 and Arntl were downregulated in the NAFLD cellular model. The current study identified lncRNA and corresponding mRNA in NAFLD, providing new insight into the pathogenesis of NAFLD. Moreover, we identified a new lncRNA FLRL2, that might participate NAFLD pathogenesis mediated by Arntl.
28275001	A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and β-cellular clocks are oscillating with distinct phases in vivo and in vitro. Diurnal transcriptome analysis in separated α and β cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and β-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.
28272914	Numerous studies over the years have documented an effect of human chronotypes on physiological and psychological processes. Studies evaluating the impact of an individual's chronotype on his/her academic achievement have indicated that morning chronotypes have an academic advantage over evening chronotypes. However, these studies did not account for the time of day in which the participants were being evaluated. The goal of the present study was to examine whether morning chronotypes do have an academic advantage over evening chronotypes when the time of day of classes and exams is taken into consideration. We obtained morningness-eveningness scores and course grades from 207 university students who took classes (and exams) at different times of the day. We confirmed that morning chronotypes attain better grades than evening chronotypes, although the association is weak (r2 = 0.02). The difference persisted even after the time of day of classes and exams was taken into consideration. This is probably due to the fact that evening chronotypes are generally more sleep deprived than morning chronotypes as a result of the early schedule of most schools, which can impair their performance both early and late in the day.
28270635	Sleep-wake cycle is controlled by the interplay between circadian rhythm and sleep homeostasis. Genetic studies, through the discovery of mutants with altered sleep-wake behaviors, have explored the molecular components that regulate our daily rhythms. In mammalian circadian clocks, negative-feedback loops composed of a set of transcription activators and inhibitors generate a cell-autonomous oscillation of transcriptional activity. Recent studies further discovered that such transcriptional feedback is controlled through post-translational modifications for the fine-tuning of the oscillation period. Compared to circadian clocks, the canonical molecular model for sleep homeostasis is not established yet. However, recent advances in mammalian forward and reverse genetic studies discovered several genes that regulate sleep duration. Interestingly, these genes include ion channels and kinases, which potentially modify these channels. A part of sleep-related ion channels is involved in Ca<sup>2+</sup>-dependent hyperpolarization of the neuronal membrane potential. Computational models suggest that the hyperpolarization pathway underlies the firing patterns observed in the cortical pyramidal neurons during sleep. Thus, ion channels controlling the membrane potential of the cortical neurons may be involved in sleep homeostasis.
28270612	The suprachiasmatic nucleus (SCN), the master circadian clock, contains a network composed of multiple types of neurons which are thought to form a hierarchical and multioscillator system. The molecular clock machinery in SCN neurons drives membrane excitability and sends time cue signals to various brain regions and peripheral organs. However, how and at what time of the day these neurons transmit output signals remain largely unknown. Here, we successfully visualized circadian voltage rhythms optically for many days using a genetically encoded voltage sensor, ArcLightD. Unexpectedly, the voltage rhythms are synchronized across the entire SCN network of cultured slices, whereas simultaneously recorded Ca2+ rhythms are topologically specific to the dorsal and ventral regions. We further found that the temporal order of these two rhythms is cell-type specific: The Ca2+ rhythms phase-lead the voltage rhythms in AVP neurons but Ca2+ and voltage rhythms are nearly in phase in VIP neurons. We confirmed that circadian firing rhythms are also synchronous and are coupled with the voltage rhythms. These results indicate that SCN networks with asynchronous Ca2+ rhythms produce coherent voltage rhythms.
28268648	Rodent models are widely used for the experimental analysis of sleep. While this is motivated by similarities in brain circuitry and electrophysiological rhythms, unlike the circadian sleep-wake cycle in humans, rodent sleep is polyphasic, containing multiple bouts of sleep and wake minutes to hours in duration over the course of a day. Each sleep bout is punctuated by several brief arousals several seconds to minutes long. Physiologically motivated mathematical models replicate the shorter timescale of arousal within sleep, but not the longer one representing prolonged wakefulness. Here, we adapt a previously published "flip-flop" model of human sleep to capture the ultradian alternation of sleep and wakefulness in mice on the longer timescale. The resulting model reproduces both the mean durations of alternating sleep and wake bouts as well as the circadian trends in their bout durations documented in our experiments on mice.
28268055	Patients in intensive care suffer from severe illnesses or injuries and from symptoms related to care and treatments. Environmental factors, such as lighting at night, can disturb patients' circadian rhythms. The aim was to investigate whether patients displayed circadian rhythms and whether a cycled lighting intervention would impact it. In this pilot study (N=60), a cycled lighting intervention in a two-bed patient room was conducted. An ordinary hospital room functioned as the control. Patient activity, heart rate, mean arterial pressure and body temperature were recorded. All data were collected during the patients' final 24h in the intensive care unit. There was a significant difference between day and night patient activity within but not between conditions. Heart rates differed between day and night significantly for patients in the ordinary room but not in the intervention room or between conditions. Body temperature was lowest at night for all patients with no significant difference between conditions. Patients in both conditions had a natural circadian rhythm; and the cycled lighting intervention showed no significant impact. As the sample size was small, a larger repeated measures study should be conducted to determine if other types of lighting or environmental factors can impact patients' well-being.
28267416	In mammals, body temperature oscillates in a daily fashion around a set point of 36°C-37°C. These fluctuations are controlled by the circadian master clock residing in the brain's suprachiasmatic nucleus and, despite their small amplitudes, contribute to the diurnal expression of genes throughout the organism. By focusing on the mechanisms underlying the temperature-dependent accumulation of the cold-inducible RNA-binding protein CIRBP - a factor involved in the tuning of amplitude and phase in circadian clocks of peripheral tissues - we have recently identified a novel mechanism governing temperature-dependent gene expression. This mechanism involves the differential spicing efficiency of primary RNA transcripts under different temperature conditions and thereby determines the fraction of Cirbp pre-mRNA processed into mature mRNA. A genome-wide transcriptome analysis revealed that this mechanism affects the output of hundreds of genes. Here we discuss our findings and future directions toward the identification of specific factors and parameters governing temperature-sensitive splicing efficacy.
28267364	Chagas disease (Ch) affects 8-10 million people in Latin America, most of them are poor. Sudden death (SD) is the major cause of death in patients with Ch. To the best of our knowledge, the present report covers the largest reported series comparing the SD of Ch versus non-Ch patients Objective: To compare the circadian rhythm of SD in Ch versus non-Ch patients.Retrospective analysis of all the cases of SD recorded in our department, including autopsied patients from 1963 until 2011. The pattern of SD of 262 patients (116 Ch and 146 non-Ch), 56.7% men, average age 54, 6 years old, divided into four groups: Group A: Ch with SD (n = 38), Group B: non-Ch with SD (n = 58), Group C. Ch with non SD (n = 89), and Group D: non-Ch with non SD (n = 81). For the statistical analysis, proportion comparison was used.	44.7% (17/38) of SDs in Group A (Ch) occurred between 6 a.m. and 5:59 p.m., while for Group B (not Ch) 70.7% (41 /58) died in that time (p < 0.005). 55.3% (21/38) of the SD in Group A (Ch) occurred between 6 p.m. and 5:59 a.m. compared with 29.3% (17/58) in Group B (p < 0, 005).	Circadian rhythm of SD in patient with Ch differs from those with non-Ch. In Ch patients, SD occurs predominantly during the night compared with non-Ch SD that occurs predominantly during the day especially during the morning.	
28265565	The horseshoe crab, Limulus polyphemus, exhibits robust circadian and circatidal rhythms, but little is known about the molecular mechanisms underlying those rhythms. In this study, horseshoe crabs were collected during the day and night as well as high and low tides, and their muscle and central nervous system tissues were processed for genome and transcriptome sequencing, respectively. The genome assembly resulted in 7.4 × 105 contigs with N50 of 4,736, while the transcriptome assembly resulted in 9.3 × 104 contigs and N50 of 3,497. Analysis of functional completeness by the identification of putative universal orthologs suggests that the transcriptome has three times more total expected orthologs than the genome. Interestingly, RNA-Seq analysis indicated no statistically significant changes in expression level for any circadian core or accessory gene, but there was significant cycling of several noncircadian transcripts. Overall, these assemblies provide a resource to investigate the Limulus clock systems and provide a large dataset for further exploration into the taxonomy and biology of the Atlantic horseshoe crab.
28265120	Traumatic life experiences are associated with alcohol use problems, an association that is likely to be moderated by genetic predisposition. To understand these interactions, we conducted a gene-by-environment genome-wide interaction study (GEWIS) of alcohol use problems in two independent samples, the Army STARRS (STARRS, N=16 361) and the Yale-Penn (N=8084) cohorts. Because the two cohorts were assessed using different instruments, we derived separate dimensional alcohol misuse scales and applied a proxy-phenotype study design. In African-American subjects, we identified an interaction of PRKG1 rs1729578 with trauma exposure in the STARRS cohort and replicated its interaction with trauma exposure in the Yale-Penn cohort (discovery-replication meta-analysis: z=5.64, P=1.69 × 10-8). PRKG1 encodes cyclic GMP-dependent protein kinase 1, which is involved in learning, memory and circadian rhythm regulation. Considering the loci identified in stage-1 that showed same effect directions in stage-2, the gene ontology (GO) enrichment analysis showed several significant results, including calcium-activated potassium channels (GO:0016286; P=2.30 × 10-5), cognition (GO:0050890; P=1.90 × 10-6), locomotion (GO:0040011; P=6.70 × 10-5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10-5). To our knowledge, this is the largest GEWIS performed in psychiatric genetics, and the first GEWIS examining risk for alcohol misuse. Our results add to a growing body of literature highlighting the dynamic impact of experience on individual genetic risk.Molecular Psychiatry advance online publication, 7 March 2017; doi:10.1038/mp.2017.24.
28264977	Circadian rhythms optimize physiology and behavior to the varying demands of the 24 h day. The master circadian clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and it regulates circadian oscillators in tissues throughout the body to prevent internal desynchrony. Here, we demonstrate for the first time that, under standard 12 h:12 h light/dark (LD) cycles, object, visuospatial, and olfactory recognition performance in C57BL/6J mice is consistently better at midday relative to midnight. However, under repeated exposure to constant light (rLL), recognition performance becomes desynchronized, with object and visuospatial performance better at subjective midday and olfactory performance better at subjective midnight. This desynchrony in behavioral performance is mirrored by changes in expression of the canonical clock genes Period1 and Period2 (Per1 and Per2), as well as the immediate-early gene Fos in the SCN, dorsal hippocampus, and olfactory bulb. Under rLL, rhythmic Per1 and Fos expression is attenuated in the SCN. In contrast, hippocampal gene expression remains rhythmic, mirroring object and visuospatial performance. Strikingly, Per1 and Fos expression in the olfactory bulb is reversed, mirroring the inverted olfactory performance. Temporal desynchrony among these regions does not result in arrhythmicity because core body temperature and exploratory activity rhythms persist under rLL. Our data provide the first demonstration that abnormal lighting conditions can give rise to temporal desynchrony between autonomous circadian oscillators in different regions, with different consequences for performance across different sensory domains. Such a dispersed network of dissociable circadian oscillators may provide greater flexibility when faced with conflicting environmental signals.SIGNIFICANCE STATEMENT A master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus regulates physiology and behavior across the 24 h day by synchronizing peripheral clocks throughout the brain and body. Without the SCN, these peripheral clocks rapidly become desynchronized. Here, we provide a unique demonstration that, under lighting conditions in which the central clock in the SCN is dampened, peripheral oscillators in the hippocampus and olfactory bulb become desynchronized, along with the behavioral processes mediated by these clocks. Multiple clocks that adopt different phase relationships may enable processes occurring in different brain regions to be optimized to specific phases of the 24 h day. Moreover, such a dispersed network of dissociable circadian clocks may provide greater flexibility when faced with conflicting environmental signals (e.g., seasonal changes in photoperiod).
28264815	Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic-pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.
28264650	Very little is known on how changes in circadian rhythms evolve. The noctuid moth Spodoptera frugiperda (Lepidoptera: Noctuidae) consists of two strains that exhibit allochronic differentiation in their mating time, which acts as a premating isolation barrier between the strains. We investigated the genetic basis of the strain-specific timing differences to identify the molecular mechanisms of differentiation in circadian rhythms.Through QTL analyses we identified one major Quantitative trait chromosome (QTC) underlying differentiation in circadian timing of mating activity. Using RADtags, we identified this QTC to be homologous to Bombyx mori C27, on which the clock gene vrille is located, which thus became the major candidate gene. In S. frugiperda, vrille showed strain-specific polymorphisms. Also, vrille expression differed significantly between the strains, with the rice-strain showing higher expression levels than the corn-strain. In addition, RT-qPCR experiments with the other main clock genes showed that pdp1, antagonist of vrille in the modulatory feedback loop of the circadian clock, showed higher expression levels in the rice-strain than in the corn-strain.	Together, our results indicate that the allochronic differentiation in the two strains of S. frugiperda is associated with differential transcription of vrille or a cis-acting gene close to vrille, which contributes to the evolution of prezygotic isolation in S. frugiperda.	
28264500	Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction.
28264001	The daily rhythm of feeding-fasting and meal-timing are emerging as important determinants of health. Circadian rhythm research in animal models and retrospective analyses of human nutrition data have shown that reduced length of overnight fasting or increased late night eating increases risk for metabolic diseases including obesity and diabetes. However, the daily rhythm in eating pattern in humans is rarely measured. Traditional methods to collect nutrition information through food diary and food log pay little attention to the timing of eating which may also change from day to day. We adopted a novel cell-phone based approach to longitudinally record all events of food and beverage intake in adults. In a feasibility study daily food-eating patterns of 93 healthy individuals were recorded for 21 days using camera phones. Analysis of the daily eating patterns of these individuals indicates deviation from conventional assumption that people eat three meals-a-day within a 12 h interval. We found that eating events are widespread throughout the day, with <30% of calories consumed before noon and >30% consumed in evening and late night hours. There was little difference in eating pattern between weekdays and weekends. In this cohort more than 50% of people spread their caloric intake events over 15 h or longer. One decile of the cohort who were spouses of shift-workers or had flexible work schedule spread their caloric intake over 20 h. Although the nutrition quality and diversity of food consumed is different between South-East Asian and Western countries, such overall disruption of daily eating-fasting rhythm is similar. Therefore, in view of hypothesis that disrupted daily eating pattern may contribute to the global increase in metabolic diseases and modification of daily eating pattern is a potential modifiable behavior to contain these diseases, monitoring eating pattern is an important aspect of lifestyle.
28262491	The genus Drosophila contains over 2,000 species that, stemming from a common ancestor in the Old World Tropics, populate today very different environments [1, 2] (reviewed in [3]). We found significant differences in the activity pattern of Drosophila species belonging to the holarctic virilis group, i.e., D. ezoana and D. littoralis, collected in Northern Europe, compared to that of the cosmopolitan D. melanogaster, collected close to the equator. These behavioral differences might have been of adaptive significance for colonizing high-latitude habitats and hence adjust to long photoperiods. Most interestingly, the flies' locomotor activity correlates with the neurochemistry of their circadian clock network, which differs between low and high latitude for the expression pattern of the blue light photopigment cryptochrome (CRY) and the neuropeptide Pigment-dispersing factor (PDF) [4-6]. In D. melanogaster, CRY and PDF are known to modulate the timing of activity and to maintain robust rhythmicity under constant conditions [7-11]. We could partly simulate the rhythmic behavior of the high-latitude virilis group species by mimicking their CRY/PDF expression patterns in a laboratory strain of D. melanogaster. We therefore suggest that these alterations in the CRY/PDF clock neurochemistry might have allowed the virilis group species to colonize high-latitude environments.
28262397	To explore the effect of depression on the sleep quality, and the circadian rhythm of ambulatory blood pressure in patients with essential hypertension.A total of 73 older patients with hypertension were screened for depression and divided into two groups. The Pittsburgh Sleep Quality Index (PSQI) and the circadian rhythm of ambulatory blood pressure were compared between the non-depressed (control) and depressed (case) group.	In the case group, 24h ambulatory SBP and DBP, and nocturnal SBP and DBP were higher than in the control group, and the circadian rhythm of non-dipper was higher (67.22% vs 40.13%，P<0.01). There was a positive correlation between PSQI and depression (r=0.432, P<0.01).	There was a significant correlation between sleep quality and depression in older patients with hypertension. Depression increases the circadian rhythm of non-dipper in older patients with hypertension.	
28262168	Morningness-eveningness preference is commonly measured by questionnaires such as the Composite Scale of Morningness (CSM). The purpose of this study is to assess the Persian translation of the CSM and explore its psychometric properties.Participants consisted of 288 students at the University of Bojnord, Iran. Of the participants selected, 47.6% were female, 52.4% were male, and all were aged between 18 and 24 (20.09±1.32). Participants were selected using the stratified random sampling method. The scale was translated into Persian using the parallel translation method. SPSS-22 and AMOS-22 were used for analyses.	Mean CSM scores were 31.43±6.32 in a range of 14-50. Internal reliability, as measured by Cronbach's α, was 0.790, which fits well with previous studies undertaken in many countries. The factor analysis revealed a two-factor structure based on parallel analysis: one factor was labeled as "morning affect" and the other as "self-assessment/activity planning." Also, the confirmatory factor analysis supported the two-factor model fit. Construct validity was also evaluated by the MEQ with the results showing that correlations were comparable to other studies (r=0.76). Results did not show any significant correlation between age (r=0.041; P=0.487) and the CSM scores. According to the results of the t-test, women and men were not significantly different in terms of the CSM scores (t=-0.264; P=0.792).	The Persian version of the CSM is freely available and can be adopted for behavioral research related to sleep and circadian function and also applied to other Persian-speaking populations.	
28261043	The mammalian circadian clock regulates the day and night cycles of various physiological functions. The circadian clock system consists of a central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in peripheral tissues. According to the results of circadian transcriptomic studies in several tissues, the majority of rhythmic genes are expressed in a tissue-specific manner and are influenced by tissue-specific circadian rhythms. Here we review the diurnal variations of musculoskeletal functions and discuss the impact of the circadian clock on homeostasis in skeletal muscle and bone. Peripheral clocks are controlled by not only photic stimulation from the central clock in the SCN but also by external cues, such as feeding and exercise. In this review, we discuss the effects of feeding and exercise on the circadian clock and diurnal variation of musculoskeletal functions. We also discuss the therapeutic potential of chrono-nutrition and chrono-exercise on circadian disturbances and the failure of homeostasis in skeletal muscle and bone.
28260357	眼压是青光眼最重要且最易控制的临床指标，具有昼夜波动性和节律性，24 h眼压测量较单次眼压测量能更好地反映眼压的变化状况。目前已经明确峰值眼压是青光眼进展的独立危险因素，然而眼压波动对青光眼进展的影响值得思考。本文重点讨论眼压波动是否为青光眼进展的独立危险因素，如何获取24 h眼压曲线以及24 h眼压监测的未来发展方向等问题，以期引起临床关注。（中华眼科杂志，2017，53：85-88）.Intraocular pressure is the most important and most easily controlled clinical parameters of glaucoma. It has a fluctuation and circadian rhythm. The 24 hours intraocular pressure measurement can better reflect the changes of intraocular pressure. It is clear that peak IOP is an independent risk factor for the progression of glaucoma, but the effect of IOP on glaucoma progression is worth exploring. This article focuses on whether IOP fluctuation is an independent risk factor for glaucoma progression, how to obtain the 24-hour intraocular pressure curve, the future direction of 24-hour intraocular pressure monitoring and other issues in order to cause clinical concern. (Chin J Ophthalmol, 2017, 53: 85-88).	
28260126	Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4-6 weeks and in case of non-response with escitalopram for 4-6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity.
28258604	Orbital movement of the Moon generates a system of gravitational fields that periodically alter the gravitational force on Earth. This lunar tidal acceleration (Etide) is known to act as an external environmental factor affecting many growth and developmental phenomena in plants. Our study focused on the lunar tidal influence on stem elongation growth, nutations and leaf movements of peppermint. Plants were continuously recorded with time-lapse photography under constant illumination as well in constant illumination following 5 days of alternating dark-light cycles. Time courses of shoot movements were correlated with contemporaneous time courses of the Etide estimates. Optical microscopy and SEM were used in anatomical studies. All plant shoot movements were synchronised with changes in the lunisolar acceleration. Using a periodogram, wavelet analysis and local correlation index, a convergence was found between the rhythms of lunisolar acceleration and the rhythms of shoot growth. Also observed were cyclical changes in the direction of rotation of stem apices when gravitational dynamics were at their greatest. After contrasting dark-light cycle experiments, nutational rhythms converged to an identical phase relationship with the Etide and almost immediately their renewed movements commenced. Amplitudes of leaf movements decreased during leaf growth up to the stage when the leaf was fully developed; the periodicity of leaf movements correlated with the Etide rhythms. For the fist time, it was documented that lunisolar acceleration is an independent rhythmic environmental signal capable of influencing the dynamics of plant stem elongation. This phenomenon is synchronised with the known effects of Etide on nutations and leaf movements.
28257553	Cathemerality, or activity throughout the 24-hr cycle, is rare in primates yet relatively common among lemurs. However, the diverse ecological conditions under which cathemerality is expressed complicates attempts to identify species-typical behavior. For example, Lemur catta and Varecia have historically been described as diurnal, yet recent studies suggest that they might exhibit cathemeral behavior under some conditions. To investigate this variation, we monitored activity patterns among lemurs that are exposed to similar captive environments. Using MotionWatch 8 ® actigraphy data loggers, we studied 88 lemurs across seven species at the Duke Lemur Center (DLC). Six species were members of the family Lemuridae (Eulemur coronatus, E. flavifrons, E. mongoz, L. catta, V. rubra, V. variegata), while a seventh was strictly diurnal and included as an out-group (Propithecus coquereli). For each 24-hr cycle (N = 503), we generated two estimates of cathemerality: mean night (MN) activity and day/night (DN) activity ratio (day and night cutoffs were based on astronomical twilights). As expected, P. coquereli engaged in the least amount of nocturnal activity according to both measures; their activity was also outside the 95% confidence intervals of all three cathemeral Eulemur species, which exhibited the greatest evidence of cathemerality. By these estimates, Varecia activity was most similar to Eulemur and exhibited substantial deviations from P. coquereli (β (MN) = 0.22 ± SE 0.12; β (DN) = -0.21 ± SE 0.12). L. catta activity patterns also deviated from P. coquereli (β (MN) = 0.12 ± SE 0.11; β (DN) = -0.15 ± SE 0.12) but to a lesser degree than either Varecia or Eulemur. Overall, L. catta displayed an intermediate activity pattern between Eulemur and P. coquereli, which is somewhat consistent with wild studies. Regarding Varecia, although additional observations in more diverse wild habitats are needed, our findings support the existence of cathemeral behavior in this genus.
28257081	The prevalence of type 2 diabetes continues to rise worldwide and is reaching pandemic proportions. The notion that this is due to obesity, resulting from excessive energy consumption and reduced physical activity, is overly simplistic. Circadian de-synchrony, which occurs when physiological processes are at odds with timing imposed by internal clocks, also promotes obesity and impairs glucose tolerance in mouse models, and is a feature of modern human lifestyles. The purpose of this review is to highlight what is known about glucose metabolism in animal and human models of circadian de-synchrony and examine the evidence as to whether shifts in meal timing contribute to impairments in glucose metabolism, gut hormone secretion and the risk of type 2 diabetes. Lastly, we examine whether restricting food intake to discrete time periods, will prevent or reverse abnormalities in glucose metabolism with the view to improving metabolic health in shift workers and in those more generally at risk of chronic diseases such as type 2 diabetes and cardiovascular disease.
28257037	The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype.
28254568	The avian circadian pacemaker system is comprised of independent clocks in the retina, pineal and hypothalamus, as shown by daily and circadian oscillations of core clock genes (Per2, Cry1, Bmal1 and Clock) in several birds including migratory blackheaded buntings (Emberiza melanocephala). This study investigated the extra-hypothalamic brain circadian clocks in blackheaded buntings, and measured Per2, Cry1, Cry2, Bmal1 and Clock mRNA expressions at 4h intervals over 24h beginning 1h after light-on in the left and right telencephalon, optic tectum and cerebellum, the brain regions involved in several physiological and cognitive functions. Because of seasonal alterations in the circadian clock dependent brain functions, we measured daily clock gene oscillations in buntings photoperiod-induced with the non-migratory state under short days (SDnM), and the pre-migratory (LDpM), migratory (LDM) and post-migratory (refractory, LDR) states under long days. Daily Per2 oscillations were not altered with changes in the photoperiodic states, except for about 2-3h phase difference in the optic tectum between the SDnM and LDpM states. However, there were about 3-5h differences in the phase and 2 to 4 fold change in the amplitude of daily Bmal1 and Cry1 mRNA oscillations between the photoperiod-induced states. Further, Cry2 and Clock genes lacked a significant oscillation, except in Cb (Cry2) and TeO and Rt (Clock) under LDR state. Overall, these results show the presence of circadian clocks in extra-hypothalamic brain regions of blackheaded buntings, and suggest tissue-dependent alterations in the waveforms of mRNA oscillations with transitions in the photoperiod-induced seasonal states in a long-day species.
28251921	Since the discovery of the non-image-forming visual system, tremendous research efforts have been dedicated to understanding its mechanisms and functional roles. Original functions associated with the melanopsin system include the photoentrainment of circadian sleep-wake cycles and the pupillary light reflex. Recent findings, however, suggest a much broader involvement of this system in an array of physiologic responses to light. This newfound insight into the underlying function of the non-image-forming system has revealed the many connections to human pathology and attendant disease states, including seasonal affective disorder, migraine, glaucoma, inherited mitochondrial optic neuropathy, and sleep dysregulation of aging. In this review, the authors discuss in detail the clinical implications of the melanopsin system.
28250173	The Darwinian fitness of mammals living in a rhythmic environment depends on endogenous daily (circadian) rhythms in behavior and physiology. Here, we discuss the mechanisms underlying the circadian regulation of physiology and behavior in mammals. We also review recent efforts to understand circadian flexibility, such as how the phase of activity and rest is altered depending on the encountered environment. We explain why shifting activity to the day is an adaptive strategy to cope with energetic challenges and show how this can reduce thermoregulatory costs. A framework is provided to make predictions about the optimal timing of activity and rest of non-model species for a wide range of habitats. This Review illustrates how the timing of daily rhythms is reciprocally linked to energy homeostasis, and it highlights the importance of this link in understanding daily rhythms in physiology and behavior.
28249777	Understanding the systems for maintaining the circadian rhythms that give organisms the flexibility to adapt to environmental changes is important in both aquaculture and fish chronobiology, because nursery lighting conditions can affect the survival and growth rates of larvae. We previously demonstrated that in flounder, the suprachiasmatic nucleus (SCN) exhibits daily rhythm in per2 expression, in sharp contrast to zebrafish, in which the SCN does not exhibit clear per2 expression rhythm. To examine whether a hierarchy exists in systems that maintain the expression rhythm of peripheral clock genes in flounder, in the present study we analyzed the in vivo and in vitro expression of three clock genes, per2, per1, and cry1, in the caudal fin and the effects of cortisol and melatonin administration on the expression of each clock gene. In vivo, the fin maintained a daily expression rhythm of all three genes, even in 24-h darkness (DD) when shifted from 12-h light:12-h dark (LD) conditions, but fin explants lost the expression rhythm after a short time of tissue culture, even under LD conditions. Cortisol, but not melatonin, significantly upregulated the expression of the three clock genes in fin both in vitro and in vivo. Therefore, we hypothesize that the SCN-pituitary-adrenal cortex pathway plays a role in the oscillation of the peripheral clock in flounder. However, in vivo, peak expression of per2 and cry1 was shifted 2-4h earlier under DD conditions, and their expression was upregulated in response to short exposures to light when larvae were kept under DD conditions. Therefore, we also hypothesize that in addition to the SCN, a light-responsive coordinating factor also functions in photo-entrainment of the peripheral clock in flounder.
28249715	Alzheimer's disease (AD) is the most common cause of dementia and currently there are no effective disease-modifying treatments available. Hallmark symptoms of AD include impaired hippocampus-dependent episodic memory and disrupted sleep and circadian rhythms. The pathways connecting these symptoms are of particular interest because it is well established that sleep and circadian disruption can impair hippocampus-dependent learning and memory. In rodents, these procedures also markedly suppress adult hippocampal neurogenesis, a form of brain plasticity that is believed to play an important role in pattern separation, and thus episodic memory. A causal role for sleep disruptions in AD pathophysiology is suggested by evidence for sleep-dependent glymphatic clearance of metabolic waste products from the brain. This review explores a complementary hypothesis that sleep and circadian disruptions in AD contribute to cognitive decline by activating neuroendocrine and neuroinflammatory signaling pathways that suppress hippocampal neurogenesis. Evidence for this hypothesis underscores the promise of sleep, circadian rhythms, and neurogenesis as therapeutic targets for remediation of memory impairment in AD.
28247856	La obesidad es un problema de salud pública a nivel mundial. El objetivo de este estudio fue determinar la asociación entre el tipo de jornada laboral y las horas de sueño diarias con la presencia de obesidad y sobrepeso.A partir de los datos de la Encuesta Nacional de Salud del año 2012, se realizó un análisis de regresión logística multinomial y se estimaron las tasas de posibilidad de riesgo de obesidad y sobrepeso frente al normopeso según el tipo de jornada laboral y las horas de sueño.	La obesidad entre quienes realizaron trabajos con jornada nocturna fue del 17,50% y en quienes tenían jornadas irregulares del 17,92%. El sobrepeso entre quienes realizaron trabajos con jornada partida fue del 40,81% y en quienes tenían jornadas nocturnas del 39,17%. La obesidad y el sobrepeso entre los que durmieron menos de seis horas al día fueron del 24,42% y del 40,99%, respectivamente. El análisis de regresión logística dio una OR=1,42; IC95%:(1,15-1,75) en trabajadores con jornada irregular la y OR=1,83; IC 95% (1,59-2,11) en personas que durmieron menos de seis horas.	Existe una asociación positiva entre la jornada irregular de trabajo y personas con patrones de sueño corto y la presencia de sobrepeso y obesidad, pero la significación estadística se pierde al estimar las OR ajustadas a los factores de confusión.	Obesity is a public health problem worldwide. The aim of the present study was to determine the association between the type of working schedule and the sleeping hours per day with obesity and overweight.	Cross-sectional study of the National Health Survey in 2012. We conducted an analysis of multinomial logistic regression and estimated the rates of possible risk of obesity and overweight versus the normal weight in relation to the type of working schedule and sleeping hours.	Obesity among those who worked at night was 17,50% and those who had irregular works was 17,92%. Overweight among those who performed part-time works was 40,81% and 39,17% in night works. The obesity and overweight among those who slept less than six hours a day were 24,42% and 40,99% respectively. Regression analysis logistic showed OR=1,83 (IC95% 1,15-1,75) in irregular works and OR= 1,83 (IC95% 1,59-2,11) in people who slept less than six hours.	Whenever overweight and obesity are present, a positive association between irregular jobs and short patterns of rest has been found, but stadistical significance is lost when estimating the OR adjusting the confounding factors.	
28246896	Melatonin is a hormone involved in the entrainment of circadian rhythms, which appears dysregulated in drug users. Further, it has been demonstrated that melatonin can modulate the reinforcing effects of several drugs of abuse and may therefore play a role in drug addiction.Here, we investigated whether administration of melatonin reduces relapse-like behavior and the motivation to seek cocaine in rats.	Male Sprague-Dawley rats were submitted to long-term cocaine self-administration training. Thereafter, melatonin effects were assessed on: (1) the motivation to work for cocaine in the break point test, (2) the relapse-like behavior in the cue-induced reinstatement test, (3) the distance traveled in the open field test, and (4) sucrose preference in a two-bottle choice paradigm. Melatonin, 25 or 50 mg/kg, was injected 3-4 h after the dark phase onset, 30 min prior to each test.	Both doses of melatonin decreased the number of active pokes in both break point and cue-induced reinstatement tests, demonstrating that melatonin can reduce the cocaine-seeking behavior and the motivation to work for cocaine. Administration of the higher dose of this hormone, however, significantly reduced the number of inactive pokes during the cue-induced reinstatement test and tended to reduce animals' locomotor activity in the open field test. Sucrose preference was unchanged in both vehicle- and melatonin-treated animal groups.	Our data suggest that melatonin administration may lower the risk of relapse triggered by cues in cocaine-experienced animals.	
28245070	Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.
28244152	Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that regulates mammalian circadian rhythms at the behavioral, molecular and neurophysiological levels. In the central circadian pacemaker, the suprachiasmatic nucleus (SCN), inhibitory phosphorylation of GSK3 exhibits a rhythm across the 24 h day. We have recently shown that GSK3 is capable of influencing both the molecular clock and SCN neuronal activity rhythms. However, it is not known whether GSK3 regulates the response to environmental cues such as light. The goal of this study was to test the hypothesis that GSK3 activation mediates light-induced SCN excitability and photic entrainment. Immunofluorescence staining in the SCN of mice showed that late-night light exposure significantly increased GSK3 activity (decreased pGSK3β levels) 30-60 min after the light-pulse. In addition, pharmacological inhibition of GSK3 blocked the expected light-induced excitability in SCN neurons; however, this effect was not associated with changes in resting membrane potential or input resistance. Behaviorally, mice with constitutively active GSK3 (GSK3-KI) re-entrained to a 6-h phase advance in the light-dark cycle in significantly fewer days than WT control animals. Furthermore, the behavioral and SCN neuronal activity of GSK3-KI mice was phase-advanced compared to WT, in both normal and light-exposed conditions. Finally, GSK3-KI mice exhibited normal negative-masking behavior and electroretinographic responses to light, suggesting that the enhanced photic entrainment is not due to an overall increased sensitivity to light in these animals. Taken together, these results provide strong evidence that GSK3 activation contributes to light-induced phase-resetting at both the neurophysiological and behavioral levels.
28244104	While angiosperm clocks can be described as an intricate network of interlocked transcriptional feedback loops, clocks of green algae have been modelled as a loop of only two genes. To investigate the transition from a simple clock in algae to a complex one in angiosperms, we performed an inventory of circadian clock genes in bryophytes and charophytes. Additionally, we performed functional characterization of putative core clock genes in the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis. Phylogenetic construction was combined with studies of spatiotemporal expression patterns and analysis of M. polymorpha clock gene mutants. Homologues to core clock genes identified in Arabidopsis were found not only in bryophytes but also in charophytes, albeit in fewer copies. Circadian rhythms were detected for most identified genes in M. polymorpha and A. agrestis, and mutant analysis supports a role for putative clock genes in M. polymorpha. Our data are in line with a recent hypothesis that adaptation to terrestrial life occurred earlier than previously expected in the evolutionary history of charophyte algae. Both gene duplication and acquisition of new genes was important in the evolution of the plant circadian clock, but gene loss has also contributed to shaping the clock of bryophytes.
28244020	Biological rhythms are fundamental for homeostasis and have recently been involved in the regulatory processes of various organs and systems. Circadian cycle proteins and hormones have a direct effect on the inflammatory response and have shown pro- or anti-inflammatory effects in animal models of autoimmune diseases. The cells of the immune system have their own circadian rhythm, and the light-dark cycle directly influences the inflammatory response. On the other hand, patients with autoimmune diseases characteristically have sleep disorders and fatigue, and in certain disease, such as rheumatoid arthritis (RA), a frank periodicity in the signs and symptoms is recognized. The joint symptoms predominate in the morning, and apparently, subjects with RA have relative adrenal insufficiency, with a cortisol peak unable to control the late night load of pro-inflammatory cytokines. Transatlantic flights represent a challenge in the adjustment of biological rhythms, since they imply sleep deprivation, time zone changes, and potential difficulties for drug administration. In patients with autoimmune diseases, the use of DMARDs and prednisone at night is probably best suited to lessen morning symptoms. It is also essential to sleep during the trip to improve adaptation to the new time zone and to avoid, as far as possible, works involving flexible or nocturnal shifts. The study of proteins and hormones related to biological rhythms will demonstrate new pathophysiological pathways of autoimmune diseases, which will emphasize the use of general measures for sleep respect and methods for drug administration at key daily times to optimize their anti-inflammatory and immune modulatory effects.
28243224	The circadian timing system consists on a distributed network of cellular clocks that together coordinate 24-h rhythms of physiology and behavior. Clock function and metabolism are tightly coupled, from the cellular to the organismal level. Genetic and non-genetic approaches in rodents have been employed to study circadian clock function in the living organism. Due to the ubiquitous expression of clock genes and the intricate interaction between the circadian system and energy metabolism, genetic approaches targeting specific tissue clocks have been used to assess their contribution in systemic metabolic processes. However, special requirements regarding specificity and efficiency have to be met to allow for valid conclusions from such studies. In this review, we provide a brief summary of different approaches developed for dissecting tissue clock function in the metabolic context in rodents, compare their strengths and weaknesses, and suggest new strategies in assessing tissue clock output and the consequences of circadian clock disruption in vivo.
28243223	Liver metabolic pathways are driven by the biological clock, and appropriate timing of 24-h patterns of metabolic gene expression as well as anabolic/catabolic processes with wake-related activity/feeding and sleep-related resting/fasting cycles preserves hepatic healthiness. The interplay among the liver metabolic pathways and the molecular clockwork is geared by the nuclear receptors, and ligand-dependent transcription factors that gauge the cellular nutritional status and redox balance, bind hormones and metabolites, and modulate the transcription of thousands target genes through their DNA-binding domain. Several nuclear receptors in the liver oscillate with circadian rhythmicity, and among these, the retinoid X receptors play a key role in metabolism regulation, intersecting with the cogs of the molecular clockwork.
28242469	A recent study reported that a special weekly scheduled time-restricted feeding regimen (TRF), i.e., no food consumption for 15h during the light (inactive) phase per day for 5 weekdays, attenuated the outcome of diverse nutritional challenges in response to high-fat diet in mice. In the present study, we wanted to further test whether this TRF could restrict body weight gain in both juvenile and adult animals when fed a high-fat diet. Fifty male Sprague-Dawley rats at ages from 5 to 27weeks were used. First, we found that freely fed rats with 60% fat diet gained weight significantly, which was associated with more calorie intake (particularly during light phase) than those fed standard food (7% fat). Secondly, we found that TRF restricted high-fat diet-induced weight gain in both groups of juvenile rats (5 and 13weeks of age) compared to freely fed rats with high-fat diet, despite the same levels of 24h-calorie intake during either weekdays or the weekend. Thirdly, we found that TRF did not restrict high-fat diet-induce weight gain in adult rats (27weeks of age). Thus, we suggest that this special TRF regimen could be further tested in humans (particularly young adults) for the purpose of obesity prevention.
28241858	The circadian clock and the daily rhythms it produces are crucial for human health, but are often disrupted by the modern environment. At the same time, circadian rhythms may influence the efficacy and toxicity of therapeutics and the metabolic response to food intake. Developing treatments for circadian dysfunction, as well as optimizing the daily timing of treatments for other health conditions, will require a simple and accurate method to monitor the molecular state of the circadian clock.Here we used a recently developed method called ZeitZeiger to predict circadian time (CT, time of day according to the circadian clock) from genome-wide gene expression in human blood.	In cross-validation on 498 samples from 60 individuals across three publicly available datasets, ZeitZeiger predicted CT in single samples with a median absolute error of 2.1 h. The predictor trained on all 498 samples used 15 genes, only two of which are part of the core circadian clock. By then applying ZeitZeiger to 475 additional samples from the same three datasets, we quantified how the circadian clock in the blood was affected by various perturbations to the sleep-wake and light-dark cycles. Finally, we extended ZeitZeiger (1) to handle intra-individual variation by making predictions based on multiple samples taken a known time apart, and (2) to handle inter-individual variation by personalizing predictions based on samples from the respective individual. Each of these strategies improved prediction of CT by ~20%.	Our results are an important step towards precision circadian medicine. In addition, our generalizable extensions to ZeitZeiger may be applicable to the growing number of biological datasets that contain multiple observations per individual.	

28241073	To maintain homeostasis, animals must ingest appropriate quantities, determined by their internal nutritional state, of suitable nutrients. In the fruit fly Drosophila melanogaster, an amino acid deficit induces a specific appetite for amino acids and thus results in their increased consumption. Although multiple processes of physiology, metabolism, and behavior are under circadian control in many organisms, it is unclear whether the circadian clock also modulates such motivated behavior driven by an internal need. Differences in levels of amino acid consumption by flies between the light and dark phases of the day:night cycle were examined using a capillary feeder assay following amino acid deprivation. Female flies exhibited increased consumption of amino acids during the dark phase compared with the light phase. Investigation of mutants lacking a functional period gene (per0), a well-characterized clock gene in Drosophila, found no difference between the light and dark phases in amino acid consumption by per0 flies. Furthermore, increased consumption of amino acids during the dark phase was observed in mated but not in virgin females, which strongly suggested that mating is involved in the rhythmic modulation of amino acid intake. Egg production, which is induced by mating, did not affect the rhythmic change in amino acid consumption, although egg-laying behavior showed a per0-dependent change in rhythm. Elevated consumption of amino acids during the dark phase was partly induced by the action of a seminal protein, sex peptide (SP), on the sex peptide receptor (SPR) in females. Moreover, we showed that the increased consumption of amino acids during the dark phase is induced in mated females independently of their internal level of amino acids. These results suggest that a post-mating SP/SPR signal elevates amino acid consumption during the dark phase via the circadian clock.

28240777	Environmental signals drive seed dormancy cycling in the soil to synchronize germination with the optimal time of year, a process essential for species' fitness and survival. Previous correlation of transcription profiles in exhumed seeds with annual environmental signals revealed the coordination of dormancy-regulating mechanisms with the soil environment. Here, we developed a rapid and robust laboratory dormancy cycling simulation. The utility of this simulation was tested in two ways: firstly, using mutants in known dormancy-related genes [DELAY OF GERMINATION 1 (DOG1), MOTHER OF FLOWERING TIME (MFT), CBL-INTERACTING PROTEIN KINASE 23 (CIPK23) and PHYTOCHROME A (PHYA)] and secondly, using further mutants, we test the hypothesis that components of the circadian clock are involved in coordination of the annual seed dormancy cycle. The rate of dormancy induction and relief differed in all lines tested. In the mutants, dog1-2 and mft2, dormancy induction was reduced but not absent. DOG1 is not absolutely required for dormancy. In cipk23 and phyA dormancy, induction was accelerated. Involvement of the clock in dormancy cycling was clear when mutants in the morning and evening loops of the clock were compared. Dormancy induction was faster when the morning loop was compromised and delayed when the evening loop was compromised.
28240698	Without a doubt, working nights is stressful and can wreak havoc on your physical, mental, and emotional health. It is like fitting a square peg into a round hole; you are living on a schedule opposite from most of the world. Your internal rhythms are disrupted socially and biologically when you work nights. But it does not have to be as disruptive as we let it be. There are lifestyle strategies to better manage working nights; some are mental approaches and some are physical or behavioral tactics.
28239685	The main characteristics of sleep-disordered breathing (SDB) are airflow limitation, chronic intermittent hypoxia, or apnea; which may lead to tissue hypoperfusion and recurrent arousal from sleep. These episodes of hypoxia or apnea can lead to tissue inflammation, and are causal factors of disturbed sleep in both men and women. Several lines of evidence suggest that sleep patterns differ along the lifespan in both male and female subjects, and this may result from the influence of female gonadotropic hormones on sleep. Compared to men, women have more sleep complaints, as women's sleep is not only influenced by gonadotropins, but also by conditions related to these hormones, such as pregnancy. It is therefore not surprising that sleep disturbances are seen during menopause, too. Factors that may play a role in this type of SDB in women include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle factors.
28238833	The core circadian clock mechanism relies on a feedback loop comprised of clock genes, such as the brain and muscle Arnt-like 1 (Bmal1), chriptochrome 1 (Cry1), and period 3 (Per3). Exposure to the light-dark cycle synchronizes the master circadian clock in the brain, and which then synchronizes circadian clocks in peripheral tissues. Birds have long been used as a model for the investigation of circadian rhythm in human neurobiology. In the present study, we examined the effects of continuous light and the combination of white and blue light on the expression of clock genes (Bmal1, Cry1, and Per3) in the central and peripheral tissues in chicks. Seventy two day-old male chicks were weighed, allocated to three groups and maintained under three light schedules: 12h white light-12h dark-cycles group (control); 24h white light group (WW group); 12h white light-12h blue light-cycles group (WB group). The mRNA levels of clock genes in the diencephalon were significantly different between the control and WW groups. On the other hand, the alteration in the mRNA levels of clock genes was similar between the control and WB groups. Similar phenomena were observed in the liver and skeletal muscle (biceps femoris). These results suggest that 12h white-12h blue light-cycles did not disrupt the circadian rhythm of clock gene expression in chicks.
28237017	In single night shifts, extending habitual wake episodes leads to sleep deprivation induced decrements of performance during the shift and re-adaptation effects the next day. We investigated whether short-wavelength depleted (=filtered) bright light (FBL) during a simulated night shift would counteract such effects. Twenty-four participants underwent a simulated night shift in dim light (DL) and in FBL. Reaction times, subjective sleepiness and salivary melatonin concentrations were assessed during both nights. Daytime sleep was recorded after both simulated night shifts. During FBL, we found no melatonin suppression compared to DL, but slightly faster reaction times in the second half of the night. Daytime sleep was not statistically different between both lighting conditions (n = 24) and there was no significant phase shift after FBL (n = 11). To conclude, our results showed positive effects from FBL during simulated single night shifts which need to be further tested with larger groups, in more applied studies and compared to standard lighting.
28236420	Mitochondria produce hydrogen peroxide (H2O2) during energy metabolism in most mammalian cells as well as during the oxidation of cholesterol associated with the synthesis of steroid hormones in steroidogenic cells. Some of the H2O2 produced in mitochondria is released into the cytosol, where it serves as a key regulator of various signaling pathways. Given that mitochondria are equipped with several H2O2-eliminating enzymes, however, it had not been clear how mitochondrial H2O2 can escape destruction by these enzymes for such release. Peroxiredoxin III (PrxIII) is the most abundant and efficient H2O2-eliminating enzyme in mitochondria of most cell types. We found that PrxIII undergoes reversible inactivation through hyperoxidation of its catalytic cysteine residue to cysteine sulfinic acid, and that release of mitochondrial H2O2 likely occurs as a result of such PrxIII inactivation. The hyperoxidized form of PrxIII (PrxIII-SO2H) is reduced and reactivated by sulfiredoxin (Srx). We also found that the amounts of PrxIII-SO2H and Srx undergo antiphasic circadian oscillation in mitochondria of the adrenal gland, heart, and brown adipose tissue of mice maintained under normal conditions. Cytosolic Srx was found to be imported into mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is likely promoted by H2O2 released from mitochondria. The imported Srx was found to be degraded by Lon protease in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of Srx underlie Srx oscillation and consequent PrxIII-SO2H oscillation in mitochondria. The rhythmic change in the amount of PrxIII-SO2H suggests that mitochondrial release of H2O2 is also likely a circadian event that conveys temporal information on steroidogenesis in the adrenal gland and on energy metabolism in heart and brown adipose tissue to cytosolic signaling pathways.
28235729	Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients.We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking.	Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls (p=0.007). Furthermore, whereas healthy controls' declarative memory performance benefited from a period of sleep compared to waking (p=0.032), patients with AD derived no such benefit from sleep (p=0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p's<0.065), and neither group showed significant sleep-enhanced performance.	We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning.	
28233690	Night eating syndrome (NES) is characterized by a delayed pattern of food intake and is clinically defined by the presence of evening hyperphagia, nocturnal ingestion, morning anorexia, and sleep problems. Although most studies report an association of obesity, depressive mood, and NES, very little is known about the impact of bariatric surgery in the course of this syndrome, particularly in patients with depressive symptoms.To assess the effects of bariatric surgery on night eating and depressive symptoms.	Tertiary hospital, Brazil.	Sixty patients consecutively submitted to bariatric surgery were included in the study. Baseline depressive symptoms were assessed by the Beck Depression Inventory-Short Form (BDI-SF) and night eating by the Night Eating Questionnaire. Measurements were repeated postoperatively for comparison.	Participants were predominantly female (M/F = 9/51). Mean (±SD) age was 34.7±9.2 years and body mass index was 46.04±7.52 kg/m². On average, BDI-SF scores improved after bariatric surgery (9.77±7.01 versus 4.70±4.60; P = .001). Patients with baseline depressive symptoms (BDI-SF>4), in contrast to those without, showed a significant improvement in Night Eating Questionnaire scores (16.03±7.73 versus 12.80±7.76; P = .01), despite a similar postoperative reduction in weight.	Bariatric surgery is associated with a reduction in depressive symptoms. After the surgical intervention, improvement of night eating can be observed predominantly in patients with preoperative depressive symptoms. These findings are consistent with the hypothesis of an important role of mood problems in NES.	
28232786	Although, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central clock in mammals, the circadian expression of clock genes has been demonstrated not only in the SCN, but also in peripheral tissues and brain regions outside the SCN. However, the physiological roles of extra-SCN circadian clocks in the brain remain largely elusive. In response, we generated Nkx2.1-Bmal1-/- mice in which Bmal1, an essential clock component, was genetically deleted specifically in the ventral forebrain, including the preoptic area, nucleus of the diagonal band, and most of the hypothalamus except the SCN. In these mice, as expected, PER2::LUC oscillation was drastically attenuated in the explants of mediobasal hypothalamus, whereas it was maintained in those of the SCN. Although, Nkx2.1-Bmal1-/- mice were rhythmic and nocturnal, they showed altered patterns of locomotor activity during the night in a 12:12-h light:dark cycle and during subjective night in constant darkness. Control mice were more active during the first half than the second half of the dark phase or subjective night, whereas Nkx2.1-Bmal1-/- mice showed the opposite pattern of locomotor activity. Temporal patterns of sleep-wakefulness and feeding also changed accordingly. Such results suggest that along with mechanisms in the SCN, local Bmal1-dependent clocks in the ventral forebrain are critical for generating precise temporal patterns of circadian behaviors.
28232040	The majority of proteins is modified with carbohydrate structures. This modification, called glycosylation, was shown to be crucial for protein folding, stability and subcellular location, as well as protein-protein interactions, recognition and signaling. Protein glycosylation is involved in multiple physiological processes, including embryonic development, growth, circadian rhythms, cell attachment as well as maintenance of organ structure, immunity and fertility. Although the general principles of glycosylation are similar among eukaryotic organisms, insects synthesize a distinct repertoire of glycan structures compared to plants and vertebrates. Consequently, a number of unique insect glycans mediate functions specific to this class of invertebrates. For instance, the core α1,3-fucosylation of N-glycans is absent in vertebrates, while in insects this modification is crucial for the development of wings and the nervous system. At present, most of the data on insect glycobiology comes from research in Drosophila. Yet, progressively more information on the glycan structures and the importance of glycosylation in other insects like beetles, caterpillars, aphids and bees is becoming available. This review gives a summary of the current knowledge and recent progress related to glycan diversity and function(s) of protein glycosylation in insects. We focus on N- and O-glycosylation, their synthesis, physiological role(s), as well as the molecular and biochemical basis of these processes.
28229973	The present study investigated whether pairing with a conspecific female would restore rhythmicity in the singing behaviour of arrhythmic male songbirds. We recorded the singing and, as the circadian response indicator, monitored the activity-rest pattern in male zebra finches (Taeniopygia guttata) housed without or with a conspecific female under 12 h light: 12 h darkness (12L:12D) or constant bright light (LL bright). Both unpaired and paired birds exhibited a significant daily rhythm in the singing and activity behaviour, but paired birds, under 12L:12D, showed a ~2 h extension in the evening. Exposure to LLbright decayed rhythmicity, but the female presence restored rhythmic patterns without affecting the 24 h song output. In the acoustic features, we found a significant difference in the motif duration between unpaired and paired male songs. Overall, these results demonstrated for the first time the role of the female in restoring the circadian phenotype of singing behaviour in male songbirds with disrupted circadian functions, although how interaction between sexes affects the circadian timing of male singing is not understood yet. It is suggested that social cues rendered by a conspecific female could improve the circadian performance by restoring rhythmicity in the biological functions of the cohabiting arrhythmic male partner.
28229310	Non-24-h sleep-wake disorder (non-24) is a circadian rhythm disorder occurring in 55-70% of totally blind individuals (those lacking conscious light perception) in which the 24-h biological clock (central, hypothalamic, circadian pacemaker) is no longer synchronized, or entrained, to the 24-h day. Instead, the overt rhythms controlled by the biological clock gradually shift progressively earlier or later (free run) in accordance with the clock's near-24-h period, resulting in a recurrent pattern of daytime hypersomnolence and night-time insomnia. Orally administered melatonin and the melatonin agonist tasimelteon have been shown to entrain (synchronize) the circadian clock, resulting in improvements in night-time sleep and daytime alertness. We review the basic principles of circadian rhythms necessary to understand and treat non-24. The time of melatonin or tasimelteon administration must be considered carefully. For most individuals, those with circadian periods longer than 24 h, low-dose melatonin should be administered about 6 h before the desired bedtime, while in a minority, those with circadian periods shorter than 24 h (more commonly female individuals and African-Americans), melatonin should be administered at the desired wake time. Small doses (e.g., 0.5 mg of melatonin) that are not soporific would thus be preferable. Administration of melatonin or tasimelteon at bedtime will entrain individuals with non-24 but at an abnormally late time, resulting in continued problems with sleep and alertness. To date, tasimelteon has only been administered 1 h before the target bedtime in patients with non-24. Issues of cost, dose accuracy, and purity may figure into the decision of whether tasimelteon or melatonin is chosen to treat non-24. However, there are no head-to-head studies comparing efficacy, and studies to date show comparable rates of treatment success (entrainment).
28229109	Life on earth has adapted to the day-night cycle by evolution of internal, so-called circadian clocks that adjust behavior and physiology to the recurring changes in environmental conditions. In mammals, a master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus receives environmental light information and synchronizes peripheral tissues and central non-SCN clocks to geophysical time. Regulatory systems such as the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), both being important for the regulation of stress responses, receive strong circadian input. In this review, we summarize the interaction of circadian and stress systems and the resulting physiological and pathophysiological consequences. Finally, we critically discuss the relevance of rodent stress studies for humans, addressing complications of translational approaches and offering strategies to optimize animal studies from a chronobiological perspective.
28228570	To evaluate urinary neurotrophin receptor p75 extracellular domain (p75ECD) levels as disease progression and prognostic biomarkers in amyotrophic lateral sclerosis (ALS).The population in this study comprised 45 healthy controls and 54 people with ALS, 31 of whom were sampled longitudinally. Urinary p75ECD was measured using an enzyme-linked immunoassay and validation included intra-assay and inter-assay coefficients of variation, effect of circadian rhythm, and stability over time at room temperature, 4°C, and repeated freeze-thaw cycles. Longitudinal changes in urinary p75ECD were examined by mixed model analysis, and the prognostic value of baseline p75ECD was explored by survival analysis.	Confirming our previous findings, p75ECD was higher in patients with ALS (5.6 ± 2.2 ng/mg creatinine) compared to controls (3.6 ± 1.4 ng/mg creatinine, p < 0.0001). Assay reproducibility was high, with p75ECD showing stability across repeated freeze-thaw cycles, at room temperature and 4°C for 2 days, and no diurnal variation. Urinary p75ECD correlated with the revised ALS Functional Rating Scale at first evaluation (r = -0.44, p = 0.008) and across all study visits (r = -0.36, p < 0.0001). p75ECD also increased as disease progressed at an average rate of 0.19 ng/mg creatinine per month (p < 0.0001). In multivariate prognostic analysis, bulbar onset (hazard ratio [HR] 3.0, p = 0.0035), rate of disease progression from onset to baseline (HR 4.4, p < 0.0001), and baseline p75ECD (HR 1.3, p = 0.0004) were predictors of survival.	The assay for urinary p75ECD is analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75ECD provides prognostic information and is currently the only biological fluid-based biomarker of disease progression.	
28228148	Depression following acute coronary syndrome (ACS) constitutes a serious and debilitating problem. Approximately one in five patients will develop significant depression following ACS and less severe depressive symptoms are even more frequent. Furthermore, anxiety symptoms and sleep-wake disturbances are frequent. The objective of the MEDACIS trial is to investigate whether prophylactic treatment with melatonin has a preventive effect on depression, depressive and anxiety symptoms, sleep, and circadian disturbances following ACS."The effect of MElatonin and Depressive symptoms, Anxiety, CIrcadian and Sleep disturbances in patients after acute coronary syndrome" trial (MEDACIS) is a multicenter, double-blinded, placebo-controlled, randomized clinical trial. A total of 240 patients with ACS and no depressive symptoms will be included in the trial for treatment with either 25 mg melatonin or placebo for a 12-week period. Development and severity of depressive symptoms will be evaluated using Major Depression Inventory every 2 weeks with the purpose of investigating the potential preventive effect of melatonin on depressive symptoms.	Previously, only selective serotonin reuptake inhibitors (SSRIs) have been investigated in a primary preventive setup in patients following ACS. However, SSRIs are associated with several side effects. An ideal intervention would constitute the highest degree of prevention of depressive symptoms with the lowest risk of side effects. In this regard, melatonin may have advantages due to its low toxicity as well as its proven anxiolytic and hypnotic effects.	
28224616	A coordinated network of molecular circadian clocks in individual cells generates 24-hr rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. As divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1-/- Cry2-/- mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST and ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology. Five months after initiation of DEN treatment, we found that Cry1-/- Cry2-/- mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1-/- Cry2-/- mice as compared to WT mice (p = 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly eightfold increase in the average number of cholangiocarcinomas in Cry1-/- Cry2-/- mice, as compared to WT mice. This study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically induced liver carcinogenesis. In addition, the pronounced shift toward cholangiocarcinoma in DEN exposed Cry1-/- Cry2-/- mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis.
28223912	Feeding behavior shows a rhythmic daily pattern, which in nocturnal rodents is observed mainly during the dark period. This rhythmicity is under the influence of the hypothalamic suprachiasmatic nucleus (SCN), the main biological clock. Nevertheless, various studies have shown that in rodent models of obesity, using high-energy diets, the general locomotor activity and feeding rhythms can be disrupted. Here, we review the data on the effects of diet-induced obesity (DIO) on locomotor activity and feeding patterns, as well as the effect on the brain sites within the neural circuitry involved in metabolic and rewarding feeding behavior. In general, DIO may alter locomotor activity by decreasing total activity. On the other hand, DIO largely alters eating patterns, producing increased overall ingestion and number of eating bouts that can extend to the resting period. Furthermore, within the hypothalamic areas, little effect has been reported on the molecular circadian mechanism in DIO animals with ad libitum hypercaloric diets and little or no data exist so far on its effects on the reward system areas. We further discuss the possibility of an uncoupling of metabolic and reward systems in DIO and highlight a gap of circadian and metabolic research that may help to better understand the implications of obesity.
28223222	The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. ClockΔ19/Δ19 mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness. Young ClockΔ19/Δ19 hearts express dysregulated mRNAs and miRNAs in the PTEN-AKT signal pathways important for cardiac hypertrophy. We found a rhythm in the Pten gene and PTEN protein in WT hearts; rhythmic oscillations are lost in ClockΔ19/Δ19 hearts. Changes in PTEN are associated with reduced AKT activation and changes in downstream mediators GSK-3β, PRAS40, and S6K1. Cardiomyocyte cultures confirm that Clock regulates the AKT signalling pathways crucial for cardiac hypertrophy. In old ClockΔ19/Δ19 mice cardiac AKT, GSK3β, S6K1 phosphorylation are increased, consistent with the development of age-dependent cardiac hypertrophy. Lastly, we show that pharmacological modulation of the circadian mechanism with the REV-ERB agonist SR9009 reduces AKT activation and heart weight in old WT mice. Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an important role in regulating cardiac growth. These findings demonstrate a crucial role for Clock in growth and renewal; disrupting Clock leads to age-dependent cardiomyopathy. Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heart disease.
28222619	Objectives We aimed to identify the clinical characteristics of ischemic colitis (IC) and to investigate the occurrence of seasonal variation. Methods From January 2008 to December 2014, 368 had IC as the reason for their admission. A total of 364 patients were enrolled in this study. We investigated patient characteristics and seasonal variations in incidence. Results The mean age (±standard deviation) of patients with IC at diagnosis was 66.8 (±16.9) years. Most patients had abdominal pain (341 cases), hematochezia (337 cases), and diarrhea (199 cases) as their chief complaints. The clinical courses of the disease were classified as transient (294 cases), stricture (17 cases), gangrenous (2 cases), and indeterminate types (51 cases). Although IC tended to occur less frequently in winter, the seasonal difference was not significant. Conclusion There is currently no evidence for seasonal variation in hospital admissions for IC.
28222291	A new study demonstrates that modern electric lighting has caused the near-24-hour biological clock to be set to a later time and that humans physiologically respond to seasonal changes in day length under conditions of natural light exposure.
28220104	A systems approach to studying biology uses a variety of mathematical, computational, and engineering tools to holistically understand and model properties of cells, tissues, and organisms. Building from early biochemical, genetic, and physiological studies, systems biology became established through the development of genome-wide methods, high-throughput procedures, modern computational processing power, and bioinformatics. Here, we highlight a variety of systems approaches to the study of biological rhythms that occur with a 24-h period-circadian rhythms. We review how systems methods have helped to elucidate complex behaviors of the circadian clock including temperature compensation, rhythmicity, and robustness. Finally, we explain the contribution of systems biology to the transcription-translation feedback loop and posttranslational oscillator models of circadian rhythms and describe new technologies and "-omics" approaches to understand circadian timekeeping and neurophysiology.
28219785	Synthetic estrogens and progestins are commonly used in human and veterinary medicine. After use, they reach aquatic environments via discharge of wastewaters from human and animals, thus posing potential risks to organisms. So far, very little is known about their combined effects in aquatic organisms. The aim of this study was to investigate the effects of binary mixtures of ethinylestradiol (EE2) and norgestrel (NGT) on embryonic zebrafish (Danio rerio) by measuring transcriptional alterations. Zebrafish embryos were exposed to EE2 and NGT alone or in combination at concentrations between 36 and 5513ngL-1 for 96h post-fertilization (hpf). The results showed that most of gene transcriptions of hypothalamic-pituitary-gonadal axis (e.g., Pgr, Mprα, Esr1, Esr2a, Vtg1, Ar, Cyp11b, Star, Gnrh3 and Fshb) and circadian rhythm signaling (e.g., Cry1a, Cry2a, Cry2b, Per3, Arntl1b, Arntl2, Clock1a, Cry3 and Cry4) displayed most pronounced alterations in the mixtures as compared to single EE2 and NGT exposures. This finding suggests exposure to the binary mixtures of EE2 and NGT produced significantly enhanced effects in fish as compared to single chemical exposures, and their coexistence could have significant environmental implications.
28219731	The ability to learn about the signs of variability in space and time is known as time place learning (TPL). To adjust their circadian rhythms, animals use stimuli that change regularly, such as the light-dark cycle, temperature, food availability or even social stimuli. Because light-dark cycle is the most important environmental temporal cue, we asked how a diurnal animal would perform TPL if this cue was removed. Zebrafish has been extensively studied in the chronobiology area due to it diurnal chronotype, thus, we studied the effects of constant light and constant dark on the time-place learning and activity profile in zebrafish. Our data show that while under constant light and dark condition zebrafish was not able of TPL, after 30days under the constant conditions, constant light led to higher activity level and less significant (robust) 24h rhythm.
28219335	Proper regulation of nuclear-encoded, organelle-targeted genes is crucial for plastid and mitochondrial function. Among these genes, MutS Homolog 1 (MSH1) is notable for generating an assortment of mutant phenotypes with varying degrees of penetrance and pleiotropy. Stronger phenotypes have been connected to stress tolerance and epigenetic changes, and in Arabidopsis T-DNA mutants, two generations of homozygosity with the msh1 insertion are required before severe phenotypes begin to emerge. These observations prompted us to examine how msh1 mutants contrast according to generation and phenotype by profiling their respective transcriptomes and small RNA populations.Using RNA-seq, we analyze pathways that are associated with MSH1 loss, including abiotic stresses such as cold response, pathogen defense and immune response, salicylic acid, MAPK signaling, and circadian rhythm. Subtle redox and environment-responsive changes also begin in the first generation, in the absence of strong phenotypes. Using small RNA-seq we further identify miRNA changes, and uncover siRNA trends that indicate modifications at the chromatin organization level. In all cases, the magnitude of changes among protein-coding genes, transposable elements, and small RNAs increases according to generation and phenotypic severity.	Loss of MSH1 is sufficient to cause large-scale regulatory changes in pathways that have been individually linked to one another, but rarely described all together within a single mutant background. This study enforces the recognition of organelles as critical integrators of both internal and external cues, and highlights the relationship between organelle and nuclear regulation in fundamental aspects of plant development and stress signaling. Our findings also encourage further investigation into potential connections between organelle state and genome regulation vis-á-vis small RNA feedback.	
28219319	Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage. Biomarker(s) with high sensitivity and specificity would facilitate AD diagnosis at early stages. Currently, CSF amyloid β 1-42, total tau, and phosphorylated tau181 are used as AD biomarkers. This report describes conventional and potential in-vitro and in-vivo biomarkers of AD. Particularly, in-vitro transcriptomic, proteomic, lipidomic, and metabolomic; body fluid biomarkers (C-reactive proteins, homocysteine, α-sunuclein index, and dehydroepiandrosterone sulphate) from blood, serum, plasma, CSF, and saliva; and neuronal, platelets, and lymphocyte microRNA, mtDNA, and Charnoly body are detected. In-vivo physiological and neurobehavioral biomarkers are evaluated by analyzing computerized EEG, event-related potentials, circadian rhythm, and multimodality fusion imaging including: CT, MRI, SPECT, and PET. More specifically, PET imaging biomarkers representing reduced fronto-temporal 18FdG uptake, increased 11C or 18F-PIB uptake, 11C-PBR28 to measure 18 kDa translocator protein (TSPO), a biomarker for inflammation; and 3-D MRI (ventriculomegaly)/MRS are performed for early and effective clinical management of AD.
28218891	Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain's circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.
28218824	Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire life span. The childhood and adolescent behavioral consequences of FXS are well appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of fragile X mental retardation 1 (Fmr1) recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism or circadian patterns of movement, feeding and drinking. After habituation, Fmr1-KO mice show significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared with wild types. In addition, Fmr1-KO mice show significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice.
28217760	Sleep disorders are prevalent in Alzheimer's disease (AD) and a major cause of institutionalization. Like AD pathology, sleep abnormalities can appear years before cognitive decline and may be predictive of dementia. A bidirectional relationship between sleep and amyloid β (Aβ) has been well established with disturbed sleep and increased wakefulness leading to increased Aβ production and decreased Aβ clearance; whereas Aβ deposition is associated with increased wakefulness and sleep disturbances. Aβ fluctuates with the sleep wake cycle and is higher during wakefulness and lower during sleep. This fluctuation is lost with Aβ deposition, likely due to its sequestration into amyloid plaques. As such, Aβ is believed to play a significant role in the development of sleep disturbances in the preclinical and clinical phase of AD. In addition to Aβ, the influence of tau AD pathology is likely important to the sleep disturbances observed in AD. Abnormal tau is the earliest observable AD-like pathology in the brain with abnormal tau phosphorylation in many sleep regulating regions such as the locus coeruleus, dorsal raphe, tuberomammillary nucleus, parabrachial nucleus, and basal forebrain prior to the appearance of amyloid or cortical tau pathology. Furthermore, human tau mouse models exhibit AD-like sleep disturbances and sleep changes are very common in other tauopathies including frontotemporal dementia and progressive supranuclear palsy. Together these observations suggest that tau pathology can induce sleep disturbances and may play a large role in the sleep disruption seen in AD. To elucidate the relationship between sleep and AD it will be necessary to not only understand the role of amyloid but also tau and how these two pathologies, together with comorbid pathology such as alpha-synuclein, interact and affect sleep regulation in the brain.
28216658	Chronobiological studies of prokaryotic organisms have generally lagged far behind the study of endogenous circadian clocks in eukaryotes, in which such systems are essentially ubiquitous. However, despite only being studied during the past 25 years, cyanobacteria have become important model organisms for the study of circadian rhythms and, presently, their timekeeping mechanism is the best understood of any system in terms of biochemistry, structural biology, biophysics and adaptive importance. Nevertheless, intrinsic daily rhythmicity among bacteria other than cyanobacteria is essentially unknown; some tantalizing information suggests widespread daily timekeeping among Eubacteria and Archaea through mechanisms that share common elements with the cyanobacterial clock but are distinct. Moreover, the recent surge of information about microbiome-host interactions has largely neglected the temporal dimension and yet daily cycles control important aspects of their relationship.
28215259	Restless legs syndrome (RLS) is characterized by the association of an urge to move, and vesperal or nocturnal sensory symptoms; it is frequently associated with periodic limb movements. Evidence from imaging and electrophysiological studies suggests that RLS is linked to changes in sensorimotor integration. Nevertheless, the underlying mechanisms have not been characterized, and the cortical origin has yet to be confirmed. The objective of the present study was to establish whether or not sensorimotor integration in RLS patients is impaired in the evening. The time-dependent modulation of motor cortex excitability following peripheral electric nerve stimulation was studied in 14 idiopathic RLS patients, and 14 paired healthy controls. Different inter-stimulus intervals were used to measure short-latency and long-latency afferent inhibition (SAI and LAI) and afferent-induced facilitation (AIF). Motor evoked potentials were recorded from the first dorsal interosseous muscle in two experimental sessions (one in the morning and one in the evening). With the exception of LAI (which was present in the morning but absent in the evening in both healthy controls and RLS patients), no circadian variations were observed in sensorimotor integration. Although SAI was present in patients with RLS, AIF was disrupted (relative to controls) - suggesting the presence of an indirect sensorimotor integration disorder affecting the long corticocortical pathways in patients with RLS. The lack of circadian modulation in sensorimotor integration suggests that clinical circadian variations have other causes.
28215254	There is a surging public interest in The Netherlands concerning sleep, sleep disorders and associated health. For a proper perspective, it is necessary to have reliable information on the prevalence of sleep characteristics at the national level. This study set out to assess prevalence rates and key characteristics of sleep and sleep disorders in The Netherlands.In 2012, a nationally representative sample of 2089 individuals, aged 18-70 years, responded to a set of 48 questions, including the Holland Sleep Disorders Questionnaire, a validated questionnaire based on the International Classification of Sleep Disorders.	Prevalence rates were: 32.1% for a general sleep disturbance (GSD), 43.2% for insufficient sleep, 8.2 for insomnia, 5.3% for circadian rhythm sleep disorder, 6.1% for parasomnia, 5.9% for hypersomnolence, 12.5% for restless legs disorder and limb movements during sleep, 7.1% for sleep related breathing disorder, and 12.2% for the presence of comorbidity, ie, the presence of two or more concurrent sleep disorders. In addition, sleep onset time as well as sleep duration showed U-shaped relationships with GSD prevalence rates, with respectively the 22:00-24:00 period and seven to 8 h as optimal associates.	Sleep disorders and insufficient sleep have a high prevalence. As matter of concern, female adolescents reached the highest prevalence rates for most sleep disorders, insufficient sleep and daytime malfunctioning.	
28215246	Previous neuroimaging studies have shown subtle structural changes of the brain in various sleep disorders, suggesting detrimental effects of disrupted sleep-wake cycle on brain structures. We aimed to identify structural changes in shift workers relative to day workers. We hypothesized that brain structures belonging to sleep-wake modulation may be altered in shift workers.Nineteen male shift workers (median age, 21 years) and 19 male day workers (median age, 21 years) voluntarily participated in the current study. Sleep questionnaires were obtained from all participants and compared between the groups. Voxel-based morphometry was used to compare regional gray matter volume between shift workers and day workers (corrected p < 0.05 with small volume correction). Separate correlation analyses were performed between regional gray matter volume change and scores of Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index (Pearson's correlation, p < 0.05).	Compared to day workers, shift workers had higher scores of Beck Depression Inventory-II, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. Compared to day workers, shift workers had a significant gray matter volume reduction in the pontomesencephalic tegmentum. Regional volume of the pontomesencephalic tegmentum negatively correlated with Pittsburgh Sleep Quality Index global score.	We observed that pontomesencephalic tegmentum volume was reduced in shift workers compared to day workers and that the smaller pontomesencephalic tegmentum volume was related to the poorer sleep quality. Our preliminary findings may be related to chronic disruption of circadian rhythm or decreased exposure to bright light in shift workers.	
28215240	At the onset of puberty, students shift their sleep to later hours, but school starts early. It is suggested that evening orientation and early school start times do not go well together. Therefore, the aim of this study was to investigate sleep problems in adolescence, and it was expected that the adolescents' eveningness orientation is associated with many sleep-related problems. Students of secondary education (n = 3201; mean = 13.8 ± 1.8 years) filled out a self-report questionnaire containing measures of morningness-eveningness, sleep time (midpoint of sleep, social "jetlag"), sleep length (on schooldays and on weekends), sleep quality, and sleep hygiene as well as questions on electronic screen media use. The impact of circadian preference on sleep time (midpoint of sleep and social jetlag), sleep length (on schooldays and on weekends), sleep quality, and sleep hygiene of adolescents was tested via multilevel analyses while controlling for covariates on the student level (age, sex, screen media use, and time leaving home) and on the class level (school type, grade level, and school start time). Morningness-eveningness was a significant predictor of all dependent variables and associations were highest (β > 0.40) for midpoint of sleep, social jetlag, problems with going to bed, problems with falling asleep, and problems with returning to wakefulness. Providing guidance for parents on sleep hygiene behavior routines for their child, an educational program in sleep hygiene, and later school start times could help to synchronize adolescents' circadian rhythms to daily educational and social demands.
28215235	Delayed sleep-wake phase disorder (DSWPD) is associated with a delayed timing of circadian rhythms, and this delay is suggested to be the basis of the disorder. However, this has been questioned due to frequent relapses following treatment based on this aetiology. Recent studies have emerged suggesting personality factors may contribute to sleep patterns in DSWPD. The aim of this study was to further investigate circadian and personality factors in DSWPD patients as well as patients with non-24-h sleep-wake rhythm disorder (N24SWD) relative to control sleepers.This sample consisted of 16 DSWPD (age = 21.1 ± 2.8, 10 m, 7 f), and three N24SWD patients (age = 24.0 ± 4.4, 2 m, 1 f). Controls were seven males and seven females (age = 23.4 ± 5.9). Before starting an 80-h modified constant routine, eligible participants' sleep patterns were monitored for a week and they completed a personality questionnaire (NEO PI-R). An ultradian routine with alternating 20-min sleep opportunities and 40 min of enforced wakefulness was used to measure the timing of endogenous circadian temperature and melatonin rhythms.	As compared with controls, DSWPD patients reported higher neuroticism, significantly lower extraversion, conscientiousness and agreeableness. Similarly, N24SWD patients' patterns of personality traits were similar to that of DSWPD. Conscientiousness, in particular, was associated with phase timings of circadian rhythms as well as sleep measures and lifestyle factors within the DSWPD group.	These findings suggest that circadian rhythm sleep-wake disorders (CRSWDs) may not only stem from circadian abnormalities but personality factors may also drive lifestyle choices, including sleep timing.	
28214989	The aim of the study was to evaluate the exposure-response (E-R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E-R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E-R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.
28214594	Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50-100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption. Shift and/or night work generally decreases the time spent sleeping, and it disrupts the circadian time structure. In the long run, this desynchronization is detrimental to health, as underscored by a large number of epidemiological studies that have uncovered elevated rates of several diseases, including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. It amounts to a public health issue in the light of the very substantial number of individuals involved. The IARC has classified shift work in group 2A of "probable carcinogens to humans" since "they involve a circadian disorganization". Countermeasures to the effects of ALAN, such as melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work. We review the evidence for the ALAN impacts on health. Furthermore, we highlight the importance of an in-depth mechanistic understanding to combat the detrimental properties of exposure to ALAN and develop strategies of prevention.
28213822	In mammals, circadian rhythms are associated with multiple physiological events. The aim of the present study was to examine the effect of lipopolysaccharide (LPS) on circadian systems in the ovary. Immature female mice were received an intra-peritoneal injection of equine chorionic gonadotropin (eCG) and LPS. Total RNA was collected from the ovary at 6-h intervals throughout a 48 h of experimental period. The expression of the circadian genes period 2 (Per2) and brain and muscle ARNT-like 1 (Bmal1) such as circadian genes was measured by quantitative PCR. Although expression of Per2 and Bmal1 in the ovary did not display clear diurnal oscillation, LPS suppressed the amplitude of Per2 expression. Additionally, LPS inhibited the expression of cytochrome P450 aromatase (CYP19) and luteinizing hormone receptor (LHr) genes in the ovary of eCG-treated mice. Our data suggest that Per2 may be associated with the inhibition of CYP19 and LHr expression by LPS in the ovaries of immature mice.
28212399	The acquisition of reliable data strongly depends on experimental design. When studying the effects of light on processes such as behaviour and physiology it is crucial to maintain all environmental conditions constant apart from the one under study. Furthermore, the precise values of the environmental factors applied during the experiment should be known. Although seemingly obvious, these conditions are often not met when the effects of light are being studied. Here, we document and discuss the wavelengths and light intensities of natural and artificial light sources. We present standardised experimental protocols together with building plans of a custom made instrument designed to accurately control light and temperature for experiments using fresh water or marine species. Infrared light is commonly used for recording behaviour and in electrophysiological experiments although the properties of fish photoreceptors potentially allow detection into the far red. As an example of our experimental procedure we have applied our protocol and instrument to specifically test the impact of infrared light (840 nm) on the zebrafish circadian clock, which controls many aspects of behaviour, physiology and metabolism. We demonstrate that infrared light does not influence the zebrafish circadian clock. Our results help to provide a solid framework for the future study of light dependent processes in aquatic organisms.
28211649	Insufficient sleep poses an important and complicated set of health risks in the adolescent population. Not only is deficient sleep (defined as both sleep duration inadequate to meet sleep needs and sleep timing misaligned with the body's circadian rhythms) at epidemic levels in this population, but the contributing factors are both complex and numerous and there are a myriad of negative physical and mental health, safety and performance consequences. Causes of inadequate sleep identified in this population include internal biological processes such as the normal shift (delay) in circadian rhythm that occurs in association with puberty and a developmentally-based slowing of the "sleep drive", and external factors including extracurricular activities, excessive homework load, evening use of electronic media, caffeine intake and early school start times. Consequences range from inattentiveness, reduction in executive functioning and poor academic performance to increased risk of obesity and cardio-metabolic dysfunction, mood disturbances which include increased suicidal ideation, a higher risk of engaging in health risk behaviors such as alcohol and substance use, and increased rates of car crashes, occupational injuries and sports-related injuries. In response to these concerns, a number of promising measures have been proposed to reduce the burden of adolescent sleep loss, including healthy sleep education for students and families, and later school start times to allow adolescents to obtain sufficient and appropriately-timed sleep.
28209805	Effects of photophase illuminance (1, 10, 100 and 330 lx of white incandescent lighting) on daily rhythms of locomotor activity, urine production and 6-sulfatoxymelatonin (6-SMT; 10 versus 330 lx) were studied in nocturnal Namaqua rock mice (Micaelamys namaquensis) and diurnal four-striped field mice (Rhabdomys pumilio). Micaelamys namaquensis was consistently nocturnal (∼90-94% nocturnal activity), whereas considerable individual variation marked activity profiles in R. pumilio, but with activity mostly pronounced around twilight (∼55-66% diurnal activity). The amplitude of daily activity was distinctly affected by light intensity and this effect was greater in M. namaquensis than in R. pumilio Only M. namaquensis displayed a distinctive daily rhythm of urine production, which correlated with its activity rhythm. Mean daily urine production appeared to be attenuated under dim photophase conditions, particularly in R. pumilio The results suggest that the circadian regulation of locomotor activity and urine production possesses separate sensitivity thresholds to photophase illuminance. Micaelamys namaquensis expressed a significant daily 6-SMT rhythm that peaked during the late night, but the rhythm was attenuated by the brighter photophase cycle (330 lx). Rhabdomys pumilio appeared to express an ultradian 6-SMT rhythm under both lighting regimes with comparable mean daily 6-SMT values, but with different temporal patterns. It is widely known that a natural dark phase which is undisturbed by artificial light is essential for optimal circadian function. Here, we show that light intensity during the photophase also plays a key role in maintaining circadian rhythms in rodents, irrespective of their temporal activity rhythm.
28209308	A pineal cyst is a benign affection of the human pineal gland on the borderline between pathology and normality. Only a small percentage of patients present with symptoms and a surgical treatment is indicated in highly selected cases. A melatonin secretion in patients with a pineal cyst before and after a pineal cyst resection has not been studied yet and the effect of surgery on human metabolism is unknown. The present study examined melatonin, cortisol and blood glucose secretion profiles perioperatively in a surgical group of 4 patients. The control group was represented by 3 asymptomatic patients with a pineal cyst. For each patient, 24-h circadian secretion curves of melatonin, cortisol and glycemia were acquired. An analysis of melatonin profiles showed an expected diurnal pattern with the night peak in patients before the surgery and in the control group. In contrast, melatonin levels in patients after the surgery were at their minimum throughout the whole 24-h period. The cortisol secretion was substantially increased in patients after the surgery. Blood glucose sampling showed no statistically significant differences. Clinical results demonstrated statistically significant headache relief measured by Visual Analogue Scale in patients after the surgery. Despite the small number of examined patients, we can conclude that patients with a pineal cyst preserved the physiological secretion of the hormone melatonin while patients who underwent the pineal cyst resection experienced a loss of endogenous pineal melatonin production, which equated with pinealectomy. Surprisingly, cortisol secretion substantially increased in patients after the surgery.
28203366	Females are markedly underinvestigated in the biological and behavioral sciences due to the presumption that cyclic hormonal changes across the ovulatory cycle introduce excess variability to measures of interest in comparison to males. However, recent analyses indicate that male and female mice and rats exhibit comparable variability across numerous physiological and behavioral measures, even when the stage of the estrous cycle is not considered. Hormonal changes across the ovulatory cycle likely contribute cyclic, intra-individual variability in females, but the source(s) of male variability has, to our knowledge, not been investigated. It is unclear whether male variability, like that of females, is temporally structured and, therefore, quantifiable and predictable. Finally, whether males and females exhibit variability on similar time scales has not been explored.These questions were addressed by collecting chronic, high temporal resolution locomotor activity (LA) and core body temperature (CBT) data from male and female BALB/c mice.	Contrary to expectation, males are more variable than females over the course of the day (diel variability) and exhibit higher intra-individual daily range than females in both LA and CBT. Between mice of a given sex, variability is comparable for LA but the inter-individual daily range in CBT is greater for males. To identify potential rhythmic processes contributing to these sex differences, we employed wavelet transformations across a range of periodicities (1-39 h).	Although variability in circadian power is comparable between the sexes for both LA and CBT, infradian variability is greater in females and ultradian variability is greater in males. Thus, exclusion of female mice from studies because of estrous cycle variability may increase variance in investigations where only male measures are collected over a span of several hours and limit generalization of findings from males to females.	
28202701	To describe differences between the sexes in the phenotype of cluster headache (CH) in a large, well-characterized clinical CH population.Patients from the Danish CH survey aged 18-65 years, diagnosed with CH according to International Classification of Headache Disorders, second edition, completed questionnaires and structured interviews.	A total of 351 patients with CH participated, with a male:female ratio of 2:1. The diurnal variation of attacks showed moments of peak prominence in men's attack cycle to be advanced by 1 hour compared to women's, despite no difference in self-reported bedtime or chronotype (p = 0.31). The onset of CH decreased with increasing age for both sexes. Diagnostic delay was numerically longer for men vs women (6.56 vs 5.50 years, p = 0.21); however, more women had previously been misdiagnosed (61.1% vs 45.5%, p < 0.01) and received the correct diagnosis at a tertiary headache center (38.8% vs 20.9%, p < 0.001). Only minor sex differences in clinical characteristics were found but chronic CH was more prevalent in women compared to men (44.0% vs 31.9%, p < 0.05).	Despite a similar clinical phenotype, diurnal attack cycle is advanced by 1 hour in men with CH compared to women. Rhythmicity is a defining characteristic of CH and these findings suggest differences in the hypothalamus' influence on attack occurrence between the sexes. In addition, women were more often misdiagnosed and diagnosis in the primary or secondary sector more often failed. Furthermore, women had chronic CH more frequently than men. A long diagnostic delay and frequent misdiagnosis emphasize the need for increased awareness of CH in both sexes.	

28202598	Three pea (Pisum sativum) loci controlling photoperiod sensitivity, HIGH RESPONSE (HR), DIE NEUTRALIS (DNE), and STERILE NODES (SN), have recently been shown to correspond to orthologs of Arabidopsis (Arabidopsis thaliana) circadian clock genes EARLY FLOWERING3 (ELF3), ELF4, and LUX ARRHYTHMO, respectively. A fourth pea locus, PHOTOPERIOD (PPD), also contributes to the photoperiod response in a similar manner to SN and DNE, and recessive ppd mutants on a spring-flowering hr mutant background show early, photoperiod-insensitive flowering. However, the molecular identity of PPD has so far remained elusive. Here, we show that the PPD locus also has a role in maintenance of diurnal and circadian gene expression rhythms and identify PPD as an ELF3 co-ortholog, termed ELF3b Genetic interactions between pea ELF3 genes suggest that loss of PPD function does not affect flowering time in the presence of functional HR, whereas PPD can compensate only partially for the lack of HR These results provide an illustration of how gene duplication and divergence can generate potential for the emergence of more subtle variations in phenotype that may be adaptively significant.
28198671	Coxsackievirus A16 (CVA16) and enterovirus 71 (EV71) are two of the major causes of hand, foot and mouth disease (HFMD) world-wide. Although many studies have focused on infection and pathogenic mechanisms, the transcriptome profile of the host cell upon CVA16 infection is still largely unknown.In this study, we compared the mRNA and miRNA expression profiles of human embryonic kidney 293T cells infected and non-infected with CVA16. We highlighted that the transcription of SCARB2, a cellular receptor for both CVA16 and EV71, was up-regulated by nearly 10-fold in infected cells compared to non-infected cells. The up-regulation of SCARB2 transcription induced by CVA16 may increase the possibility of subsequent infection of CVA16/EV71, resulting in the co-infection with two viruses in a single cell. This explanation would partly account for the co-circulation and genetic recombination of a great number of EV71 and CVA16 viruses. Based on correlation analysis of miRNAs and genes, we speculated that the high expression of SCARB2 is modulated by down-regulation of miRNA has-miR-3605-5p. At the same time, we found that differentially expressed miRNA target genes were mainly reflected in the extracellular membrane (ECM)-receptor interaction and circadian rhythm pathways, which may be related to clinical symptoms of patients infected with CVA16, such as aphthous ulcers, cough, myocarditis, somnolence and potentially meningoencephalitis. The miRNAs hsa-miR-149-3p and hsa-miR-5001-5p may result in up-regulation of genes in these morbigenous pathways related to CVA16 and further cause clinical symptoms.	The present study elucidated the changes in 293T cells upon CVA16 infection at transcriptome level, containing highly up-regulated SCARB2 and genes in ECM-receptor interaction and circadian rhythm pathways, and key miRNAs in gene expression regulation. These results provided novel insight into the pathogenesis of HFMD induced by CVA16 infection.	
28198416	Many psychiatric disorders emerge during adolescence. The study of executive functions in animal models of these disorders critically requires short-duration tasks measuring these functions before the animal ages. Here, a novel 5-choice serial reaction time task (5-CSRTT) protocol is presented, to measure attention and impulsivity within one week, without scheduled food deprivation and with little animal handling. Mice were allowed 24-h/day task access from their home-cage, during which they could self-pace task progression and earn unlimited food rewards depending on task performance. Manipulation of task parameters in this self-paced 5-CSRTT protocol (SP-5C) affected attentional performance and impulsivity to a similar extent as previously observed in the 5-CSRTT. Task activity followed intrinsic circadian rhythm, distinctive for the SP-5C protocol, with task performance stable over the day. The sensitivity of the SP-5C protocol to detect strain differences between C57BL/6J, DBA/2 J, BXD16 and BXD62 mice was demonstrated as well as its suitability for testing adolescent mice. Acute administration of the muscarinic acetylcholine receptor antagonist scopolamine impaired attentional performance, providing initial pharmacological validation of the task. The SP-5C substantially shortens the assessment of impulsivity and attention, increases test efficiency and enables the assessment of adolescent mouse models of psychiatric disorders.
28196398	How nonhuman primates deal with birth, at the moment of delivery, and during the following days, remains poorly explored because of the unpredictability of this event, particularly for forest-dwelling arboreal species. Available studies highlight intra- and interspecific variation which suggest flexibility of the timing of delivery, of behavior associated with labor contractions and parturition, and the social context and ambient noise surrounding delivery. Here, we present the findings of a two-decade survey of reproduction in a population of captive Campbell's monkeys. Analysis of 34 births (with a female-biased sex ratio) showed that deliveries occurred systematically at night and more frequently during week-ends and in fall (September-November). This suggests the existence of both circadian and infradian biological rhythms. We present the first detailed description of a birth for this species and its short-term social consequences. In line with previous findings for other monkeys and apes, labor (estimated by unusual stretching postures) and parturition were rapid, and delivery occurred in a clear social and vocal context. During the following days, the new mother became the center of attention of for young (kin and non-kin) females and rose through the hierarchy. We discuss socio-ecological factors, notably captivity conditions and the high degree of tolerance in the species' social system, and confirm the existence of both "rigidity" and "flexibility" in the primates' adaptive reproductive strategies.
28196106	Drosophila melanogaster is a common model used to study circadian rhythms in behavior and circadian clocks. However, numerous circadian rhythms have also been detected in non-clock neurons, especially in the first optic neuropil (lamina) of the fly's visual system. Such rhythms have been observed in the number of synapses and in the structure of interneurons, which exhibit changes in size and shape in a circadian manner. Although the patterns of these changes are known, the mechanism remains unclear. In the present study, we investigated the role of the TOR signaling pathway and autophagy in regulating circadian rhythms based on the behavior and structural plasticity of the lamina L2 monopolar cell dendritic trees. In addition, we examined the cyclic expression of the TOR signaling pathway (Tor, Pi3K class 1, Akt1) and autophagy (Atg5 and Atg7) genes in the fly's brain. We observed that Tor, Atg5 and Atg7 exhibit rhythmic expressions in the brain of wild-type flies in day/night conditions (LD 12:12) that are abolished in per01 clock mutants. The silencing of Tor in per expressing cells shortens a period of the locomotor activity rhythm of flies. In addition, silencing of the Tor and Atg5 genes in L2 cells disrupts the circadian plasticity of the L2 cell dendritic trees measured in the distal lamina. In turn, silencing of the Atg7 gene in L2 cells changes the pattern of this rhythm. Our results indicate that the TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in the behavior and plasticity of neurons in the brain of adult flies.
28195837	Attention-deficit/hyperactivity disorder (ADHD) is frequently accompanied with sleep disorders such as obstructive sleep apnea, periodic limb movement disorder, restless legs syndrome (RLS), and circadian rhythm disorder. We have limited information about the effects of medical therapies used in the treatment of ADHD on RLS. This article discusses the effects of atomoxetine treatment on both disorders in a patient followed by diagnoses of ADHD and RLS.
28195542	microRNAs (miRNAs) circulate in the blood and negatively regulate the expression of mRNAs. Some miRNAs are associated with the development of autoimmune thyroid diseases (AITD); however, there are few reports on the association between miRNA expression and the pathogenesis of AITD or the physiological variations of circulating miRNAs, which are important to examine as biomarkers.We examined the circadian and day-to-day variations in the expression levels of 5 miRNAs (miR-125a, miR-146a, miR-155, let-7e and miR-106a) in plasma and peripheral blood mononuclear cells (PBMC). We also analysed the expression levels of two of these miRNAs (miR-146a and miR-155) in 20 healthy controls, 60 Graves' disease (GD) patients and 50 Hashimoto's disease (HD) patients.	For each miRNA, we observed wide intraindividual variation [coefficient of variation value (CV): 70%-100%] compared to measurement error (CV: 20%-40%). In patients with AITD, HD, GD in remission and mild HD, the expression levels of miR-146a in PBMC were increased 296%, 328%, 348% and 464% above the levels in healthy controls, respectively (p=0.0443 and p=0.0273, p=0.0267 and p=0.0052, respectively). In severe HD, the expression level of miR-155 in plasma was increased to 347% of that in healthy controls (p=0.0256).	The expression levels of miRNAs in plasma and PBMC showed wide intraindividual variation. In addition, miR-146a may be associated with the development of AITD.	
28193212	Adrenal corticomedullary mixed tumours are very rare. Its mechanism is rarely reported. Here we report the first case of a corticomedullary mixed tumour resembling a "small adrenal gland" with distinct arrangement of the cortical and medullary layers. We further hypothesize regarding the tumorigenic mechanism of this tumour.A 58-year man had been diagnosed with diabetes and hypertension for 3 years. His 24-h urine vanillylmandelic acid (VMA) levels were slightly elevated. An abnormal circadian cortisol rhythm was noted, and his cortisol levels were not suppressed by dexamethasone. Abdominal computed tomography (CT) revealed a right adrenal gland lesion (diameter, 30 × 38 mm), while an enhanced CT showed enhancement and hypervascularization. The tumour was positive for adrenocorticotropic hormone, chromogranin A (CGA), and steroidogenic factor-1 (SF-1) on the tumour surface. Acetaldehyde dehydrogenase 1(ALDH1), CD44, CD133, Nestin, Nerve growth factor receptor (NGFR), and Sex determining region y-box 9(SOX9) staining were positive. Although administration of medications for diabetes and hypertension was stopped until surgery was performed, the blood sugar level and blood pressure were maintained after surgery.	This is the first report about a possible mechanism by which cancer stem cells induce adrenal corticomedullary tumours.	
28190167	Studies have shown that experimental fasting can affect cognitive function, sleep, and wakefulness patterns. However, the effects of experimental fasting cannot be generalized to fasting during Ramadan due to its unique characteristics. Therefore, there has been increased interest in studying the effects of fasting during Ramadan on sleep patterns, daytime sleepiness, cognitive function, sleep architecture, and circadian rhythm.In this review, we critically discuss the current research findings in those areas during the month of Ramadan.	Available data that controlled for sleep/wake schedule, sleep duration, light exposure, and energy expenditure do not support the notion that Ramadan intermittent fasting increases daytime sleepiness and alters cognitive function. Additionally, recent well-designed studies showed no effect of fasting on circadian rhythms. However, in non-constrained environments that do not control for lifestyle changes, studies have demonstrated sudden and significant delays in bedtime and wake time.	Studies that controlled for environmental factors and sleep/wake schedule reported no significant disturbances in sleep architecture. Nevertheless, several studies have consistently reported that the main change in sleep architecture during fasting is a reduction in the proportion of REM sleep.	
28188587	Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.
28188273	Circadian rhythm of stomatal aperture is mainly regulated by light/darkness. Blue and red light induce stomatal opening through different mechanisms that are mediated by special receptors. ROP2, a member of Rho GTPase family in Arabidopsis (Arabidopsisthaliana), has been found to negatively regulate light-induced stomatal opening. However, the upstream guanine nucleotide exchange factor (GEF) RopGEFs have not been revealed, and it is unclear which photoreceptor is required for the action of RopGEFs-ROPs. Here, we showed that RopGEF2 acted as a negative regulator in phytochrome B (phyB)-mediated red light-induced stomatal opening. Meanwhile, ROP7, another member of ROP family, acting redundantly with ROP2, was regulated by RopGEF2 in this process. RopGEF2 interacted with ROP7 and ROP2 and enhanced their intrinsic nucleotide exchange rates. Furthermore, the direct interactions between phyB and RopGEF2 were detected in vitro and in plants, and phyB enhanced the GEF activity of RopGEF2 toward both ROP7 and ROP2 under light. In addition, RopGEF4 functioned redundantly with RopGEF2 in red light-induced stomatal opening by activating both ROP7 and ROP2, and RopGEF2/RopGEF4 acted genetically downstream of phyB; however, the GEF activity of RopGEF4 was not directly enhanced by phyB. These results revealed that red light-activated phyB enhances the GEF activities of RopGEF2 and RopGEF4 directly or indirectly, and then activate both ROP7 and ROP2 in guard cells. The negative mechanism triggered by phyB prevents the excessive stomatal opening under red light.
28186121	Circadian rhythms are controlled by a network of clock neurons in the central pacemaker, the suprachiasmatic nucleus (SCN). Core clock genes, such as Bmal1, are expressed in SCN neurons and in other brain cells, such as astrocytes. However, the role of astrocytic clock genes in controlling rhythmic behaviour is unknown. Here we show that ablation of Bmal1 in GLAST-positive astrocytes alters circadian locomotor behaviour and cognition in mice. Specifically, deletion of astrocytic Bmal1 has an impact on the neuronal clock through GABA signalling. Importantly, pharmacological modulation of GABAA-receptor signalling completely rescues the behavioural phenotypes. Our results reveal a crucial role of astrocytic Bmal1 for the coordination of neuronal clocks and propose a new cellular target, astrocytes, for neuropharmacology of transient or chronic perturbation of circadian rhythms, where alteration of astrocytic clock genes might contribute to the impairment of the neurobehavioural outputs such as cognition.
28183457	Prior studies have shown a cross-sectional association between body mass index (BMI) and salivary diurnal cortisol profile features (cortisol features); however, to our knowledge prior population-based studies have not examined the longitudinal association of body-mass index (BMI) with cortisol features.To examine the association of (1) prior annual BMI percent change over 7years with cortisol features, (2) baseline cortisol features with subsequent change in BMI over 6years and (3) the association of change in cortisol features with change in BMI over 6years.	Longitudinal study.	Multi-Ethnic Study of Atherosclerosis (MESA) Stress I & II Studies (2004-2006 & 2010-2012).	1685 ethnically diverse men and women attended either MESA Stress exam (mean age 65±10years at MESA Stress I; mean age 69±9years at MESA Stress II).	Log-transformed cortisol features including wake-up cortisol, cortisol awakening response, early decline slope (30min to 2h post-awakening), late decline slope (2h post-awakening to bedtime), bedtime, and total area under the curve (AUC) cortisol.	Over 7years, following multivariable adjustment, (1) a 1% higher prior annual BMI % increase was associated with a 2.9% (95% CI: -5.0%, -0.8%) and 3.0% (95% CI: -4.7%, -1.4%) lower current wake-up and total AUC cortisol, respectively; (2) there was no significant association between baseline cortisol features and subsequent change in BMI and (3) among participants with BMI≥30kg/m2, flattening of the late decline slope was associated with increases in BMI (every 1-unit increase late decline slope were associated with a 12.9% increase (95%CI: -1%, 26.8%) in BMI, respectively).	We found a significant association between prior annual BMI % change and cortisol features, but no significant association between baseline cortisol features and subsequent change in BMI. In participants with obesity increases in BMI were associated with less pronounced declined. Collectively, our results suggest that greater adiposity may lead to a blunted diurnal cortisol profile.	
28182648	Locomotor activity rhythms are controlled by a network of ~150 circadian neurons within the adult Drosophila brain. They are subdivided based on their anatomical locations and properties. We profiled transcripts "around the clock" from three key groups of circadian neurons with different functions. We also profiled a non-circadian outgroup, dopaminergic (TH) neurons. They have cycling transcripts but fewer than clock neurons as well as low expression and poor cycling of clock gene transcripts. This suggests that TH neurons do not have a canonical circadian clock and that their gene expression cycling is driven by brain systemic cues. The three circadian groups are surprisingly diverse in their cycling transcripts and overall gene expression patterns, which include known and putative novel neuropeptides. Even the overall phase distributions of cycling transcripts are distinct, indicating that different regulatory principles govern transcript oscillations. This surprising cell-type diversity parallels the functional heterogeneity of the different neurons.
28181718	We studied sleep in a rural population in Madagascar to (i) characterize sleep in an equatorial small-scale agricultural population without electricity, (ii) assess whether sleep is linked to noise levels in a dense population, and (iii) examine the effects of experimentally introduced artificial light on sleep timing.Using actigraphy, sleep-wake patterns were analyzed for both daytime napping and nighttime wakefulness in 21 participants for a sum total of 292 days. Functional linear modeling was used to characterize 24-h time-averaged circadian patterns and to investigate the effect of experimentally introduced mobile field lights on sleep timing. We also obtained the first polysomnography (PSG) recordings of sleep in a traditional population.	In every measure of sleep duration and quality, the Malagasy population experienced shorter and lower quality sleep when compared to similarly measured postindustrial values. The population slept for a total of 6.5 h per night and napped during 89% of recorded days. We observed a peak in activity after midnight for both sexes on 49% of nights, consistent with segmented sleep. Access to mobile field lights had no statistical effect on nighttime sleep timing. From PSG, we documented relatively short rapid eye movement (14%), poor sleep efficiency (66%), and high wake after sleep onset (162 min).	Sleep in this population is segmented, similar to the "first" sleep and "second" sleep reported in the historical record. Moreover, although average sleep duration and quality were lower than documented in Western populations, circadian rhythms were more stable across days.	
28178375	Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.
28178150	To compare the effect of selective laser trabeculoplasty (SLT) and travoprost on 24-hour IOP fluctuations in primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG).Sixty eyes were included. Sixteen and 14 eyes of POAG patients were randomized to receive 360° SLT or 0.004% travoprost, respectively. Fourteen and 16 eyes of NTG patients were randomized to receive either SLT or travoprost, respectively. The 24-hour IOP data were collected before treatment and 6 to 8 weeks after treatment. IOP was measured at 2 hours intervals in the sitting position during daytime (9 AM to 7 PM) and in the supine position during nighttime (9 PM to 7 AM). Main outcome measure was the percentage of eyes that achieved posttreatment 24-hour IOP fluctuations <3 mm Hg. Success in fluctuation reduction was defined as at least a 50% reduction in these fluctuations.	Fifty-eight eyes were analyzed. Overall, eyes in the SLT and the travoprost groups achieved a significant reduction in IOP compared with the baseline IOP values (-3.7 mm Hg [P = 0.002] vs -4.1 mm Hg [P < 0.001], respectively). There was no significant difference in IOP reduction in both groups according to type of glaucoma. During the diurnal period, 100% of POAG eyes in the travoprost group achieved posttreatment IOP fluctuations <3 mm Hg, and 87% of eyes in the SLT group achieved the same level of fluctuations (P < 0.001). Ninety-six percent of NTG eyes in the travoprost group, and 82% of eyes in the SLT group had IOP fluctuations <3 mm Hg (P = 0.01). Success in fluctuation reduction was 75% and 92% for the SLT and travoprost groups, respectively (P = 0.005). The effect of travoprost on IOP reduction in POAG and NTG patients was significant both during the daytime and the nighttime, while the SLT's effect was significant only during the nighttime.	Both travoprost and SLT can significantly reduce the IOP in patients with POAG and NTG. Based on habitual positions, travoprost better controls IOP fluctuations than SLT, especially during the daytime.	
28177907	The number of studies on the association between clock genes' polymorphisms and cancer susceptibility has increased over the last years but the results are often conflicting and no comprehensive overview and quantitative summary of the evidence in this field is available.Literature search identified 27 eligible studies comprising 96756 subjects (cases: 38231) and investigating 687 polymorphisms involving 14 clock genes. Overall, 1025 primary and subgroup meta-analyses on 366 gene variants were performed. Study distribution by tumor was as follows: breast cancer (n=15), prostate cancer (n=3), pancreatic cancer (n=2), non-Hodgkin's lymphoma (n=2), glioma (n=1), chronic lymphocytic leukemia (n=1), colorectal cancer (n=1), non-small cell lung cancer (n=1) and ovarian cancer (n=1).We identified 10 single nucleotide polymorphisms (SNPs) significantly associated with cancer risk: NPAS2 rs10165970 (mixed and breast cancer shiftworkers), rs895520 (mixed), rs17024869 (breast) and rs7581886 (breast); CLOCK rs3749474 (breast) and rs11943456 (breast); RORA rs7164773 (breast and breast cancer postmenopausal), rs10519097 (breast); RORB rs7867494 (breast cancer postmenopausal), PER3 rs1012477 (breast cancer subgroups) and assessed the level of quality evidence to be intermediate. We also identified polymorphisms with lower quality statistically significant associations (n=30).	Our work supports the hypothesis that genetic variation of clock genes might affect cancer risk. These findings also highlight the need for more efforts in this research field in order to fully establish the contribution of clock gene variants to the risk of developing cancer.	We conducted a systematic review and meta-analysis of the evidence on the association between clock genes' germline variants and the risk of developing cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Subgroup meta-analysis was also performed based on participant features and tumor type. The breast cancer subgroup was further stratified by work conditions, estrogen receptor/progesterone receptor status and menopausal status, conditions associated with the risk of breast cancer in different studies.	
28177832	Flowering time is a very important agronomic trait and the development of molecular markers associated with this trait can facilitate crop breeding. CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), a core oscillator component of circadian rhythms that affect metabolic pathways in plants, has been implicated in flowering time control in species of Brassica. CCA1 gene sequences from three Brassica rapa inbred lines, showing either early flowering or late flowering phenotypes, were analyzed and a high level of sequence variation was identified, especially within the fourth intron. Using this information, three PCR primer sets were designed and tested using various inbred lines of B. rapa. The usage of InDel markers was further validated by evaluation of flowering time and high resolution melting (HRM) analysis. Both methods, PCR and HRM, validated the use of newly developed markers. Additional sequence analyses of Brassica plants with diploid (AA, BB, or CC) and allotetraploid genomes further confirmed a large number of sequence polymorphisms in the CCA1 gene, including insertions/deletions in the fourth intron. Our results demonstrated that sequence variations in CCA1 can be used to develop valuable trait-related molecular markers for Brassica crop breeding.
28174180	Light syncronizes body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern life, the extended and/or irregular light exposure impairs circadian rhythms and consequently promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the arginine vasopressin (AVP) neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to PVN. Furthermore, intracerebroventricular (icv) injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than icv injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm, and linking irregular light exposure to arrhythmic feeding and consequently obesity and metabolic diseases.
28173893	Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls.Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires.	Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL.	BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.	
28173758	Sleep is regulated by two main processes. The circadian process provides a 24-h rhythm and the homeostatic process reflects sleep pressure, which increases in the course of wakefulness and decreases during sleep. Both of these processes undergo major changes during development. For example, sleep homeostasis, measured by means of electroencephalogram (EEG) slow-wave activity (SWA, EEG power between 0.5 and 4.5 Hz), peaks around puberty and decreases during adolescence. In humans and rats these changes have been related to cortical maturation. We aimed to explore whether additional parameters as state dynamic (dynamic of sleep/wake behavior) parameters of movement velocity, trajectories and micro-arousals provide markers of rat maturation. The state dynamics reflect the stability of sleep within a specific sleep stage. We applied a state space technique (SST), a quantitative and unbiased method, based on frequency band ratios of the EEG to analyze the development of different sleep/wake states and state dynamics between vigilance states. EEG of recording electrodes at the frontal and parietal lobe were analyzed using conventional scoring criteria and SST.We found that movement velocity, trajectories between sleep states and micro-arousals changed as an inverse U-shaped curve across maturation. At all ages, movement velocity over the frontal lobe is higher compared to the parietal lobe, while the number of trajectories and micro-arousals are reduced. Furthermore, we showed that SWA correlates negatively with movement velocity and the number of micro-arousals. The velocity in the parietal lobe correlates positively with the number of micro-arousals. As for SWA, trajectories seem primarily to depend on sleep homeostasis regulatory mechanisms while the movement velocity seems to be modulated by other sleep regulators like the circadian rhythms.	New insights in sleep/wake state dynamics are established with the SST, because trajectories, micro-arousals and velocities are not evident by traditional scoring methods. These dynamic measures may represent new indicators for changes in sleep regulatory processes across maturation.	
28171872	To determine the relationship between the rate of glaucomatous visual field loss and the amplitude of a 24-h intraocular pressure (IOP)-related profile measured using a contact lens sensor (CLS).This observational study included 22 patients with glaucoma and an IOP of consistently ≤21 mm Hg during office hours. All subjects underwent Goldmann tonometry, standard automated perimetry (SAP), dilated fundus examination, and had a CLS recording. A cosine function was used to obtain peak (acrophase), trough (bathyphase), and amplitude measurements. Prior rates of change in SAP mean deviation were calculated and compared to CLS parameters.	The patients had a mean (± SD) age of 66.6 ± 8.2 years (range 54-89 years). Mean follow-up was 6.6 ± 5.0 years with 8.3 ± 3.2 reliable SAP tests. The mean rate of change in SAP was -0.86 ± 1.0 dB per year (range -0.11 to -2.12 dB). Regression analysis suggested faster rates of prior visual field loss in eyes with higher-amplitude CLS curves, but this did not reach statistical significance (R2 = 0.174, p = 0.053). The CLS accurately identified waking and sleeping periods. 59.1% of eyes had a nocturnal acrophase (peaking between 23:00 and 07:00). There was no significant difference in rates of visual field change between patients with nocturnal or diurnal acrophase (-0.71 ± 1.17 and -1.07 ± 0.84 dB/year, respectively, p = 0.437).	CLS recordings in patients with normal-tension glaucoma (defined by office hours IOP) indicated that 60% of patients had peak IOP during nocturnal hours, which may not be captured using conventional methods of IOP measurement. Novel parameters obtained using the CLS may provide information for predicting the risk of visual field changes for patients with glaucoma.	
28169087	Individuals with psychotic disorders experience disruptions to both the sleep and circadian components of the sleep/wake cycle. Recent evidence has supported a role of sleep disturbances in emerging psychosis. However, less is known about how circadian rhythm disruptions may relate to psychosis symptoms and prognosis for adolescents with clinical high-risk (CHR) syndromes. The present study examines circadian rest/activity rhythms in CHR and healthy control (HC) youth to clarify the relationships among circadian rhythm disturbance, psychosis symptoms, psychosocial functioning, and the longitudinal course of illness.Thirty-four CHR and 32 HC participants were administered a baseline evaluation, which included clinical interviews, 5days of actigraphy, and a sleep/activity diary. CHR (n=29) participants were re-administered clinical interviews at a 1-year follow-up assessment.	Relative to HC, CHR youth exhibited more fragmented circadian rhythms and later onset of nocturnal rest. Circadian disturbances (fragmented rhythms, low daily activity) were associated with increased psychotic symptom severity among CHR participants at baseline. Circadian disruptions (lower daily activity, rhythms that were more fragmented and/or desynchronized with the light/dark cycle) also predicted severity of psychosis symptoms and psychosocial impairment at 1-year follow-up among CHR youth.	Circadian rhythm disturbances may represent a potential vulnerability marker for emergence of psychosis, and thus, rest/activity rhythm stabilization has promise to inform early-identification and prevention/intervention strategies for CHR youth. Future studies with longer study designs are necessary to further examine circadian rhythms in the prodromal period and rates of conversion to psychosis among CHR teens.	
28168516	Intensive care units provide specialised care for critically ill patients around the clock. However, intensive care unit patients have disrupted circadian rhythms. Furthermore, disrupted circadian rhythms are associated with worse outcome. As light is the most powerful 're-setter' of circadian rhythm, we measured light intensity on intensive care unit. Light intensity was low compared to daylight during the 'day'; frequent bright light interruptions occurred over 'night'. These findings are predicted to disrupt circadian rhythms and impair entrainment to external time. Bright lighting during daytime and black out masks at night might help maintain biological rhythms in critically ill patients and improve clinical outcomes.
28165421	Over recent years, a deeper comprehension of the molecular mechanisms that control biological clocks and circadian rhythms has been achieved. In fact, many studies have contributed to unravelling the importance of the molecular clock for the regulation of our physiology, including hormonal and metabolic homeostasis. Here we will review the structure, organisation and molecular machinery that make our circadian clock work, and its relevance for the proper functioning of physiological processes. We will also describe the interconnections between circadian rhythms and endocrine homeostasis, as well as the underlying consequences that circadian dysregulations might have in the development of several pathologic affections. Finally, we will discuss how a better knowledge of such relationships might prove helpful in designing new therapeutic approaches for endocrine and metabolic diseases.
28164449	Weight gain, obesity and diabetes have reached alarming levels in the developed world. Traditional risk factors such as over-eating, poor nutritional choices and lack of exercise cannot fully account for the high prevalence of metabolic disease. This review paper examines the scientific evidence on two novel risk factors that contribute to dys-regulated metabolic physiology: sleep disruption and circadian misalignment. Specifically, fundamental relationships between energy metabolism and sleep and circadian rhythms and the impact of sleep and circadian disruption on metabolic physiology are examined. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic function, and many participate in shift work and social activities at times when the internal physiological clock is promoting sleep. These behaviours predispose an individual for poor metabolic health by promoting excess caloric intake in response to reduced sleep, food intake at internal biological times when metabolic physiology is not prepared, decreased energy expenditure when wakefulness and sleep are initiated at incorrect internal biological times, and disrupted glucose metabolism during short sleep and circadian misalignment. In addition to the traditional risk factors of poor diet and exercise, disturbed sleep and circadian rhythms represent modifiable risk factors for prevention and treatment of metabolic disease and for promotion of healthy metabolism.
28164170	Hypertension is common in patients with chronic kidney disease (CKD) and is the most important modifiable risk factor for CKD progression and adverse cardiovascular events in these patients. Diagnosis and successful management of hypertension are critically dependent on accurate blood pressure (BP) measurement. This is most relevant to CKD patients, in whom BP control is difficult to achieve and in whom early antihypertensive treatment is imperative to prevent kidney and cardiovascular complications. Accumulated data indicate that ambulatory blood pressure monitoring (ABPM) is better in detecting hypertension than office BP measurement. ABPM is also a superior prognostic marker compared with office BP and has successfully identified hypertensive CKD patients at increased risk. Additionally, ABPM provides information on circadian BP variation and short-term BP variability, which is associated with cardiovascular and renal outcomes. This paper reviews the evidence for the usefulness of ABPM in detection and management of hypertension in CKD patients and discusses our current understanding of the pathophysiology of altered circadian BP rhythm and variability in CKD and the role of abnormal BP patterns detected by ABPM in relation to outcomes in CKD. In addition, this Review examines the emerging role of antihypertensive chronotherapy to tailor BP management to the circadian BP pattern abnormality detected by 24-hour ABPM.
28163263	This study investigated the correlation between the body surface temperature (BST) and core body temperature of ewes and changes in BST during the prepartum stage in pregnant ewes. Four non-pregnant adult ewes were used in the first experiment. The BST of the upper neck, vaginal temperature (VT), and ambient temperature (AT) were measured every 10 min for seven days and analyzed for correlations. The mean (± SD) BST and VT of ewes during the study period were 35.4 ± 1.7°C and 39.1 ± 0.4°C, respectively, with a correlation of r = 0.62, P < 0.001. This finding suggested that the BST was associated with core body temperature in ewes. In the subsequent experiment, seven pregnant ewes in their third trimester were used to evaluate changes in BST measured at the upper neck 72 h before parturition. The mean BST at -24-0 h (0 h = time of parturition) was significantly lower than that at -72- -48 h and -48- -24 h (P < 0.05). The BST tended to decrease toward parturition; all BST measurements at -16- -3 h were significantly lower than those at -72 h (P < 0.05). A clear circadian rhythm in the BST was observed at two days and the day before parturition and an unclear circadian rhythm was observed on the day of parturition. Therefore, these findings indicate that the BST also decreases before parturition, as do vaginal and rectal temperatures.
28163090	The accumulation of amyloid-β (Aβ) peptides in the brain of Alzheimer disease patients is associated to cognitive deficit, increased oxidative stress, and alterations in the circadian rhythms. Brain-derived neurotrophic factor (BDNF) and Neurogranin (RC3), play an important role in the synaptic plasticity underlying memory and learning. Previously, we observed BDNF and RC3 expression follow a daily rhythmic pattern in the hippocampus of young rats. The objective of this study was to investigate the effects of an intracerebroventricular (i.c.v) injection of aggregated Aβ peptide (1-42) on temporal patterns of ApoE protein, Bdnf and Rc3 mRNA, lipid peroxidation (LPO) and reduced glutathione (GSH) levels, in the rat hippocampus. We observed an i.c.v. injection of Aβ aggregates phase shifts daily BDNF and RC3 expression as well as LPO and decreased the mesor of GSH rhythms. ApoE protein levels vary rhythmically throughout the day. ApoE levels increase at ZT 03:39±00:22 in the hippocampus of control rats and at ZT 06:30±00:28 in the treated animals. Thus, elevated levels of Aβ aggregates, characteristic of AD, altered temporal patterns of cognition related-factors, probably, as a consequence of changes in the daily variation of ApoE-mediated Aβ aggregates clearance as well as in the 24h rhythms of the cellular redox state.
28162920	Post-operative patients experience sleep disturbances. Animal studies demonstrate that general anaesthesia (GA) can disrupt circadian rhythms and cause changes in the molecular clock, indicating that anaesthesia contributes to post-operative circadian disruption. Here we review the effect of anaesthesia on the circadian clock and its rhythms in order to summarise current findings outline commonalities between studies and propose mechanisms by which effects may be mediated.1) GA has strong effects on the main neurotransmitter systems linked with circadian control (Gamma aminobutyric acid/N-methyl-D-aspartate (GABA/NMDA)) and may act by interfering with light-entrainment of the clock. 2) Expression of the core clock gene per2 is inhibited by GA (possibly via a NMDA/glycogen synthase kinase 3β (GSK3β) pathway). 3) GA's effect on circadian rhythms appears greatest when administered during animals' active phases 4) GA may have different effects when administered under free-running and entrained conditions. 5) Anaesthesia may mimic the mechanism involved in adaptation of the clock to changes in daylength. There is agreement that GA can strongly affect the circadian clock. How anaesthesia-induced changes in the molecular clock lead to changes in behaviour remains unclear. The answer, and what it may mean for patients post-operatively, will rely on systematic studies at molecular, behavioural, and clinical levels using standardised protocols.	

28160436	Melatonin is a neurohormone primarily synthesized by the pineal gland following a circadian rhythm with a high level during the night and a low level during the day. Alterations in the synthesis and secretion of melatonin have been reported in various mood disorders, including major depressive disorder. However, the role of endogenous melatonin in the pathophysiology of depressive disorder is unclear. Melatonin primarily acts through two G protein-coupled receptors, termed MT1 and MT2 . The present study investigated the effect of genetic deletion of the MT1 and/or MT2 receptors on tests associated with depression- and anxiety-like behaviors in C3H/HeN mice. Deletion of the MT1 and/or MT2 receptors caused a deficit in hedonic and social interaction behavior, and increased anxiety-like behavior. It is likely that dysregulations of the MT1 and/or MT2 melatonin receptors could be involved in the pathophysiology of depression and anxiety.
28160224	This study aimed to examine the behavioural sleep-wake rhythm in 36 adults with autism spectrum disorder (ASD) and to determine the prevalence of circadian sleep-wake rhythm disorders compared to age- and sex-matched controls. Participants completed an online questionnaire battery, a 14-day sleep-wake diary and 14-day actigraphy assessment. The results indicated that a higher proportion of adults with ASD met criteria for a circadian rhythm sleep-wake disorder compared to control adults. In particular, delayed sleep-wake phase disorder was particularly common in adults with ASD. Overall the findings suggest that individuals with ASD have sleep patterns that may be associated with circadian rhythm disturbance; however factors such as employment status and co-morbid anxiety and depression appear to influence their sleep patterns.
28159888	Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.
28159094	Pediatric disorders tend to affect the immediate support unit, adults and children. High costs for direct consumption of medical care are offset by early diagnosis and treatment of pediatric sleep disorders. Pediatric sleep disorders are underdiagnosed and undertreated. Attention-deficit/hyperactivity disorder may result from insufficient or fragmented sleep. Delaying school start time resulted in decreased car crashes in teen drivers and improved mood.
28158242	MicroRNAs (miRNAs) are a group of endogenous non-coding small RNAs that have critical regulatory functions in almost all known biological processes at the post-transcriptional level in a variety of organisms. The oriental fruit moth Grapholita molesta is one of the most serious pests in orchards worldwide and threatens the production of Rosacea fruits. In this study, a de novo small RNA library constructed from mixed stages of G. molesta was sequenced through Illumina sequencing platform and a total of 536 mature miRNAs consisting of 291 conserved and 245 novel miRNAs were identified. Most of the conserved and novel miRNAs were detected with moderate abundance. The miRNAs in the same cluster normally showed correlated expressional profiles. A comparative analysis of the 79 conserved miRNA families within 31 arthropod species indicated that these miRNA families were more conserved among insects and within orders of closer phylogenetic relationships. The KEGG pathway analysis and network prediction of target genes indicated that the complex composed of miRNAs, clock genes and developmental regulation genes may play vital roles to regulate the developmental circadian rhythm of G. molesta. Furthermore, based on the sRNA library of G. molesta, suitable reference genes were selected and validated for study of miRNA transcriptional profile in G. molesta under two biotic and six abiotic experimental conditions. This study systematically documented the miRNA profile in G. molesta, which could lay a foundation for further understanding of the regulatory roles of miRNAs in the development and metabolism in this pest and might also suggest clues to the development of genetic-based techniques for agricultural pest control.
28156168	Organisms are believed to have evolved circadian clocks as adaptations to deal with cyclic environmental changes, and therefore it has been hypothesized that evolution in constant environments would lead to regression of such clocks. However, previous studies have yielded mixed results, and evolution of circadian clocks under constant conditions has remained an unsettled topic of debate in circadian biology. In continuation of our previous studies, which reported persistence of circadian rhythms in Drosophila melanogaster populations evolving under constant light, here we intended to examine whether circadian clocks and the associated properties evolve differently under constant light and constant darkness. In this regard, we assayed activity-rest, adult emergence and oviposition rhythms of D. melanogaster populations which have been maintained for over 19 years (~330 generations) under three different light regimes - constant light (LL), light-dark cycles of 12:12 h (LD) and constant darkness (DD). We observed that while circadian rhythms in all the three behaviors persist in both LL and DD stocks with no differences in circadian period, they differed in certain aspects of the entrained rhythms when compared to controls reared in rhythmic environment (LD). Interestingly, we also observed that DD stocks have evolved significantly higher robustness or power of free-running activity-rest and adult emergence rhythms compared to LL stocks. Thus, our study, in addition to corroborating previous results of circadian clock evolution in constant light, also highlights that, contrary to the expected regression of circadian clocks, rearing in constant darkness leads to the evolution of more robust circadian clocks which may be attributed to an intrinsic adaptive advantage of circadian clocks and/or pleiotropic functions of clock genes in other traits.
28155916	In mammals, the master circadian clock is located in the suprachiasmatic nucleus (SCN), where most neurons show circadian rhythms of intracellular Ca2+ levels. However, the origin of these Ca2+ rhythms remains largely unknown. In this study, we successfully monitored the intracellular circadian Ca2+ rhythms together with the circadian PER2 and firing rhythms in a single SCN slice ex vivo, which enabled us to explore the origins. The phase relation between the circadian PER2 and Ca2+ rhythms, but not between the circadian PER2 and firing rhythms, was significantly altered in Cry1/Cry2 double knockout mice, which display a loss of intercellular synchronization in the SCN. In addition, in Cry1/Cry2 double knockout mice, circadian Ca2+ rhythms were abolished in the dorsolateral SCN, but were maintained in the majority of the ventromedial SCN. These findings indicate that intracellular circadian Ca2+ rhythms are composed of an exogenous and endogenous component involving PER2 expression.
28154744	Photic and non-photic environmental factors are suggested to modulate the development of circadian rhythms in infants. Our aim is to evaluate the development of biological rhythms (circadian or ultradian) in newborns in transition from Neonatal Intensive Care Units (NICU) to home and along the first 6 months of life, to identify masking and entraining environment factors along development. Ten newborns were evaluated in their last week inside the NICU and in the first week after being delivered home; 6 babies were also followed until 6 months of corrected age. Activity, recorded with actimeters, wrist temperature and observed sleep and feeding behavior were recorded continuously along their last week inside the NICU and in the first week at home and also until 6 months of corrected age for the subjects who remained in the study. Sleep/wake and activity/rest cycle showed ultradian patterns and the sleep/wake was strongly influenced by the 3 h feeding schedule inside the NICU, while wrist temperature showed a circadian pattern that seemed no to be affected by environmental cycles. A circadian rhythm emerges for sleep/wake behavior in the first week at home, whereas the 3 h period vanishes. Both activity/rest and wrist temperature presented a sudden increase in the contribution of the circadian component immediately after babies were delivered home, also suggesting a masking effect of the NICU environment. We found a positive correlation of postconceptional age and the increase in the daily component of activity and temperature along the following 6 months, while feeding behavior became arrhythmic.
28154742	Delirium is associated with circadian rhythm disruption. In this study we have explored whether circadian variation of melatonin is an indicator for delirium. Melatonin levels were determined from the first day of hospitalization and up to three days after the onset of delirium. Patients who did not developed delirium exhibited a daily melatonin rhythm, while in patients that developed delirium, the melatonin rhythm was lost and mean melatonin levels were found decreased as early as three days before the diagnosis of delirium, indicating that on arrival to the hospital circadian melatonin disruption can be used as an indicator of delirium.
28154741	South American subterranean rodents are mainly described as solitary and mutual synchronization was never observed among individuals maintained together in laboratory. We report that a single birth event was capable of disrupting the robust nocturnal activity rhythm of singly housed tuco-tucos from north-west Argentina. "Around-the-clock activity" was displayed by 8 out of 13 animals whose cages were closer to the newborn pups. However, experimental exposure to a pup vocalization did not produce a similar effect on the rhythms of adult animals. Our results indicate an effect of social interaction in the expression of biological rhythms even in solitary animals.
28154740	Sleep-related health disorders are increasing worldwide; diagnosis and treatment of such sleep diseases are commonly invasive and sometimes unpractical or expensive. Actigraphy has been recently introduced as a tool for the study of sleep and circadian disorders; however, there are several devices that claim to be useful for research and have not been thoroughly tested. This comparative study provides activity, sleep and temperature information regarding several of the most commonly used actigraphers: Micro-Mini Motion Logger; Act Trust; Misfit Flash; Fitbit Flex & Thermochron. Twenty-two healthy young subjects were assessed with five different commercial actigraphs (Micro-Mini Motionlogger Watch, Condor Act Trust, MisFit Flash and Fitbit Flex) and a temperature recorder (Thermochron), and also completed a sleep diary for a week. There were not significant differences in the analysis of rest-activity pattern between devices. Temperature rhythm comparison between the Act Trust and the Thermochron showed significant differences in rhythm percentage (p<0.05) and mesor (p<0.0563) but not in amplitude or acrophase. Although data accessibility and ease of use was very different for the diverse devices, there were no significant differences for sleep onset, total sleep time and sleep efficiency recordings, where applicable. In conclusion, depending on the type of study and analysis desired (as well as cost and compliance of use), we propose some relative advantages for the different actigraphy/temperature recording devices.
28154738	We present a study of Per3 expression in six different tissues of the non-human primate Cebus apella (capuchin monkey). The aim of this study was to verify whether the expression of the Per3 gene in different tissues of capuchin monkey occurs in a circadian pattern, its phase and the phase relationships between these different tissues during the 24 h of a day. We observed that gene expression oscillated in all of the tissues studied during this time period, although only the liver and muscle presented a robust circadian pattern. This preliminary study highlights the possibility of using Cebus apella as a model to study circadian rhythms at the gene expression level and opens an opportunity for future researches.
28154473	Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
28153982	Circadian patterns of activity are considered ubiquitous and adaptive, and are often invoked as a mechanism for temporal niche partitioning. Yet, comparisons of rhythmic behavior in related animal species are uncommon. This is particularly true of Lepidoptera (butterflies and moths), in which studies of whole-animal patterns of behavior are far outweighed by examinations of tissue-specific molecular clocks. Here, we used a comparative approach to examine the circadian patterns of flight behavior in Manduca sexta and Hyles lineata [two distantly related species of hawkmoth (Sphingidae)]. By filming isolated, individual animals, we were able to examine rhythmic locomotor (flight) activity at the species level, as well as at the level of the individual sexes, and in the absence of interference from social interaction. Our results confirmed classic descriptions of strictly nocturnal behavior in M. sexta and demonstrated a dramatically different activity pattern in H. lineata Furthermore, we showed distinct species and sex-specific differences in the maintenance of the endogenous rhythm under conditions of constant darkness. In both species, female activity peaked in advance of males whereas male activity coincided with periods of female sexual receptivity. This suggests a role for circadian patterns of locomotor activity in synchronizing periods of sexual receptivity between the sexes.
28153924	In plants, the circadian system controls a plethora of processes, many with agronomic importance, such as photosynthesis, photoprotection, stomatal opening, and photoperiodic development, as well as molecular processes, such as gene expression. It has been suggested that modifying circadian rhythms may be a means to manipulate crops to develop improved plants for agriculture. However, there is very little information on how the clock influences the performance of crop plants. We used a noninvasive, high-throughput technique, based on prompt chlorophyll fluorescence, to measure circadian rhythms and demonstrated that the technique works in a range of plants. Using fluorescence, we analyzed circadian rhythms in populations of wild barley (Hordeum vulgare ssp. spontaneum) from widely different ecogeographical locations in the Southern Levant part of the Fertile Crescent, an area with a high proportion of the total genetic variation of wild barley. Our results show that there is variability for circadian traits in the wild barley lines. We observed that circadian period lengths were correlated with temperature and aspect at the sites of origin of the plants, while the amplitudes of the rhythms were correlated with soil composition. Thus, different environmental parameters may exert selection on circadian rhythms.
28152213	Melatonin affects a variety of physiological processes including circadian rhythms, cellular redox status, and immune function. Importantly, melatonin significantly influences T-cell-mediated immune responses, which are crucial to protect mammals against cancers and infections, but are associated with pathogenesis of many autoimmune diseases. This review focuses on our current understanding of the significance of melatonin in T-cell biology and the beneficial effects of melatonin in T-cell response-based diseases. In addition to expressing both membrane and nuclear receptors for melatonin, T cells have the four enzymes required for the synthesis of melatonin and produce high levels of melatonin. Meanwhile, melatonin is highly effective in modulating T-cell activation and differentiation, especially for Th17 and Treg cells, and also memory T cells. Mechanistically, the influence of melatonin in T-cell biology is associated with membrane and nuclear receptors as well as receptor-independent pathways, for example, via calcineurin. Several cell signaling pathways, including ERK1/2-C/EBPα, are involved in the regulatory roles of melatonin in T-cell biology. Through modulation in T-cell responses, melatonin exerts beneficial effects in various inflammatory diseases, such as type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. These findings highlight the importance of melatonin signaling in T-cell fate determination, and T cell-based immune pathologies.
28152061	Nearly all living systems feature a temperature-independent oscillation period in circadian clocks. This ubiquitous property occurs at the system level and is rooted in the network architecture of the clock machinery. To investigate the mechanism of this prominent property of the circadian clock and provide general guidance for generating robust genetic oscillators with temperature-compensated oscillations, we theoretically explored the design principle and core network topologies preferred by oscillations with a temperature-independent period. By enumerating all topologies of genetic regulatory circuits with three genes, we obtained four network motifs, namely, a delayed negative feedback oscillator, repressilator, activator-inhibitor oscillator and substrate-depletion oscillator; hybrids of these motifs constitute the vast majority of target network topologies. These motifs are biased in their capacities for achieving oscillations and the temperature sensitivity of the period. The delayed negative feedback oscillator and repressilator are more robust for oscillations, whereas the activator-inhibitor and substrate-depletion oscillators are superior for maintaining a temperature-independent oscillation period. These results suggest that thermally robust oscillation can be more plausibly achieved by hybridizing these two categories of network motifs. Antagonistic balance and temperature insulation mechanisms for achieving temperature compensation are typically found in these topologies with temperature robustness. In the temperature insulation approach, the oscillation period relies on very few parameters, and these parameters are influenced only slightly by temperature. This approach prevents the temperature from affecting the oscillation period and generates circadian rhythms that are robust against environmental perturbations.
28152057	Flavonoids are natural polyphenols that are widely found in plants. The effects of flavonoids on obesity and numerous diseases such as cancer, diabetes, and Alzheimer's have been well studied. However, little is known about the relationships between flavonoids and the circadian clock. In this study, we show that continuous or transient application of flavonoids to the culture medium of embryonic fibroblasts from PER2::LUCIFERASE (PER2::LUC) mice induced various modifications in the circadian clock amplitude, period, and phase. Transient application of some of the tested flavonoids to cultured cells induced a phase delay of the PER2::LUC rhythm at the down slope phase. In addition, continuous application of the polymethoxy flavonoids nobiletin and tangeretin increased the amplitude and lengthened the period of the PER2::LUC rhythm. The nobiletin-induced phase delay was blocked by co-treatment with U0126, an ERK inhibitor. In summary, among the tested flavonoids, polymethoxy flavones increased the amplitude, lengthened the period, and delayed the phase of the PER2::LUC circadian rhythm. Therefore, foods that contain polymethoxy flavones may have beneficial effects on circadian rhythm disorders and jet lag.
28151433	Phase synchronization between two weakly coupled oscillators occurs in many natural systems. Since it is difficult to unambiguously detect such synchronization in experimental data, several methods have been proposed for this purpose. Five popular approaches are systematically optimized and compared here.We study and apply the automated synchrogram method, the reduced synchrogram method, two variants of a gradient method, and the Fourier mode method, analyzing 24h data records from 1455 post-infarction patients, the same data with artificial inaccuracies, and corresponding surrogate data generated by Fourier phase randomization.	We find that the automated synchrogram method is the most robust of all studied approaches when applied to records with missing data or artifacts, whereas the gradient methods should be preferred for noisy data and low-accuracy R-peak positions. We also show that a strong circadian rhythm occurs with much more frequent phase synchronization episodes observed during night time than during day time by all five methods.	In specific applications, the identified characteristic differences as well as strengths and weaknesses of each method in detecting episodes of cardio-respiratory phase synchronization will be useful for selecting an appropriate method with respect to the type of systematic and dynamical noise in the data.	
28148829	In group-living animals, social interactions influence various traits including circadian activity. Maternal care, in particular, can have a strong effect on the circadian activity of parents or nurses across taxa. In social insects, nest-mates are known to have diverse activity rhythms; however, what kind of social environment is crucial in shaping an individual's rhythm is largely unknown. Here, we show that the focal brood types being taken care of (i.e. egg, larva and pupa) have significant effects on individual activity/rest rhythm, using the monomorphic ant Diacamma (putative species indicum). When isolated from a colony, nurses exhibited a clear circadian rhythm. However, when paired with eggs or larvae, they exhibited around-the-clock activity with no apparent rhythm. In contrast, a clear activity rhythm emerged when nurses were paired with a pupa, requiring little care. Such brood-type-specific changes in circadian activity are considered to arise from the difference in caretaking demands. Our finding may contribute to the understanding of the organization of a colony in the context of behavioural variability under different microenvironments.
28145903	Circadian rhythms play an influential role in nearly all aspects of physiology and behavior in the vast majority of species on Earth. The biological clockwork that regulates these rhythms is dynamic over the lifespan: rhythmic activities such as sleep/wake patterns change markedly as we age, and in many cases they become increasingly fragmented. Given that prolonged disruptions of normal rhythms are highly detrimental to health, deeper knowledge of how our biological clocks change with age may create valuable opportunities to improve health and longevity for an aging global population. In this Review, we synthesize key findings from the study of circadian rhythms in later life, identify patterns of change documented to date, and review potential physiological mechanisms that may underlie these changes.
28143926	The basic helix-loop-helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ∼24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here we show that CRY1 binds directly to the PAS domain core of CLOCK:BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.
28143912	The hypoxia response system and circadian clock system are interconnected.
28143743	This study investigated the influence of diurnal photosynthetic activity on the morphology, molecular composition, crystallinity, and gelatinization properties of normal barley starch (NBS) and waxy barley starch (WBS) granules from plants cultivated in a greenhouse under normal diurnal (16h light) or constant light photosynthetic conditions. Growth rings were observed in all starch samples regardless of lighting conditions. The size distribution of whole and debranched WBS analyzed by gel-permeation chromatography did not appear to be influenced by the different lighting regimes, however, a greater relative crystallinity measured by wide-angle X-ray scattering and greater crystalline quality as judged by differential scanning calorimetry was observed under the diurnal lighting regime. NBS cultivated under the diurnal photosynthetic lighting regime displayed lower amylose content (18.7%), and shorter amylose chains than its counterpart grown under constant light. Although the relative crystallinity of NBS was not influenced by lighting conditions, lower onset, peak, and completion gelatinization temperatures were observed in diurnally grown NBS compared to constant light conditions. It is concluded that normal barley starch is less influenced by the diurnal photosynthetic lighting regime than amylose-free barley starch suggesting a role of amylose to prevent structural disorder and increase starch granule robustness against environmental cues.
28140399	Temporal organization of physiology is critical for human health. In the past, humans experienced predictable periods of daily light and dark driven by the solar day, which allowed for entrainment of intrinsic circadian rhythms to the environmental light-dark cycles. Since the adoption of electric light, however, pervasive exposure to nighttime lighting has blurred the boundaries of day and night, making it more difficult to synchronize biological processes. Many systems are under circadian control, including sleep-wake behavior, hormone secretion, cellular function and gene expression. Circadian disruption by nighttime light perturbs those processes and is associated with increasing incidence of certain cancers, metabolic dysfunction and mood disorders. This review focuses on the role of artificial light at night in mood regulation, including mechanisms through which aberrant light exposure affects the brain. Converging evidence suggests that circadian disruption alters the function of brain regions involved in emotion and mood regulation. This occurs through direct neural input from the clock or indirect effects, including altered neuroplasticity, neurotransmission and clock gene expression. Recently, the aberrant light exposure has been recognized for its health effects. This review summarizes the evidence linking aberrant light exposure to mood.
28139817	Recent data indicate that Alzheimer's disease (AD) is associated with disturbances of the circadian rhythm in patients. We examined the effect of amyloid-β (Aβ) peptide, the main component of the senile plaques playing a critical role in the deregulation of calcium (Ca<sup>2+</sup>) homeostasis in AD, on the circadian oscillation of cytosolic calcium (Ca<sup>2+</sup>) levels <i><i>in vitro</i></i>. The experiments we carried out in human primary skin fibroblasts. This cell line was previously shown to exhibit circadian rhythms of clock genes. Moreover, the basic clock properties of these peripheral cells closely mimic those measured physiologically and behaviorally in human and do not change during aging. In this study we showed that i) cytosolic Ca<sup>2+</sup> oscillations depend on the activation of purinergic P2X7 receptors; and ii) these oscillations are abolished in the presence of Aβ. In total, our new findings may help to deepen our understanding of the molecular mechanisms involved in AD-related circadian alterations.
28138902	Members of the plant glycine-rich RNA-binding proteins (GR-RBPs) family have been reported in flowering, development, circadian rhythms, biotic and abiotic stresses. Particularly, GR-RBPs are reported to function as RNA chaperones, promoting growth and acclimation during cold shock. It is indispensable to further question the efficacy and mechanism of GR-RBPs under various environmental strains. Monitoring the expression of stress-regulated proteins under stress conditions has been a beneficial strategy to study their functional roles. In an effort to elucidate the NtGR-RBP1 function, stress markers such as salinity, drought, low temperature and heat stresses were studied. The NtGR-RBP1 gene was expressed in E. coli followed by the exposure to stress conditions. Recombinant E. coli expressing NtGR-RBP1 were more tolerant to stresses, e.g., salinity, drought, cold and heat shock. Recombinants exhibited higher growth rates compared to control in spot assays. The tolerance was further confirmed by monitoring the growth in liquid culture assays. Cells expressing NtGR-RBP1 under salt (500 mM NaCl), drought (20% PEG), cold (4 and 20 °C) and heat stresses (50 °C) had enhanced growing ability and better endurance. Our study supports the notion that the protective role of NtGR-RBP1 may contribute to growth and survival during diverse environmental stresses.
28138105	Attention-deficit hyperactivity disorder (ADHD) is notorious for its debilitating consequences and early age of onset. The need for early diagnosis and intervention has frequently been underscored. Previous studies have attempted to clarify the bidirectional relationship between ADHD and sleep problems, proposing a potential role for sleep problems as early predictors of ADHD. Sleep deprivation, sleep-disordered breathing, and circadian rhythm disturbances have been extensively studied, yielding evidence with regard to their induction of ADHD-like symptoms. Genetic-phenotypic differences across individuals regarding the aforementioned sleep problems have been elucidated along with the possible use of these characteristics for early prediction of ADHD. The long-term consequences of sleep problems in individuals with ADHD include obesity, poor academic performance, and disrupted parent-child interactions. Early intervention has been proposed as an approach to preventing these debilitating outcomes of ADHD, with novel treatment approaches ranging from melatonin and light therapy to myofunctional therapy and adjustments of the time point at which school starts.
28137450	Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF1 receptor-deficient (CRF1-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF1-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF1-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF1-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF1-/- mice by exogenous corticosterone does not affect CRF1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF1 receptor in cocaine reward, independently of the closely related HPA axis activity.
28134281	Circadian locomotor behaviour is controlled by a pacemaker circuit composed of clock-containing neurons. To interrogate the mechanistic relationship between the molecular clockwork and network communication critical to the operation of the Drosophila circadian pacemaker circuit, we established new fluorescent circadian reporters that permit single-cell recording of transcriptional and post-transcriptional rhythms in brain explants and cultured neurons. Live-imaging experiments combined with pharmacological and genetic manipulations demonstrate that the neuropeptide pigment-dispersing factor (PDF) amplifies the molecular rhythms via time-of-day- and activity-dependent upregulation of transcription from E-box-containing clock gene promoters within key pacemaker neurons. The effect of PDF on clock gene transcription and the known role of PDF in enhancing PER/TIM stability occur via independent pathways downstream of the PDF receptor, the former through a cAMP-independent mechanism and the latter through a cAMP-PKA dependent mechanism. These results confirm and extend the mechanistic understanding of the role of PDF in controlling the synchrony of the pacemaker neurons. More broadly, our results establish the utility of the new live-imaging tools for the study of molecular-neural interactions important for the operation of the circadian pacemaker circuit.
28134247	Circadian clocks drive ∼24 h rhythms in tissue physiology. They rely on transcriptional/translational feedback loops driven by interacting networks of clock complexes. However, little is known about how cell-intrinsic circadian clocks sense and respond to their microenvironment. Here, we reveal that the breast epithelial clock is regulated by the mechano-chemical stiffness of the cellular microenvironment in primary cell culture. Moreover, the mammary clock is controlled by the periductal extracellular matrix in vivo, which contributes to a dampened circadian rhythm during ageing. Mechanistically, the tension sensing cell-matrix adhesion molecule, vinculin, and the Rho/ROCK pathway, which transduces signals provided by extracellular stiffness into cells, regulate the activity of the core circadian clock complex. We also show that genetic perturbation, or age-associated disruption of self-sustained clocks, compromises the self-renewal capacity of mammary epithelia. Thus, circadian clocks are mechano-sensitive, providing a potential mechanism to explain how ageing influences their amplitude and function.
28129482	To evaluate the association between nocturia and the incidence of depressive symptoms.Of 1 127 participants in the HEIJO-KYO population-based cohort, 866 elderly individuals (mean age 71.5 years) without depressive symptoms at baseline were followed for a median period of 23 months. Nocturnal voiding frequency was logged using a standardized urination diary and nocturia was defined as a frequency of ≥2 voids per night. Depressive symptoms were assessed using the Geriatric Depression Scale.	During the follow-up period, 75 participants reported the development of depressive symptoms (score ≥6). The nocturia group (n = 239) exhibited a significantly higher hazard ratio (HR) for incident depressive symptoms than the non-nocturia group (n = 627) in the Cox proportional hazard model, which was adjusted for age, gender, alcohol consumption, day length and presence of hypertension and chronic kidney disease (HR 1.69, 95% confidence interval [CI] 1.05-2.72; P = 0.032]. The significance remained after adjustment for sleep disturbances (HR 1.68, 95% CI 1.02-2.75; P = 0.040). Analysis stratified by gender showed that the association between nocturia and the incidence of depressive symptoms was significant in men (HR 2.51, 95% CI 1.27-4.97; P = 0.008) but not in women (HR 1.12, 95% CI 0.53-2.44; P = 0.74).	Nocturia is significantly associated with a higher incidence of depressive symptoms in the general elderly population, and gender differences may underlie this association.	
28128995	The circadian system is known to play a role in glucose metabolism. Chronotype reflects the interindividual variability in the phase of entrainment. Those with later chronotype typically prefer later times in the day for different activities such as sleep or meals. Later chronotype has been shown to be associated with metabolic syndrome, increased diabetes risk and poorer glycemic control in type 2 diabetes patients. In addition, "social jetlag", a form of circadian misalignment due to a mismatch between social rhythms and the circadian clock, has been shown to be associated with insulin resistance. Other sleep disturbances (insufficient sleep, poor sleep quality and sleep apnea) have also been shown to affect glucose metabolism. In this study, we explored whether there was a relationship between chronotype, social jetlag and hemoglobin A1c (HbA1c) levels in prediabetes patients, independent of other sleep disturbances. A cross-sectional study was conducted at the Department of Family Medicine, Ramathibodi Hospital, Bangkok, from October 2014 to March 2016 in 1014 non-shift working adults with prediabetes. Mid-sleep time on free day adjusted for sleep debt (MSFsc) was used as an indicator of chronotype. Social jetlag was calculated based on the absolute difference between mid-sleep time on weekdays and weekends. The most recent HbA1c values and lipid levels were retrieved from clinical laboratory databases. Univariate analyses revealed that later MSFsc (p = 0.028) but not social jetlag (p = 0.48) was significantly associated with higher HbA1c levels. Multivariate linear regression analysis was applied to determine whether an independent association between MSFsc and HbA1c level existed. After adjusting for age, sex, alcohol use, body mass index (BMI), social jetlag, sleep duration, sleep quality and sleep apnea risk, later MSFsc was significantly associated with higher HbA1c level (B = 0.019, 95% CI: 0.00001, 0.038, p = 0.049). The effect size of one hour later MSFsc on HbA1c (standardized coefficient = 0.065) was approximately 74% of that of the effect of one unit (kg/m2) increase in BMI (standardized coefficient = 0.087). In summary, later chronotype is associated with higher HbA1c levels in patients with prediabetes, independent of social jetlag and other sleep disturbances. Further research regarding the potential role of chronotype in diabetes prevention should be explored.
28127845	Sleep problems in people with dementia are common and place a high burden on caregivers. Although hypnotic agents are often used to treat sleep disturbances, their use is associated with a considerable number of high-risk side-effects such as daytime sleepiness, amnesia, and an increased frequency of falling. The administration of bright light therapy (BLT) in the morning was a non-pharmacological remedy that was expected to treat sleep disorders in patients with dementia by entraining the circadian rhythm to ameliorate disturbances to the normal sleep-wake cycle. However, there are some unsolved issues related to the application of BLT, including the types of dementia for which it is effective and its efficacy in the different stages of cognitive decline and dementia. Furthermore, a protocol for effective BLT has not yet been proposed.In this study, we explored the efficacy of BLT in the treatment of 17 participants, including those with Alzheimer's type dementia (AD) (n = 8), vascular dementia (n = 4), and dementia with Lewy bodies (n = 5). Patients sat in front of the light box for 1 h/day from 0900 to 1000. The patients underwent treatment every day for 2 weeks.	BLT led to the improvement of sleep disturbance in four participants, all of whom were AD patients. The four AD patients showed a shorter duration of illness and/or had mild to moderate AD.	BLT could be an effective strategy for treating dementia patients, depending on their type and grade of their dementia. To confirm this hypothesis, it would be necessary to study a larger number of cases. Non-pharmacological therapies for sleep disorders should be emphasized as a safe form of treatment for patients with dementia.	
28123673	Nucleotide sequences of the circadian rhythm genes, period and timeless, were studied for the first time in mosquitoes Culex pipiens Linnaeus, 1758. In this work we evaluated variations of the studied genome fragments for the two forms of Culex pipiens (forma "pipiens" - mosquitoes common for aboveground habitats, forma "molestus" - underground mosquitoes). We compared Culex pipiens from Russia with transatlantic Culex pipiens and subtropical Culex quinquefasciatus Say, 1823. Our results show that intraspecies variability is higher for the gene period than for the gene timeless. The revealed substitutions in nucleotide sequences and especially in amino acid sequences grouped the individuals of the two forms into distinct clusters with high significance. The detected fixed amino acid substitutions may appear essential for functioning of the circadian rhythm proteins in Culex pipiens, and may be correlated with adaptations of the taxa within the group Culex pipiens. Our results suggest that natural selection favors fixed mutations and the decrease in diversity of the genes period and timeless in mosquitoes of the Culex pipiens f. "molestus" compared with the Culex pipiens f. "pipiens", is probably correlated with adaptive features of Culex pipiens f. "molestus". The studied genome regions may be considered as promising molecular-genetic markers for identification, population and phylogenetic analysis of similar species and forms of the Culex pipiens complex.
28123653	This paper assesses hypothesis that sufficient sleep duration and proper circadian rhythms during the early stages of life are indispensable to a successful life. Successful life was defined according to the famous cohort studies of Mischel's and Dunedin. To assess the hypothesis, neuronal elements presumably affecting early daily habits and successful life are reviewed. The effect of sufficient sleep duration and proper circadian rhythms during early stages of life on the development of the prefrontal cortex has been found to be the key issue to verify the hypothesis. Socioeconomic status is found to be another issue to be studied.
28123391	Bamboo, one of the fastest growing plants, can be a promising model system to understand growth. The study provides an insight into the complex interplay between environmental signaling and cellular machineries governing initiation and persistence of growth in a subtropical bamboo (Dendrocalamus hamiltonii). Phenological and spatio-temporal transcriptome analysis of rhizome and shoot during the major vegetative developmental transitions of D. hamiltonii was performed to dissect factors governing growth. Our work signifies the role of environmental cues, predominantly rainfall, decreasing day length, and high humidity for activating dormant bud to produce new shoot, possibly through complex molecular interactions among phosphatidylinositol, calcium signaling pathways, phytohormones, circadian rhythm, and humidity responses. We found the coordinated regulation of auxin, cytokinin, brassinosteroid signaling and cell cycle modulators; facilitating cell proliferation, cell expansion, and cell wall biogenesis supporting persistent growth of emerging shoot. Putative master regulators among these candidates were identified using predetermined Arabidopsis thaliana protein-protein interaction network. We got clues that the growth signaling begins far back in rhizome even before it emerges out as new shoot. Putative growth candidates identified in our study can serve in devising strategies to engineer bamboos and timber trees with enhanced growth and biomass potentials.
28121174	To investigate whether the elimination of β1- and β2-adrenergic receptors alters the diurnal intraocular pressure (IOP) rhythm in mice.β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice were anesthetized intraperitoneally, with their IOPs measured via microneedle method. After entrainment to a 12-h light-dark (LD) cycle (light phase 6:00-18:00), IOPs were measured every 3 h from 9:00 to 24:00 (group 1, β1-/β2-adrenergic receptor double-knockout mice, n = 11; C57BL/6J, n = 15). The IOP measurements at 15:00 and 24:00 under a 12-h LD cycle and in the constant darkness (1 day and 8 days after exposure to darkness, respectively) were performed in another group of β1-/β2-adrenergic receptor double-knockout mice (group 2, n = 12). IOP variance throughout the day and mean IOP differences among time points were evaluated using a linear mixed model.	β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice showed biphasic IOP curves, low during the light phase and high during the dark phase; the fluctuation was significant (P < 0.001). The peak IOP (18.7 ± 1.4 mmHg) occurred at 24:00 and the trough IOP (13.5 ± 1.5 mmHg) occurred at 15:00 in β1-/β2-adrenergic receptor double-knockout mice group. IOP curves of β1-/β2-adrenergic receptor double-knockout and C57BL/6J were nearly parallel, and the IOPs of β1-/β2-adrenergic receptor double-knockout mice were significantly higher than those of C57BL/6J mice (P < 0.001). Under constant dark (DD) conditions, IOP at 24:00 (18.1 ± 1.5 mmHg) was significantly higher than that at 15:00 (13.3 ± 1.2 mmHg) (P < 0.001). The transition from the LD cycle to DD environment produced no significant change in IOP (P = 0.728).	Elimination of both β1- and β2-adrenergic receptors did not disturb the biphasic diurnal IOP rhythm in mice.	
28117839	Meta-analyses of genome-wide association studies (meta-GWASs) and candidate gene studies have identified genetic variants associated with cardiovascular diseases, metabolic diseases and mood disorders. Although previous efforts were successful for individual disease conditions (single disease), limited information exists on shared genetic risk between these disorders. This article presents a detailed review and analysis of cardiometabolic diseases risk (CMD-R) genes that are also associated with mood disorders. First, we reviewed meta-GWASs published until January 2016, for the diseases 'type 2 diabetes, coronary artery disease, hypertension' and/or for the risk factors 'blood pressure, obesity, plasma lipid levels, insulin and glucose related traits'. We then searched the literature for published associations of these CMD-R genes with mood disorders. We considered studies that reported a significant association of at least one of the CMD-R genes and 'depression' or 'depressive disorder' or 'depressive symptoms' or 'bipolar disorder' or 'lithium treatment response in bipolar disorder', or 'serotonin reuptake inhibitors treatment response in major depression'. Our review revealed 24 potential pleiotropic genes that are likely to be shared between mood disorders and CMD-Rs. These genes include MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, REST, FTO, POMC, BDNF, CREB, ITIH4, LEP, GSK3B, SLC18A1, TLR4, PPP1R1B, APOE, CRY2, HTR1A, ADRA2A, TCF7L2, MTNR1B and IGF1. A pathway analysis of these genes revealed significant pathways: corticotrophin-releasing hormone signaling, AMPK signaling, cAMP-mediated or G-protein coupled receptor signaling, axonal guidance signaling, serotonin or dopamine receptors signaling, dopamine-DARPP32 feedback in cAMP signaling, circadian rhythm signaling and leptin signaling. Our review provides insights into the shared biological mechanisms of mood disorders and cardiometabolic diseases.
28117135	Sleep problems are common, reported by a quarter of parents with children under the age of 5 years, and have been associated with poor behavior, worse school performance, and obesity, in addition to negative secondary effects on maternal and family well-being. Yet, it has been shown that pediatricians do not adequately address sleep in routine well-child visits, and underdiagnose sleep issues. Pediatricians receive little formal training in medical school or in residency regarding sleep medicine. An understanding of the physiology of sleep is critical to a pediatrician׳s ability to effectively and confidently counsel patients about sleep. The biological rhythm of sleep and waking is regulated through both circadian and homeostatic processes. Sleep also has an internal rhythmic organization, or sleep architecture, which includes sleep cycles of REM and NREM sleep. Arousal and sleep (REM and NREM) are active and complex neurophysiologic processes, involving both neural pathway activation and suppression. These physiologic processes change over the life course, especially in the first 5 years. Adequate sleep is often difficult to achieve, yet is considered very important to optimal daily function and behavior in children; thus, understanding optimal sleep duration and patterns is critical for pediatricians. There is little experimental evidence that guides sleep recommendations, rather normative data and expert recommendations. Effective counseling on child sleep must account for the child and parent factors (child temperament, parent-child interaction, and parental affect) and the environmental factors (cultural, geographic, and home environment, especially media exposure) that influence sleep. To promote health and to prevent and manage sleep problems, the American Academy of Pediatrics (AAP) recommends that parents start promoting good sleep hygiene, with a sleep-promoting environment and a bedtime routine in infancy, and throughout childhood. Thus, counseling families on sleep requires an understanding of sleep regulation, physiology, developmental patterns, optimal sleep duration recommendations, and the many factors that influence sleep and sleep hygiene.
28116919	We aimed to investigate the relationship between the morning blood pressure (BP) surge and arterial stiffness in patients with newly diagnosed hypertension.Three hundred and twenty four (mean age 51.7 ± 11.4 years) patients who had newly diagnosed hypertension with 24 h ambulatory BP monitoring were enrolled. Parameters of arterial stiffness, pulse wave velocity and augmentation index (Aix) were measured by applanation tonometry and aortic distensibility was calculated by echocardiography.	Compared with the other groups, pulse wave velocity, day-night systolic BP (SBP) difference (p < 0.001, for all) and hs-CRP (p = 0.005) were higher in morning BP surge high group. Aortic distensibility values were significantly lower in morning BP surge high group compared to the other groups (p < 0.05, for all). Morning BP surge was found to be independently associated with pulse wave velocity (β = 0.286, p < 0.001), aortic distensibility (β= -0.384, p < 0.001) and day-night SBP difference (β = 0.229, p < 0.001) in multivariate linear regression analysis.	We found independent relationship between morning BP surge and arterial stiffness which is a surrogate endpoint for cardiovascular diseases. The inverse relationship between morning BP surge and aortic distensibility and direct relation found in our study is new to the literature.	
28116759	Splitting of the behavioural activity phase has been found in nocturnal rodents with suprachiasmatic nucleus (SCN) coupling disorder. A similar phenomenon was observed in the sleep phase in the diurnal human discussed here, suggesting that there are so-called evening and morning oscillators in the SCN of humans. The present case suffered from bipolar disorder refractory to various treatments, and various circadian rhythm sleep disorders, such as delayed sleep phase, polyphasic sleep, separation of the sleep bout resembling splitting and circabidian rhythm (48 h), were found during prolonged depressive episodes with hypersomnia. Separation of sleep into evening and morning components and delayed sleep-offset (24.69-h cycle) developed when lowering and stopping the dose of aripiprazole (APZ). However, resumption of APZ improved these symptoms in 2 weeks, accompanied by improvement in the patient's depressive state. Administration of APZ may improve various circadian rhythm sleep disorders, as well as improve and prevent manic-depressive episodes, via augmentation of coupling in the SCN network.
28115741	In 17 patients with rapid cycling bipolar disorder, time-series analyses detected synchronies between mood cycles and three lunar cycles that modulate the amplitude of the moon's semi-diurnal gravimetric tides: the 14.8-day spring-neap cycle, the 13.7-day declination cycle and the 206-day cycle of perigee-syzygies ('supermoons'). The analyses also revealed shifts among 1:2, 1:3, 2:3 and other modes of coupling of mood cycles to the two bi-weekly lunar cycles. These shifts appear to be responses to the conflicting demands of the mood cycles' being entrained simultaneously to two different bi-weekly lunar cycles with slightly different periods. Measurements of circadian rhythms in body temperature suggest a biological mechanism through which transits of one of the moon's semi-diurnal gravimetric tides might have driven the patients' bipolar cycles, by periodically entraining the circadian pacemaker to its 24.84-h rhythm and altering the pacemaker's phase-relationship to sleep in a manner that is known to cause switches from depression to mania.Molecular Psychiatry advance online publication, 24 January 2017; doi:10.1038/mp.2016.263.
28115724	Laboratory studies have demonstrated that circadian clocks align physiology and behavior to 24-h environmental cycles. Examination of athletic performance has been used to discern the functions of these clocks in humans outside of controlled settings. Here, we examined the effects of jet lag, that is, travel that shifts the alignment of 24-h environmental cycles relative to the endogenous circadian clock, on specific performance metrics in Major League Baseball. Accounting for potential differences in home and away performance, travel direction, and team confounding variables, we observed that jet-lag effects were largely evident after eastward travel with very limited effects after westward travel, consistent with the >24-h period length of the human circadian clock. Surprisingly, we found that jet lag impaired major parameters of home-team offensive performance, for example, slugging percentage, but did not similarly affect away-team offensive performance. On the other hand, jet lag impacted both home and away defensive performance. Remarkably, the vast majority of these effects for both home and away teams could be explained by a single measure, home runs allowed. Rather than uniform effects, these results reveal surprisingly specific effects of circadian misalignment on athletic performance under natural conditions.
28114877	Daily activity rhythms that are dominated by internal clocks are called circadian rhythms. A central clock is located in the suprachiasmatic nucleus of the hypothalamus, and peripheral clocks are located in most mammalian peripheral cells. The central clock is entrained by light/dark cycles, whereas peripheral clocks are entrained by feeding cycles. The effects of nutrients on the central and peripheral clocks have been investigated during the past decade and much interaction between them has come to light. For example, a high-fat diet prolongs the period of circadian behavior, a ketogenic diet advances the onset of locomotor activity rhythms, and a high-salt diet advances the phase of peripheral molecular clocks. Moreover, some food factors such as caffeine, nobiletin, and resveratrol, alter molecular and/or behavioral circadian rhythms. Here, we review nutrients and food factors that modulate mammalian circadian clocks from the cellular to the behavioral level.
28112452	The neurotransmitter dopamine (DA) is known to be involved in a multitude of physiological processes. We investigated sexually dimorphic effects of disruptions in DA homeostasis and its relationship to senescence using three different Drosophila melanogaster mutants namely Catsup (Catsup26 ) with elevated DA levels, and pale (ple2 ), Punch (PuZ22 ) with depleted DA levels. In all genotypes including controls, DA levels were significantly lower in old (45-50-day-old) flies compared with young (3-5-day-old) in both sexes. Interestingly, females had lower DA content than males at young age whereas this difference was not observed in old age, suggesting that males had a larger decline in DA levels with age. Females, in general, were longer lived compared with males in all genotypes except ple2 mutants with depleted DA levels. This phenotype was abolished in the ple2 rescue flies. Interestingly, females also demonstrated marked age-related decline in circadian locomotor activity compared with males. Old Catsup26 males with elevated DA levels accumulated significantly lower levels of lipid peroxidation product 4-hydroxy 2-nonenal (4-HNE) compared with age-matched wild type, ple2 and PuZ22 mutant males. In Catsup26 revertant lines this phenomenon was absent. We also observed a sexually dimorphic response in the expression levels of key stress and aging associated and/or related transcription factor genes across genotypes with elevated or depleted DA levels which was reverted to wild type levels in specific rescue lines. Taken together, our results reveal a novel sexually dimorphic involvement of DA in senescence characteristics of D. melanogaster.
28112045	Firefly luciferase (Fluc) is frequently used to report circadian gene expression rhythms in mammalian cells and tissues. During longitudinal assays it is generally assumed that enzymatic substrates are in saturating excess, such that total bioluminescence is directly proportional to Fluc protein level. To test this assumption, we compared the enzyme kinetics of purified luciferase with its activity in mammalian cells. We found that Fluc activity in solution has a lower Michaelis constant (Km) for luciferin, lower temperature dependence, and lower catalytic half-life than Fluc in cells. In consequence, extracellular luciferin concentration significantly affects the apparent circadian amplitude and phase of the widely used PER2::LUC reporter in cultured fibroblasts, but not in SCN, and we suggest that this arises from differences in plasma membrane luciferin transporter activity. We found that at very high concentrations (>1 mM), luciferin lengthens circadian period, in both fibroblasts and organotypic SCN slices. We conclude that the amplitude and phase of circadian gene expression inferred from bioluminescence recordings should be treated with some caution, and we suggest that optimal luciferin concentration should be determined empirically for each luciferase reporter and cell type.
28110240	Lead levels (Pb) have been linked to both hyper- and hypo-reactivity of hypothalamic-pituitary-adrenal axis (HPA) axis to acute stress in animals and humans. Similarly, allostatic load (AL), the 'wear and tear' of chronic stress, is associated with inadequate HPA axis activity. We examined whether Pb levels would be associated with altered diurnal cortisol profile, as a primary mediator of AL, during aging. Pb levels were measured from blood samples (BPb) of 126 Brazilian individuals (105 women), between 50 and 82 years old. Six neuroendocrine, metabolic, and anthropometric biomarkers were analyzed and values were transformed into an AL index using clinical reference cut-offs. Salivary samples were collected at home over 2 days at awakening, 30-min after waking, afternoon, and evening periods to determine cortisol levels. A multiple linear regression model showed a positive association between BPb as the independent continuous variable and cortisol awakening response (R2=0.128; B=0.791; p=0.005) and overall cortisol concentration (R2=0.266; B=0.889; p<0.001) as the outcomes. Repeated measures ANOVA showed that individuals with high BPb levels showed higher cortisol at 30min after awakening (p=0.003), and in the afternoon (p=0.002) than those with low BPb values. Regarding AL, regression model showed that BPb was positively associated with AL index (R2=0.100; B=0.204; p=0.032). Correlation analyzes with individual biomarkers showed that BPb was positively correlated with HDL cholesterol (p=0.02) and negatively correlated with DHEA-S (p=0.049). These findings suggest that Pb exposure, even at levels below the reference blood lead level for adults recommended by the National Institute for Occupational Safety and Health and by the Center for Disease Control and Prevention, may contribute to AL and dysregulated cortisol functioning in older adults. Considering these findings were based on cross-sectional data future research is needed to confirm our exploratory results.
28109907	The endogenous and self-sustained circadian rhythm generated and maintained in suprachiasmatic nucleus and peripheral tissues can coordinate various molecular, biochemical and physiological processes in living organisms resulting in the adaptation to environmental cues, e.g. light. Multifactorial breast cancer etiology also involves circadian gene alterations, especially among individuals exposed to light at night. Indeed, shift work that causes circadian disruption has been classified by the International Agency for Research on Cancer as a probable human carcinogen, group 2A. Thus it seems extremely important to recognize specific susceptible gene variants among around 20 candidate circadian genes that may be linked with breast cancer etiology. The aim of this review was to evaluate recent data investigating a putative link between circadian gene polymorphisms and breast cancer risk. We summarize fifteen epidemiological studies, including five studies on shift work that have indicated BMAL1, BMAL2, CLOCK, NPAS2, CRY1, CRY2, PER1, PER3 and TIMELESS as a candidate breast cancer risk variants.
28108951	Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.
28108206	Despite the conflicting evidence about postvoid residual (PVR) and its variation in time and corresponding voided volume (VV), studies with urinary diaries and systematic measurements of PVR after each void have never been conducted in nursing home (NH) residents.To describe the circadian rhythm of PVR and residual fraction (RF, the net quantity of PVR) and to identify the time window with the highest PVR and RF.	A multicentre prospective study conducted between 2014 and 2015 in 5 Belgian NHs. A convenience sample of cognitively intact residents completed a 24-hour frequency volume chart with PVR.	Participants (n = 73) had a median age of 84 years (interquartile range 82-89) and moderate impairment of activities of daily living; 69% were women. In residents with nocturia, mean PVR was higher during the night [45 mL (26-80)] than during the day [36 mL (18-61)]. In residents without nocturia no difference was detected. In spite of the variation between diurnal and nocturnal VV and PVR in residents with nocturia, all residents emptied their bladder as effectively during daytime as during nighttime [mean RF = 20% (12-32)]. Maximum PVR and RF in residents with nocturia (n = 57) showed a circadian variation. The highest PVR and RF were found during the day. The PVR and RF of the first morning void were an indicator of the maximum nocturnal PVR and RF.	PVR and VV should be measured in NH residents during the waking hours (first morning void excepted) to detect the clinically relevant maximum PVR and RF.	
28106813	The symptoms of asthma, breathlessness, insomnia, etc. all have relevance to pulmonary rhythmic disturbances. Epidemiology and toxicology studies have demonstrated that exposure to ambient air particles can result in pulmonary dysfunction. However, there are no data directly supporting a link between air pollution and circadian rhythm disorder. In the present study, we found that breathing highly polluted air resulted in changes of the molecular clock genes expression in lung by transcriptome profiling analyses in a rodent model. Compared to those exposed to filtered air, in both pregnant and offspring rats in the unfiltered group, key clock genes (Per1, Per2, Per3, Rev-erbα and Dbp) expression level decreased and Bmal1 expression level increased. In both rat dams and their offspring, after continuous exposure to unfiltered air, we observed significant histologic evidence for both perivascular and peribronchial inflammation, increased tissue and systemic oxidative stress in the lungs. Our results suggest that chronic exposure to particulate matter can induce alterations of clock genes expression, which could be another important pathway for explaining the feedbacks of ambient particle exposure in addition to oxidative stress and inflammation.
28105938	Transcriptional changes that contribute to the organism's longevity and prevent the age-dependent decline of biological functions are not well understood. Here, we overexpressed pro-longevity gene encoding glutamate-cysteine ligase catalytic subunit (Gclc) and analyzed age-dependent changes in transcriptome that associated with the longevity, stress resistance, locomotor activity, circadian rhythmicity, and fertility.Here we reproduced the life extension effect of neuronal overexpression of the Gclc gene and investigated its influence on the age-depended dynamics of transcriptome and biological functions such as fecundity, spontaneous locomotor activity and circadian rhythmicity, as well as on the resistance to oxidative, proteotoxic and osmotic stresses. It was shown that Gclc overexpression reduces locomotor activity in the young and middle ages compared to control flies. Gclc overexpression slowed down the age-dependent decline of locomotor activity and circadian rhythmicity, and resistance to stress treatments. Gclc level demonstrated associations with the expression of genes involved in a variety of cellular processes including Jak-STAT, MAPK, FOXO, Notch, mTOR, TGF-beta signaling pathways, translation, protein processing in endoplasmic reticulum, proteasomal degradation, glycolysis, oxidative phosphorylation, apoptosis, regulation of circadian rhythms, differentiation of neurons, synaptic plasticity and transmission.	Our study revealed that Gclc overexpression induces transcriptional changes associated with the lifespan extension and uncovered pathways that may be associated with the age-dependent decline of biological functions.	
28105441	Cryptochrome proteins (CRYs), which can bind noncovalently to cofactor (chromophore) flavin adenine dinucleotide (FAD), occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice), ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1) being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY). The lowered proliferation of β-cells is a primary cause of age-dependent β-cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β-cells in the Tg mice. This review, based mainly on the author's investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β-cell dysfunction, and regeneration.
28105380	Serinus canaria is a widespread domestic ornamental songbird, whose limited knowledge of biology make compelling studies aimed to monitor stress. Here, a commercial enzyme immunoassay was adopted to measure immunoreactive corticosterone (CORT) in single Serinus canaria dropping sample, to monitor the daily fecal excretion of CORT in birds bred singly or in-group and to detect the effect promoted by aviary or small transport cage restraint. A robust daily rhythm of CORT was recorded in animals held on short-day light cycle, independent of bred conditions (single or group), which persisted when space availability was modified in single bred animal (transfer in aviary and transport cages). By contrast, a significant change in CORT excretion was recorded when group bred animals are restrained in a smaller cage. The daily rhythm in CORT excretion in response to manipulation showed the greatest response at the beginning of the light period, followed by the absence of the peak usually recorded at the end of the dark phase. These data indicated that EIA could be used as a reliable noninvasive approach to monitor the stress induced by restraint conditions in Serinus canaria.
28104016	目的： 研究阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome，OSAHS)合并难治性高血压(resistant hypertension，RH)患者中，OSAHS的治疗对血压控制的意义。 方法： 80例OSAHS合并RH患者[至少3种抗高血压药(包括利尿剂)治疗，仍不能将收缩压和舒张压控制在目标水平(140/90 mmHg, 1 mmHg＝0.133 kPa)]行手术或持续正压通气治疗，治疗前及治疗6个月后行多道睡眠监测和动态血压监测，记录呼吸暂停低通气指数(apnea hypopnea index，AHI)、最低血氧饱和度(SaO(2))、血压、夜间血压下降率，比较治疗前后降压药物种类的变化。 结果： 治疗后，AHI由(32.9±10.8)次/h(x±s，下同)降至(9.4±6.5)次/h，最低SaO(2)由(0.682±0.062)增至(0.884±0.056)，差异均有统计学意义(t值分别为18.863、26.614，P值均<0.001)。全天收缩压由(150.5±9.8) mmHg降至(140.7±6.8) mmHg，舒张压由(97.8±7.3) mmHg降至(88.6±6.3) mmHg；日间收缩压由(154.3±8.9) mmHg降至(144.8±5.8) mmHg，舒张压由(100.6±7.4) mmHg降至(91.3±5.5) mmHg；夜间收缩压由(145.5±8.8) mmHg降至(135.8±5.7) mmHg，舒张压由(93.8±6.4) mmHg降至(84.6±5.9) mmHg，差异均有统计学意义(t值分别为7.832、6.903、7.005、6.848、8.025、7.554，P值均<0.001)。夜间收缩压下降值为(11.5±2.2)mmHg、舒张压下降值为(10.2±3.1)mmHg，日间收缩压下降值为(9.0±2.8)mmHg、舒张压下降值为(7.9±3.5)mmHg，夜间收缩压及舒张压下降较日间更明显，差异均有统计学意义(t值分别为9.732、6.936，P值均<0.001)。夜间血压下降率<10%的患者比例由治疗前的75.0%降为治疗后的37.5%，差异有统计学意义(χ(2)＝22.857，P<0.01)，提示血压昼夜节律变化情况好转。45例患者服用的降压药物种类减少，由治疗前的(3.2±0.4)种减为治疗后的(2.6±0.5)种，差异有统计学意义(t＝9.276，P<0.01)。 结论： OSAHS合并RH患者中，治疗OSAHS能有效改善血压控制水平，改善血压昼夜节律，减少降压药物的使用。.Objective: To investigate the effect of the treatments for obstructive sleep apnea hypopnea syndrome (OSAHS) on the resistant hypertension (RH) of patients. Methods: Eighty patients with OSAHS and RH (blood pressure could not be controlled under 140/90 mmHg (1 mmHg=0.133 kPa) even with more than three kinds of antihypertensive drugs including diuretics) received surgery or continuous positive airway pressure (CPAP) treatment. The results of polysomnography monitoring, ambulatory blood pressure monitoring, and the dosage of antihypertensive medication were recorded before and six months after the treatment. Results: Apnea hypopnea index (AHI) decreased from (32.9±10.8) before treatment to (9.4±6.5) after treatment, while the lowest oxygen saturation (SaO(2)) increased from (0.682±0.062) to (0.884±0.056), with significant differences (t value was 18.863 and 26.614, respectively; both P<0.001). Twenty-four hours systolic blood pressure (SBP)/diastolic blood pressure (DBP) decreased respectively from ((150.5±9.8)/(97.8±7.3)) mmHg to ((140.7±6.8)/(88.6±6.3)) mmHg, daytime SBP/DBP decreased from ((154.3±8.9)/(100.6±7.4)) mmHg to ((144.8±5.8)/(91.3±5.5)) mmHg, and nighttime SBP/DBP decreased from ((145.5±8.8)/(93.8±6.4)) mmHg to ((135.8±5.7)/(84.6±5.9)) mmHg, with significant differences (t value was 7.832, 6.903, 7.005, 6.848, 8.025, 7.554, respectively; all P<0.001). The reduction of nighttime SBP /DBP was ((11.5±2.2)/(10.2±3.1)) mmHg, and the reduction of daytime SBP/DBP was ((9.0±2.8)/(7.9±3.5)) mmHg. The reduction of nighttime SBP/DBP was more obvious than daytime SBP/DBP, with significant differences (t value was 9.732 and 6.936, respectively; both P<0.001). Before treatment, nighttime blood pressure decrease rate below 10% was showed in 75 percent of patients, and after treatment, this rate only in 37.5 percent of patients (χ(2)=22.857, P<0.01). The numbers of required antihypertensive drugs decreased in 45 (56.3%) cases, the average numbers of antihypertensive drugs decreased from (3.2±0.4) before treatment to (2.6±0.5) after treatment, with a significant difference (t=9.276, P<0.01). Conclusions: After treatment of OSAHS, the blood pressure of the patients with OSAHS and RH dropped significantly, the circadian rhythm of blood pressure condition was better, the varieties of antihypertensive drugs taken in these patients were reduced significantly.	
28103237	Insect behaviors are often influenced by light conditions including photoperiod, light intensity, and wavelength. Understanding pest insect responses to changing light conditions may help with developing alternative strategies for pest control. Little is known about the behavioral responses of leafhoppers (Hemiptera: Cicadellidae) to light conditions. The behavior of the tea green leafhopper, Empoasca onukii Matsuda, was examined when exposed to different light photoperiods or wavelengths. Observations included the frequency of locomotion and cleaning activities, and the duration of time spent searching. The results suggested that under normal photoperiod both female and male adults were generally more active in darkness (i.e., at night) than in light. In continuous darkness (DD), the locomotion and cleaning events in Period 1 (7:00-19:00) were significantly increased, when compared to the leafhoppers under normal photoperiod (LD). Leafhoppers, especially females, changed their behavioral patterns to a two day cycle under DD. Under continuous illumination (continuous quartz lamp light, yellow light at night, and green light at night), the activities of locomotion, cleaning, and searching were significantly suppressed during the night (19:00-7:00) and locomotion activities of both females and males were significantly increased during the day (7:00-19:00), suggesting a shift in circadian rhythm. Our work suggests that changes in light conditions, including photoperiod and wavelength, can influence behavioral activities of leafhoppers, potentially affecting other life history traits such as reproduction and development, and may serve as a method for leafhopper behavioral control.
28102700	High fat diet (HFD) consumption alters the synchronized circadian timing system resulting in harmful loss, gain or shift of transcriptional oscillations. The aryl hydrocarbon receptor (AhR) shares structural homology to clock genes, containing both PAS domains and basic helix-loop helix structural motifs, allowing for interaction with components of the primary circadian feedback loop. Activation of AhR alters circadian rhythmicity, primarily through inhibition of Clock/Bmal1-mediated regulation of Per1. AhR-deficient mice are protected from diet-induced metabolic dysfunction, exhibiting enhanced insulin sensitivity and glucose tolerance. This study examined whether AhR haploinsufficiency can also protect against diet-induced alterations in rhythm. After feeding AhR+/+ and AhR+/- mice an HFD (60% fat) for 15 weeks, samples were collected every 4 hours over a 24-hour period. HFD altered the rhythm of serum glucose and the metabolic transcriptome, including hepatic nuclear receptors Rev-erbα and PPARγ in wild-type c57bl6/j mice. AhR reduction provided protection against diet-induced transcriptional oscillation changes; serum glucose and metabolic gene rhythms were protected from the disruption caused by HFD feeding. These data highlight the critical role of AhR signaling in the regulation of metabolism and provide a potential therapeutic target for diseases characterized by rhythmic desynchrony.
28101904	Circadian rhythms are endogenous oscillations with a period of about 24 h driven by a circadian clock. So far, variable oscillators have been found in insects. To explore the circadian clock of Tribolium castaneum, we cloned the clock gene timeless (Tctimeless). Its open reading frame is 3240 bp in length and consists of 10 exons. Tctimeless is highly expressed in the late pupal stage. Tissue-specific expression analysis in late adult stages revealed high expression of Tctimeless in the head, epidermis, fat body and accessory glands. Silencing of Tctimeless by RNA interference (RNAi) at the late larval stages caused a failure to initiate eclosion. Tctimeless knockdown in late pupal stages led to a gender-independent decline in egg production and progeny survival. As a core clock gene, Tctimeless exhibited one expression peak in the middle of the circadian day. Knockdown of Tctimeless disrupted daily expression patterns of Tccycle, Tcclock, Tcperiod and itself, while Tctimeless and Tcperiod expression patterns over the circadian day were also perturbed when Tccycle or Tcclock is suppressed by RNAi. This study identified a complex transcriptional relationship among circadian clock genes in T. castaneum.
28100918	Improvement in cardiovascular (CV) morbidity and mortality in the EMPA-REG OUTCOME study provides new insight into the therapeutic use of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. Although SGLT2 inhibitors have several pleiotropic effects, the underlying mechanism responsible for their cardioprotective effects remains undetermined. In this regard, the absence of a nocturnal fall in blood pressure (BP), that is, non-dipping BP, is a common phenomenon in type 2 diabetes and has a crucial role in the pathogenesis of CV morbidity and mortality. In most clinical trials, SGLT2 inhibitors reduce both systolic BP (~3-5 mm Hg) and diastolic BP (~2 mm Hg) in patients with type 2 diabetes. In addition, recent clinical and animal studies have revealed that SGLT2 inhibitors enable the change in BP circadian rhythm from a non-dipper to a dipper type, which is possibly associated with the improvement in CV outcomes in patients with type 2 diabetes. In this review, recent data on the effect of SGLT2 inhibitors on the circadian rhythm of BP will be summarized. The possible underlying mechanisms responsible for the SGLT2 inhibitor-induced improvement in the circadian rhythm of BP will also be discussed.
28100634	Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)-transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone-induced, JAK2 kinase-mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.
28100421	This review highlights a selection of literature in the area of osteoarthritis biology published between the 2015 and 2016 Osteoarthritis Research Society International (OARSI) World Congress. Highlights were selected from a pubmed search covering cartilage, bone, inflammation and pain. A personal selection was made based, amongst other things, on topics presented during the 2015 conference. This covers circadian rhythm, TGF-β signaling, autophagy, SIRT6, exercise, lubricin, TLR's, pain and NGF. Furthermore, in this review we have made an effort to connect these seemingly distant topics into one scheme of connections between them, revealing a theoretical big picture underneath.
28100336	The time phase of epileptic seizures has attracted more and more attention. Epileptic seizures have their own circadian rhythm. The same type of epilepsy has different seizure frequencies in different time periods and states (such as sleeping/awakening state and natural day/night cycle). The circadian rhythm of epileptic seizures has complex molecular and endocrine mechanisms, and currently there are several hypotheses. Clarification of the circadian rhythm of epileptic seizures and prevention and administration according to such circadian rhythm can effectively control seizures and reduce the adverse effects of drugs. The research on the circadian rhythm of epileptic seizures provides a new idea for the treatment of epilepsy.
28100031	The hippocampus is subjected to diurnal/circadian rhythms on both the morphological and molecular levels. Certain aspects of cell proliferation in the adult hippocampus are regulated by melatonin and accompanied by apoptosis to ensure proper tissue maintenance and function. The present study investigated Zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine hippocampus and their regulation by melatonin receptor type1 and type2 (MT1/2)-mediated signaling. Adult melatonin-proficient C3H/HeN mice and melatonin-proficient (C3H/HeN) mice with targeted deletion of MT1/2 were adapted to a 12-h light, 12-h dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 in combination with different markers for the diverse cell types residing in the hippocampus served to identify and quantify proliferating and apoptotic cells in the hippocampal subregions. ZT-dependent changes in cell proliferation and apoptosis were found exclusively in the subgranular zone (SGZ) and granule cell layer (GCL) of melatonin-proficient mice with functional MT1/2. Cell proliferation in the SGZ showed ZT-dependent changes indicated by an increase of proliferating immature neurons during the dark phase of the 24-h light-dark cycle. Apoptosis showed ZT-dependent changes in the SGZ and GCL indicated by an increase of apoptotic immature neurons at ZT06 (SGZ) and a decrease of immature and mature neurons at ZT18 (GCL). Our results indicate that ZT-dependent changes in proliferation of immature neurons in the SGZ are counterbalanced by ZT-dependent changes in apoptosis of immature and mature neurons in the SGZ and GCL exclusively in mice with functional MT1/2. Therefore, MT1/2-mediated signaling appears to be crucial for generation and timing of ZT-dependent changes in cell proliferation and apoptosis and for differentiation of proliferating cells into neurons in the SGZ. © 2017 Wiley Periodicals, Inc.
28099865	A fugue is characterized by the systematic repetition of a principal theme in simultaneous melodic lines. In this issue of Immunity, Druzd et al. (2017) show that a similar phenomenon occurs in lymph nodes (LNs), in which lymphocyte entry and exit is governed by repetitive circadian rhythms.
28099762	Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.
28099496	Daily activities within an ant colony need precise temporal organization, and an endogenous clock appears to be essential for such timing processes. A clock drives locomotor rhythms in isolated workers in a number of ant species, but its involvement in activities displayed in the social context is unknown. We compared locomotor rhythms in isolated individuals and behavioral rhythms in the social context of workers of the ant Camponotus rufipes. Both forager and nurse workers exhibited circadian rhythms in locomotor activity under constant conditions, indicating the involvement of an endogenous clock. Activity was mostly nocturnal and synchronized with the 12:12h light-dark-cycle. To evaluate whether rhythmicity was maintained in the social context and could be synchronized with non-photic zeitgebers such as feeding times, daily behavioral activities of single workers inside and outside the nest were quantified continuously over 24 hours in 1656 hours of video recordings. Food availability was limited to a short time window either at day or at night, thus mimicking natural conditions of temporally restricted food access. Most foragers showed circadian foraging behavior synchronized with food availability, either at day or nighttime. When isolated thereafter in single locomotor activity monitors, foragers mainly displayed arrhythmicity. Here, high mortality suggested potential stressful effects of the former restriction of food availability. In contrast, nurse workers showed high overall activity levels in the social context and performed their tasks all around the clock with no circadian pattern, likely to meet the needs of the brood. In isolation, the same individuals exhibited in turn strong rhythmic activity and nocturnality. Thus, endogenous activity rhythms were inhibited in the social context, and timing of daily behaviors was flexibly adapted to cope with task demands. As a similar socially-mediated plasticity in circadian rhythms was already shown in honey bees, the temporal organization in C. rufipes and honey bees appear to share similar basic features.
28099477	Offspring of murine dams chronically fed a protein-restricted diet have an increased risk for metabolic and neurobehavioral disorders. Previously we showed that adult offspring, developmentally exposed to a chronic maternal low-protein (MLP) diet, had lower body and hind-leg muscle weights and decreased liver enzyme serum levels. We conducted energy expenditure, neurobehavioral and circadian rhythm assays in male offspring to examine mechanisms for the body-weight phenotype and assess neurodevelopmental implications of MLP exposure. C57BL/6J dams were fed a protein restricted (8%protein, MLP) or a control protein (20% protein, C) diet from four weeks before mating until weaning of offspring. Male offspring were weaned to standard rodent diet (20% protein) and single-housed until 8-12 weeks of age. We examined body composition, food intake, energy expenditure, spontaneous rearing activity and sleep patterns and performed behavioral assays for anxiety (open field activity, elevated plus maze [EPM], light/dark exploration), depression (tail suspension and forced swim test), sociability (three-chamber), repetitive (marble burying), learning and memory (fear conditioning), and circadian behavior (wheel-running activity during light-dark and constant dark cycles). We also measured circadian gene expression in hypothalamus and liver at different Zeitgeber times (ZT). Male offspring from separate MLP exposed dams had significantly greater body fat (P = 0.03), less energy expenditure (P = 0.004), less rearing activity (P = 0.04) and a greater number of night-time rest/sleep bouts (P = 0.03) compared to control. MLP offspring displayed greater anxiety-like behavior in the EPM (P<0.01) but had no learning and memory deficit in fear-conditioning assay (P = 0.02). There was an effect of time on Per1, Per 2 and Clock circadian gene expression in the hypothalamus but not on circadian behavior. Thus, transplacental and early developmental exposure of dams to chronic MLP reduces food intake and energy expenditure, increases anxiety like behavior and disturbs sleep patterns but not circadian rhythm in adult male offspring.
28098350	There is increasing evidence that the circadian clock is a significant driver of photosynthesis that becomes apparent when environmental cues are experimentally held constant. We studied whether the composition of photosynthetic pigments is under circadian regulation, and whether pigment oscillations lead to rhythmic changes in photochemical efficiency. To address these questions, we maintained canopies of bean and cotton, after an entrainment phase, under constant (light or darkness) conditions for 30-48 h. Photosynthesis and quantum yield peaked at subjective noon, and non-photochemical quenching peaked at night. These oscillations were not associated with parallel changes in carbohydrate content or xanthophyll cycle activity. We observed robust oscillations of Chl a/b during constant light in both species, and also under constant darkness in bean, peaking when it would have been night during the entrainment (subjective nights). These oscillations could be attributed to the synthesis and/or degradation of trimeric light-harvesting complex II (reflected by the rhythmic changes in Chl a/b), with the antenna size minimal at night and maximal around subjective noon. Considering together the oscillations of pigments and photochemistry, the observed pattern of changes is counterintuitive if we assume that the plant strategy is to avoid photodamage, but consistent with a strategy where non-stressed plants maximize photosynthesis.
28097908	Elucidating the biological mechanisms involved in attention-deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age.We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted.	From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected P = 0.016; OR = 2.27 95%CI: 1.15-4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected P = 0.007; OR = 3.30 95%CI: 1.33-8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin.	Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD.	
28096235	Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged obese CT-1-deficient (CT-1-/-) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young lean CT-1-/- mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1-/- mice. However, the pattern was altered in CT-1-/- mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.
28095943	Sleep disturbances are a common issue for those who provide informal care to someone with a life-limiting condition. The negative consequences of poor sleep are well documented. The purpose of the present study was to determine the sleep patterns of caregivers of patients with advanced cancer.An extensive systematic review of studies reporting empirical sleep data was undertaken in 2015 in accordance with the PRISMA Statement. A total of eight electronic databases were searched, with no date restrictions imposed. Additionally, a search of the bibliographies of the studies identified during the electronic search was conducted. Search terms included: "sleep," "insomnia," "sleep disturbance," "circadian rhythm," "caregiver," "carer," "advanced cancer," "palliative cancer," and MESH suggestions. The inclusion criteria required studies to be in English and to report primary qualitative and/or quantitative research that examined sleep in caregivers of patients with advanced cancer. Unpublished studies, conference papers, and dissertations were excluded.	Overall, 10 studies met the inclusion criteria and were included in the review. Two major findings emerged from the data synthesis. First, at least 72% of caregivers reported moderate to severe sleep disturbance as measured by the Pittsburgh Sleep Quality Index. Second, objective measurement of caregivers' sleep identified that some caregivers experienced up to a 44% reduction in their total sleep time compared to the recommended eight hours.	Reduction in total sleep time appears to be the biggest issue facing caregivers' sleep. Future studies need to explore the specific factors that cause these sleep disturbances and thus help to identify interventions to optimize sleep.	
28095742	We examine whether the lithium response is associated with changes in the expression of core clock genes.The effect of a therapeutic concentration of lithium (1 mM) on the expression levels of 17 circadian genes was examined in lymphoblastoid cell lines (LCLs) derived from two well-characterized groups of bipolar disorder patients, defined as lithium non-responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real-time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure.	At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3β was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group × Lithium interactions existed for NR1D1 at d2 (P = 0.02), and CRY1 at d4 (P = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time × Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time × Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium.	In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient's lithium response status.	
28092973	Ambulatory systolic-diastolic pressure regression index (ASDPRI) as a composite marker of cardiovascular (CV) properties is related to CV complications. However, genetic determinants of ASDPRI are not known. The aim of this study is to report the relationship between certain single nucleotide polymorphisms (SNP) and ASDPRI in hypertensive patients with CAD confirmed by coronary angiography.A total of 1345 hypertensive subjects with CAD were included. SNPs were selected from genome-wide association studies. SNPs were reported to be associated with coronary artery disease risk. There were significant differences in 24 h and daytime and nighttime ASDPRIs for PHCTR1, LPA and ADAMTS7 polymorphisms. Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for ASDPRI.	Analysis of covariance revealed a significant relationship between the PPAB2B (β - 0.85; 95 CI -1.85--0.16, p < 0.02), WDR12 (β - 1.31; 95 CI -2.19--0.43, p < 0.01) polymorphisms and nighttime ASDPRI dipping. Analysis of covariance revealed a significant relationship between GRS 18 and 24-h ASDPRI (β 0.34; 95 CI 0.16-0.31, p < 0.01).	In conclusion, ADAMTS7 and LPA polymorphisms are related to 24-h ASDPRI but PPAB2B and WDR12 gene polymorphisms are associated with nighttime ASDPRI dipping. A total of 24-h ASDPRI is determined by GRS18.	
28092624	The monitoring of rumen content temperature can be useful for the evaluation of cow health condition and heat. The aim of this research was to evaluate the influence of the circadian rhythm (time of day) and season on reticulorumen acidity (pH) and temperatures (RT) in lactating dairy cows. The research was performed on ten 2nd - lactation, clinically healthy Lithuanian Black and White fresh dairy cows (up to 1 day after calving). The cows were milked twice daily at 05:00 and 17:00. The cows were kept in a loose housing system, and were fed a feed ration throughout the year at the same time, balanced according to their physiological needs. Cow feeding took place every day at 06:00 and 18:00. The pH and temperature of the contents of cow reticulorumens were measured using specific smaXtec boluses manufactured for animal care. The temperature starts rising 6 hours after the evening feeding and milking, whereas 1 hour after the morning milking, it starts decreasing. The lowest temperature observed in the springtime was 38.81±0.001, and the highest was in autumn 39.17±0.001. The pH starts decreasing 3 hours after the morning feed, whereas 4 hours after the evening feed, it starts increasing. The lowest pH was observed in the summertime - 5.99±0.001, and the highest was in autumn and springtime - 6.18±0.001. In conclusion the reticulorumen temperature in lactating cows was found to be influenced by the circadian rhythm and season. The acidity of the reticulorumen content changes similar to the temperature. The pH of the reticulorumen contents was also found to be influenced by the circadian rhythm and season.
28090714	Stem Leydig cell (SLC) transplantation could provide a new strategy for treating the testosterone deficiency. Our previous study demonstrated that CD51 (also called integrin αv) might be a putative cell surface marker for SLCs, but the physiological function and efficacy of CD51+ SLCs treatment remain unclear. Here, we explore the potential therapeutic benefits of CD51+ SLCs transplantation and whether these transplanted cells can be regulated by the hypothalamic-pituitary-gonadal (HPG) axis. CD51+ cells were isolated from the testes of 12-weeks-old C57BL/6 mice, and we showed that such cells expressed SLC markers and that they were capable of self-renewal, extensive proliferation, and differentiation into multiple mesenchymal cell lineages and LCs in vitro. As a specific cytotoxin that eliminates Leydig cells (LCs) in adult rats, ethane dimethanesulfonate (EDS) was used to ablate LCs before the SLC transplantation. After being transplanted into the testes of EDS-treated rats, the CD51+ cells differentiated into mature LCs, and the recipient rats showed a partial recovery of testosterone production and spermatogenesis. Notably, a testosterone analysis revealed a circadian rhythm of testosterone secretion in cell-transplanted rats, and these testosterone secretions could be suppressed by decapeptyl (a luteinizing hormone-releasing hormone agonist), suggesting that the transplanted cells might be regulated by the HPG axis. This study is the first to demonstrate that CD51+ SLCs can restore the neuroendocrine regulation of testicular function by physiologically recovering the expected episodic changes in diurnal testosterone serum levels and that SLC transplantation may provide a new tool for the studies of testosterone deficiency treatment. Stem Cells 2017;35:1222-1232.
28090585	In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression.

28089618	The reference method to study protein and arginine metabolism in critically ill children is measuring plasma amino acid appearances with stable isotopes during a short (4-8 h) time period and extrapolate results to 24-h. However, 24-h measurements may be variable due to critical illness related factors and a circadian rhythm could be present. Since only short duration stable isotope studies in critically ill children have been conducted before, the aim of this study was to investigate 24-h appearance of specific amino acids representing protein and arginine metabolism, with stable isotope techniques in continuously fed critically ill children.In eight critically ill children, admitted to the pediatric (n = 4) or cardiovascular (n = 4) intensive care unit, aged 0-10 years, receiving continuous (par)enteral nutrition with protein intake 1.0-3.7 g/kg/day, a 24-h stable isotope tracer protocol was carried out. L-[ring-2H5]-phenylalanine, L-[3,3-2H2]-tyrosine, L-[5,5,5-2H3]-leucine, L-[guanido-15N2]-arginine and L-[5-13C-3,3,4,4-2H4]-citrulline were infused intravenously and L-[15N]-phenylalanine and L-[1-13C]leucine enterally. Arterial blood was sampled every hour.	Coefficients of variation, representing intra-individual variability, of the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline were high, on average 14-19% for intravenous tracers and 23-26% for enteral tracers. No evident circadian rhythm was present. The pattern and overall 24-h level of whole body protein balance differed per individual.	In continuously fed stable critically ill children, the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline show high variability. This should be kept in mind when performing stable isotope studies in this population. There was no apparent circadian rhythm.	
28088873	Nocturnal human sleep is composed of cycles between rapid eye movement (REM) sleep and non-REM (NREM) sleep. In adults, the structure of ultradian cycles between NREM and REM sleep is well characterized; however, less is known about the developmental trajectories of ultradian sleep cycles across early childhood. Cross-sectional studies indicate that the rapid ultradian cycling of active-quiet sleep in infancy shifts to a more adult-like pattern of NREM-REM sleep cycling by the school-age years, yet longitudinal studies elucidating the details of this transition are scarce. To address this gap, we examined ultradian cycling during nocturnal sleep following 13 h of prior wakefulness in 8 healthy children at 3 longitudinal points: 2Y (2.5-3.0 years of age), 3Y (3.5-4.0 years of age), and 5Y (5.5-6.0 years of age). We found that the length of ultradian cycles increased with age as a result of increased NREM sleep episode duration. In addition, we observed a significant decrease in the number of NREM sleep episodes as well as a nonsignificant trend for a decrease in the number of cycles with increasing age. Together, these findings suggest a concurrent change in which cycle duration increases and the number of cycles decreases across development. We also found that, consistent with data from adolescents and adults, the duration of NREM sleep episodes decreased with time since lights-off whereas the duration of REM sleep episodes increased over this time period. These results indicate the presence of circadian modulation of nocturnal sleep in preschool children. In addition to characterizing changes in ultradian cycling in healthy children ages 2 to 5 years, this work describes a developmental model that may provide insights into the emergence of normal adult REM sleep regulatory circuitry as well as potential trajectories of dysregulated ultradian cycles such as those associated with affective disorders.
28088510	To investigate the effect of nocturnal blood pressure (BP) dips on the occurrence of optic disc hemorrhage (ODH) in normal-tension glaucoma (NTG) patients and determine whether ODH is associated with greater likelihood of visual field progression (VFP).Prospective case-control study.	This study enrolled 698 eyes of 349 consecutive NTG patients who were ≥40 years old, underwent 24-hour intraocular pressure and ambulatory BP monitoring in the habitual position, were examined for ODH every 4-6 months with optic disc photography, and had ≥5 reliable visual field tests with minimum follow-up of 3 years. NTG patients were classified into 2 groups: "nonphysiologic" dippers, including nondippers and overdippers, and "physiologic" dippers. Odds ratios for the association between the "nonphysiologic" group and ODH were calculated using logistic regression models. Kaplan-Meier analyses were performed to compare outcomes with reference to the presence of ODH for VFP.	Overall, ODH and VFP were detected in 107 (15.3%) eyes and 60 (8.6%) eyes among total 698 eyes, respectively. Overdippers showed a significantly greater frequency of ODH than nondippers or dippers. Being an overdipper was a significant and an independent risk factor for ODH occurrence during follow-up. The rates of VFP were 6%, 7%, and 24% for dippers, nondippers, and overdippers, respectively. Eyes with ODH were associated with greater likelihoods of subsequent VFP than those without. VFP occurred only in eyes with ODH.	Being an overdipper is a significant risk factor for ODH in NTG eyes. The detection of ODH during follow-up is a potent predictor of future VFP.	
28087238	Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.
28086750	In the history of population genetics balancing selection has been considered as an important evolutionary force, yet until today little is known about its abundance and its effect on patterns of genetic diversity. Several well-known examples of balancing selection have been reported from humans, mice, plants, and parasites. However, only very few systematic studies have been carried out to detect genes under balancing selection. We performed a genome scan in Drosophila melanogaster to find signatures of balancing selection in a derived (European) and an ancestral (African) population. We screened a total of 34 genomes searching for regions of high genetic diversity and an excess of SNPs with intermediate frequency.In total, we found 183 candidate genes: 141 in the European population and 45 in the African one, with only three genes shared between both populations. Most differences between both populations were observed on the X chromosome, though this might be partly due to false positives. Functionally, we find an overrepresentation of genes involved in neuronal development and circadian rhythm. Furthermore, some of the top genes we identified are involved in innate immunity.	Our results revealed evidence of genes under balancing selection in European and African populations. More candidate genes have been found in the European population. They are involved in several different functions.	
28083535	Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non-pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice.
28078538	Sleep, as one of the most important requirements of our brain, has a mystical nature. Despite long-standing studies, the molecular mechanisms and physiological properties of sleep have not been defined well as the complexity of the mammals' brain make it difficult to investigate the mechanisms and properties of sleep. Although some features of sleep have changed during evolution, its existence in such a simple animal, Caenorhabditis elegans, not only signifies the importance of sleep in even simple animals, but also allows the scientist to assess the core mechanism and biological events in an uncomplicated organism. This article reviews the information which exists about the characteristics of sleep in C. elegans, its circadian rhythm, the neurons and neurotransmitters responsible for each state, and the signaling molecules involved. Although much still remains to be resolved about the sleep of C. elegans, the available knowledge helps the scientists to recognize the properties better of this mysterious function of the brain.
28077681	Diurnal changes in gut microbiota localization and function alter host physiology through circadian epigenetic and transcriptional changes.
28076831	This study investigates whether the toxicity in kidneys as well as oxidative stress varied according to the dosing time of an immunosuppressive agent "mycophenolate mofetil (MMF)" in Wistar Rat. 300mg/kg of MMF was injected by intraperitonal at four different circadian stages (1, 7, 13 and 19h after light onset, HALO). Rats were sacrificed after 3days, and the kidneys were removed for determination of oxidative stress and histological analysis. Biochemical variable (creatinine, urea) was performed. Statistical analysis showed that MMF administration at 7 HALO produced a renal toxicity assessed by the significant increase in both blood creatinine and urea and antioxidant activity assessed by malondialdehyde and protein carbonyl levels indicating an induction of lipid peroxidation in oxidative damage. Whereas, at this time MMF induced a decrease the enzyme activities of renal catalase and superoxide dismutase, with a renal histopathology alterations (glomerular atrophy and lesions within proximal tubules). However, when MMF was injected in the middle of the dark-activity phase it produced a very mild renal toxicity and low oxidative stress. The obtained data indicate that the maximum of renal toxicity is observed when MMF was injected in the middle of the light- rest span in rats.
28076761	In a recent issue of Cancer Cell, Kettner and colleagues (2016) link disruption of normal circadian rhythms to NASH and associated liver cancer, suggesting that molecular clocks, as well as their regulators and target genes, might provide novel therapeutic targets in these diseases.
28076760	Circadian clocks regulate most aspects of physiology and metabolism. Genome-wide approaches have uncovered widespread circadian rhythms in the transcriptome, cistrome, and epigenome of mice, and now two proteomics studies in this issue (Robles et al., 2016; Wang et al., 2016) reveal extensive circadian regulation of the nuclear and phosphoproteome.
28076642	Disorders of circadian rhythms have been reported in studies of both depressed children and of depressed adolescents. The aim of this study was to evaluate whether there is a relationship between the 24-hour spectral power (24h SP) of the activity/rest rhythm and the clinical course of depression in adolescents.Six 14 to 17-year-old adolescents were recruited for the study. They were all suffering from major depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, as identified by the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Depressive symptoms were assessed using the Children's Depression Rating Scale - Revised (CDRS-R) and clinical evaluations. Locomotor activity was monitored over a period of 13 consecutive weeks. Activity was measured for 10-minute periods using wrist-worn activity monitors. All patients were prescribed sertraline from after the first week up until the end of the study.	We found a relationship between high CDRS values and low 24-hour spectral power.	The 24h SP of the activity/rest rhythm correlated significantly (negatively) with the clinical ratings of depression.	
28076377	From photosynthetic bacteria to mammals, the circadian clock evolved to track diurnal rhythms and enable organisms to anticipate daily recurring changes such as temperature and light. It orchestrates a broad spectrum of physiology such as the sleep/wake and eating/fasting cycles. While we have made tremendous advances in our understanding of the molecular details of the circadian clock mechanism and how it is synchronized with the environment, we still have rudimentary knowledge regarding its connection to help regulate diurnal physiology. One potential reason is the sheer size of the output network. Diurnal/circadian transcriptomic studies are reporting that around 10% of the expressed genome is rhythmically controlled. Zebrafish is an important model system for the study of the core circadian mechanism in vertebrate. As Zebrafish share more than 70% of its genes with human, it could also be an additional model in addition to rodent for exploring the diurnal/circadian output with potential for translational relevance. Here we performed comparative diurnal/circadian transcriptome analysis with established mouse liver and other tissue datasets. First, by combining liver tissue sampling in a 48h time series, transcription profiling using oligonucleotide arrays and bioinformatics analysis, we profiled rhythmic transcripts and identified 2609 rhythmic genes. The comparative analysis revealed interesting features of the output network regarding number of rhythmic genes, proportion of tissue specific genes and the extent of transcription factor family expression. Undoubtedly, the Zebrafish model system will help identify new vertebrate outputs and their regulators and provides leads for further characterization of the diurnal cis-regulatory network.
28074036	Cyanobacteria evolved a robust circadian clock, which has a profound influence on fitness and metabolism under daily light-dark (LD) cycles. In the model cyanobacterium Synechococcus elongatus PCC 7942, a functional clock is not required for diurnal growth, but mutants defective for the response regulator that mediates transcriptional rhythms in the wild-type, regulator of phycobilisome association A (RpaA), cannot be cultured under LD conditions. We found that rpaA-null mutants are inviable after several hours in the dark and compared the metabolomes of wild-type and rpaA-null strains to identify the source of lethality. Here, we show that the wild-type metabolome is very stable throughout the night, and this stability is lost in the absence of RpaA. Additionally, an rpaA mutant accumulates excessive reactive oxygen species (ROS) during the day and is unable to clear it during the night. The rpaA-null metabolome indicates that these cells are reductant-starved in the dark, likely because enzymes of the primary nighttime NADPH-producing pathway are direct targets of RpaA. Because NADPH is required for processes that detoxify ROS, conditional LD lethality likely results from inability of the mutant to activate reductant-requiring pathways that detoxify ROS when photosynthesis is not active. We identified second-site mutations and growth conditions that suppress LD lethality in the mutant background that support these conclusions. These results provide a mechanistic explanation as to why rpaA-null mutants die in the dark, further connect the clock to metabolism under diurnal growth, and indicate that RpaA likely has important unidentified functions during the day.
28073541	Dinoflagellates are unicellular eukaryotes capable of forming spectacular harmful algal blooms (HABs). Eutrophication of coastal waters by fertilizer runoff, nitrate in particular, has contributed to recent increases in the frequency, magnitude and geographic extent of HABs. Although physiological nitrate uptake and assimilation in dinoflagellates have often been measured in the field and in the laboratory, no molecular components involved in nitrate transport have yet been reported. This study reports the first identification and characterization of dinoflagellate nitrate transporters, found in the transcriptome of the bloom-forming Lingulodinium polyedrum. Of the 23 putative transporters found by BLAST searches, only members of the nitrate transporter 2 (NRT2) family contained all key amino acids known to be essential for nitrate transport. The dinoflagellate NRT2 sequences have 12 predicted transmembrane domains, as do the NRT2 sequences of bacteria, plants and fungi. The NRT2 sequences in Lingulodinium appear to have two different evolutionary origins, as determined by phylogenetic analyses. The most expressed transcript of all putative nitrate transporters was determined by RNA-Seq to be LpNRT2.1. An antibody raised against this transporter showed that the same amount of protein was found at different times over the light dark cycle and with different sources of N. Finally, global nitrate uptake was assessed using a 15N tracer, which showed that the process was not under circadian-control as previously suggested, but simply light-regulated.
28072877	Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study, an APPswePS1dE9 AD mouse model has been analyzed for motor cortex theta, beta and gamma frequency alterations using computerized 3D stereotaxic electrode positioning and implantable video-EEG radiotelemetry to perform long-term M1 recordings from both genders considering age, circadian rhythm and activity status of experimental animals. We previously demonstrated that APPswePS1dE9 mice exibit complex alterations in hippocampal frequency power and another recent investigation reported a global increase of alpha, beta and gamma power in APPswePS1dE9 in females of 16-17 weeks of age. In this cortical study in APPswePS1dE9 mice we did not observe any changes in theta, beta and particularly gamma power in both genders at the age of 14, 15, 18 and 19 weeks. Importantly, no activity dependence of theta, beta and gamma activity could be detected. These findings clearly point to the fact that EEG activity, particularly gamma power exhibits developmental changes and spatial distinctiveness in the APPswePS1dE9 mouse model of Alzheimer's disease.
28072817	Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila.
28072592	Interest in the metabolic syndrome-associated osteoarthritis phenotype is increasing. Here, we summarize recently published significant findings.Meta-analyses confirmed an association between type 2 diabetes and osteoarthritis and between cardiovascular diseases and osteoarthritis. Recent advances in the study of metabolic syndrome-associated osteoarthritis have focused on a better understanding of the role of metabolic diseases in inducing or aggravating joint damage. In-vivo models of obesity, diabetes, or dyslipidemia have helped to better decipher this association. They give emerging evidence that, beyond the role of common pathogenic mechanisms for metabolic diseases and osteoarthritis (i.e., low-grade inflammation and oxidative stress), metabolic diseases have a direct systemic effect on joints. In addition to the impact of weight, obesity-associated inflammation is associated with osteoarthritis severity and may modulate osteoarthritis progression in mouse models. As well, osteoarthritis synovium from type 2 diabetic patients shows insulin-resistant features, which may participate in joint catabolism. Finally, exciting data are emerging on the association of gut microbiota and circadian rhythm and metabolic syndrome-associated osteoarthritis.	The systemic role of metabolic syndrome in osteoarthritis pathophysiology is now better understood, but new avenues of research are being pursued to better decipher the metabolic syndrome-associated osteoarthritis phenotype.	
28071753	Hamsters are an ideal animal model for a variety of biomedical research areas such as cancer, virology, circadian rhythms, and behavioural neuroscience. The use of hamsters has declined, however, most likely due to the dearth of genetic tools available for these animals. Our laboratory uses hamsters to study acute social stress, and we are beginning to investigate the genetic mechanisms subserving defeat-induced behavioural change. We have been limited, however, by the lack of genetic resources available for hamsters. In this study, we sequenced the brain transcriptome of male and female Syrian hamsters to generate the necessary resources to continue our research. We completed a de novo assembly and after assembly optimization, there were 113,329 transcripts representing 14,530 unique genes. This study is the first to characterize transcript expression in both female and male hamster brains and offers invaluable information to promote understanding of a host of important biomedical research questions for which hamsters are an excellent model.
28070566	Multiple interactions between the immune system and sleep are known, including the effects of microbial challenge on sleep or the effects of sleep loss on facets of the immune response. Cytokines regulate, in part, sleep and immune responses. Here we examine the role of an anti-inflammatory cytokine, interleukin-37 (IL-37) on sleep in a mouse strain that expresses human IL-37b (IL37tg mice). Constitutive expression of the IL-37 gene in the brains of these mice under resting conditions is low; however, upon an inflammatory stimulus, expression increases dramatically. We measured sleep in three conditions; a) under baseline conditions and after 6 h of sleep loss, b) after bolus intraperitoneal administration of lipopolysaccharide (LPS) or IL-1β and c) after intranasal influenza virus challenge. Under baseline conditions, the IL37tg mice had 7% more spontaneous non-rapid eye movement sleep (NREMS) during the light period than wild-type (WT) mice. After sleep deprivation both WT mice and IL37tg mice slept an extra 21% and 12%, respectively, during the first 6 h of recovery. NREMS responses after sleep deprivation did not significantly differ between WT mice and IL37tg mice. However, in response to either IL-1β or LPS, the increases in time spent in NREMS were about four-fold greater in the WT mice than in the IL37tg mice. In contrast, in response to a low dose of mouse-adapted H1N1 influenza virus, sleep responses developed slowly over the 6 day recording period. By day 6, NREMS increased by 10% and REMS increased by 18% in the IL37tg mice compared to the WT mice. Further, by day 4 IL37tg mice lost less weight, remained more active, and retained their body temperatures closer to baseline values than WT mice. We conclude that conditions that promote IL-37 expression attenuate morbidity to severe inflammatory challenge.
28068899	The study of epigenetic processes and mechanisms present a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children at-risk for obesity despite the relevance of this developmental stage to trajectories of weight gain. We hypothesized that salivary DNA methylation patterns of key obesogenic genes in Hispanic children would 1) correlate with maternal BMI and 2) allow for identification of pathways associated with children at-risk for obesity.Genome-wide DNA methylation was conducted on 92 saliva samples collected from Hispanic preschool children using the Infinium Illumina HumanMethylation 450 K BeadChip (Illumina, San Diego, CA, USA), which interrogates >484,000 CpG sites associated with ~24,000 genes. The analysis was limited to 936 genes that have been associated with obesity in a prior GWAS Study. Child DNA methylation at 17 CpG sites was found to be significantly associated with maternal BMI, with increased methylation at 12 CpG sites and decreased methylation at 5 CpG sites. Pathway analysis revealed methylation at these sites related to homocysteine and methionine degradation as well as cysteine biosynthesis and circadian rhythm. Furthermore, eight of the 17 CpG sites reside in genes (FSTL1, SORCS2, NRF1, DLC1, PPARGC1B, CHN2, NXPH1) that have prior known associations with obesity, diabetes, and the insulin pathway.	Our study confirms that saliva is a practical human tissue to obtain in community settings and in pediatric populations. These salivary findings indicate potential epigenetic differences in Hispanic preschool children at risk for pediatric obesity. Identifying early biomarkers and understanding pathways that are epigenetically regulated during this critical stage of child development may present an opportunity for prevention or early intervention for addressing childhood obesity.	
28068807	Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or present in excess. It is lipophilic and is transported bound to cortisol-binding globulin (CBG) and albumin; a small fraction (∼10%) of total serum cortisol is unbound and biologically active. Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. Automated immunoassays are used to measure cortisol but lack specificity and show significant inter-assay differences. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity; however, cortisol cut-offs used in the short Synacthen and Dexamethasone suppression tests are yet to be validated for these assays. Urine free cortisol is used to screen for Cushing's syndrome. Unbound cortisol is excreted unchanged in the urine and 24-h urine free cortisol correlates well with mean serum-free cortisol in conditions of cortisol excess. Urine free cortisol is measured predominantly by immunoassay or LC-MS/MS. Salivary cortisol also reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum. LC-MS/MS is the method of choice for measuring salivary cortisol; however, its use is limited by the lack of a single, validated reference range and poorly standardized assays. This review examines the methods available for measuring cortisol in serum, urine and saliva, explores cortisol in disease and considers the difficulties of measuring cortisol in acutely unwell patients and in neonates.
28066327	Circadian clocks orchestrate the daily changes in physiology and behavior of light-sensitive organisms. These clocks measure about 24 h and tick in a self-sustained and cell-autonomous manner. Mounting evidence points toward a tight intertwining between circadian clocks and metabolism. Although various aspects of circadian control of metabolic functions have been extensively studied, our knowledge regarding circadian mitochondrial function is rudimentary. In this review, we will survey the current literature related to the circadian nature of mitochondrial biology: from mitochondrial omics studies (e.g., proteome, acetylome, and lipidome), through dissection of mitochondrial morphology, to analyses of mitochondrial processes such as nutrient utilization and respiration. We will describe potential mechanisms that are implicated in circadian regulation of mitochondrial functions in mammals and discuss the possibility of a mitochondrial-autonomous oscillator.
28066175	Although, glial cells have well characterized functions in the developing and mature brain, it is only in the past decade that roles for these cells in behavior and plasticity have been delineated. Glial astrocytes and glia-neuron signaling, for example, are now known to have important modulatory functions in sleep, circadian behavior, memory and plasticity. To better understand mechanisms of glia-neuron signaling in the context of behavior, we have conducted cell-specific, genome-wide expression profiling of adult Drosophila astrocyte-like brain cells and performed RNA interference (RNAi)-based genetic screens to identify glial factors that regulate behavior. Importantly, our studies demonstrate that adult fly astrocyte-like cells and mouse astrocytes have similar molecular signatures; in contrast, fly astrocytes and surface glia-different classes of glial cells-have distinct expression profiles. Glial-specific expression of 653 RNAi constructs targeting 318 genes identified multiple factors associated with altered locomotor activity, circadian rhythmicity and/or responses to mechanical stress (bang sensitivity). Of interest, 1 of the relevant genes encodes a vesicle recycling factor, 4 encode secreted proteins and 3 encode membrane transporters. These results strongly support the idea that glia-neuron communication is vital for adult behavior.
28065371	To measure the real T1 relaxation time of the lumbar intervertebral discs in a young and healthy population, using different inversion recovery times, and assess diurnal variation.Intervertebral discs from D12 to S1 of 50 healthy volunteers from 18 to 25 years old were evaluated twice the same day, in the morning and in the late afternoon. Dedicated MRI sequences with different inversion recovery times (from 100 to 2500ms) were used to calculate the real T1 relaxation time. Three regions of interest (ROIs) were defined in each disc, the middle representing the nucleus pulposus (NP) and the outer parts the annulus fibrosus (AF) anterior and posterior. Diurnal variation and differences between each disc level were analyzed.	T1 mean values in the NP were 1142±12ms in the morning and 1085±13ms in the afternoon, showing a highly significant decrease of 57ms (p<0.001). A highly significant difference between the levels of the spine was found. The mean T1 of the anterior part of the AF was 577±9ms in the morning and 554±8ms in the afternoon. For the posterior part, the mean values were 633±8ms in the morning and 581±7ms in the evening. It shows a highly significant decrease of 23ms for the anterior part and 51ms for the posterior part (all p<0.001).	T1 mapping is a promising method of intervertebral disc evaluation. Significant diurnal variation and difference between levels of the lumbar spine were demonstrated. A potential use for longitudinal study in post-operative follow up or sport medicine needs to be evaluated.	
28064405	Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on.
28063234	Cross-cultural sleep research is critical to deciphering whether modern sleep expression is the product of recent selective pressures, or an example of evolutionary mismatch to ancestral sleep ecology. We worked with the Hadza, an equatorial, hunter-gatherer community in Tanzania, to better understand ancestral sleep patterns and to test hypotheses related to sleep segmentation.We used actigraphy to analyze sleep-wake patterns in thirty-three volunteers for a total of 393 days. Linear mixed effects modeling was performed to assess ecological predictors of sleep duration and quality. Additionally, functional linear modeling (FLM) was used to characterize 24-hr time averaged circadian patterns.	Compared with post-industrialized western populations, the Hadza were characterized by shorter (6.25 hr), poorer quality sleep (sleep efficiency = 68.9%), yet had stronger circadian rhythms. Sleep duration time was negatively influenced by greater activity, age, light (lux) exposure, and moon phase, and positively influenced by increased day length and mean nighttime temperature. The average daily nap ratio (i.e., the proportion of days where a nap was present) was 0.54 (SE = 0.05), with an average nap duration of 47.5 min (SE = 2.71; n = 139).	This study showed that circadian rhythms in small-scale foraging populations are more entrained to their ecological environments than Western populations. Additionally, Hadza sleep is characterized as flexible, with a consistent early morning sleep period yet reliance upon opportunistic daytime napping. We propose that plasticity in sleep-wake patterns has been a target of natural selection in human evolution.	
28063156	Metabolic syndrome is often associated with disruption of circadian rhythm of systemic haemodynamics and cardiovascular disease. Experiments were conducted to investigate the effects of luseogliflozin, a selective SGLT2 inhibitor, on circadian rhythm of sympathetic nervous function and locomotor activity (LA) in metabolic syndrome rats. The difference in the low frequency component of systolic blood pressure between the dark and light period significantly increased in the luseogliflozin-treated SHRcp. LA also increased in the dark period compared with the light period following luseogliflozin treatment. These data suggest that circadian rhythm of sympathetic nervous function and LA is improved by luseogliflozin in metabolic syndrome rats, which may contribute to SGLT2 inhibitor-induced improvement of cardiovascular outcomes.
28061531	Previous studies have observed how the time of radiotherapy delivery can impact toxicities and outcomes. The goal of this study was to determine whether treatment time influenced radiotherapy response for bone metastases.Patients who received radiation treatment to painful bone metastases from January 2000 to December 2010 were included in our analysis. Demographic and treatment information including performance status, primary site, treatment dose and fraction, and response were collected prospectively. Treatment times were extracted from patient medical records. Patients were allocated to 8:00 AM-11:00 AM, 11:01 AM-2:00 PM, or 2:01 PM-5:00 PM cohorts based on their treatment times. To compare treatment response between the three cohorts, the Fisher exact test was used. A two-sided P value of <0.05 was considered statistically significant. Analysis was repeated with males and females separately.	A total of 194 patients were included. The median age was 68 years and 55.5% of patients responded to treatment. The dose and fraction of radiation received differed significantly between treatment cohorts using all allocation methods. Females in the 11:01 AM-2:00 PM cohort exhibited a significantly higher response rate (P=0.02) and differing proportions of response types (P=0.03) compared to the 8:00 AM- 11:00 AM and 2:01 PM-5:00 PM cohorts when allocated using all treatment times. No significant differences in response were seen between cohorts when all patients were analysed together or analysed for males only.	Treatment time may affect response in female patients receiving radiotherapy for painful bone metastases. Subsequent chronotherapy studies in radiation should investigate these gender differences.	
28060940	ClockΔ19/Δ19 mice is an experimental model mouse for nocturia (NOC). Using the bladder mucosa obtained from ClockΔ19/Δ19 mice, we investigated the gene expression rhythms of mechanosensory cation channels such as transient receptor potential cation channel subfamily V member 4 (TRPV4) and Piezo1, and main ATP release pathways including vesicular nucleotide transporter (VNUT) and Connexin26(Cx26), in addition to clock genes.Eight- to twelve-week-old male C57BL/6 mice (WT) and age- and sex-matched C57BL/6 ClockΔ19/Δ19 mice, which were bred under 12-h light/dark conditions for 2 weeks, were used. Gene expression rhythms and transcriptional regulation mechanisms in clock genes, mechanosensor, Cx26 and VNUT were measured in the mouse bladder mucosa, collected every 4 hours from WT and ClockΔ19/Δ19 mice using quantitative RT-PCR, a Western blot analysis, and ChIP assays.	WT mice showed circadian rhythms in clock genes as well as mechanosensor, Cx26 and VNUT. Their expression was low during the sleep phase. The results of ChIP assays showed Clock protein binding to the promotor regions and the transcriptional regulation of mechanosensor, Cx26 and VNUT. In contrast, all of these circadian expressions were disrupted in ClockΔ19/Δ19 mice. The gene expression of mechanosensor, Cx26 and VNUT was maintained at a higher level in spite of the sleep phase.	Mechanosensor, Cx26 and VNUT expressed with circadian rhythm in the mouse bladder mucosa. The disruption of circadian rhythms in these genes, induced by the abnormalities in clock genes, may be factors contributing to NOC because of hypersensitivity to bladder wall extension.	
28060565	Circadian clocks regulate rhythmic gene expression levels by means of mRNA oscillations that are mainly driven by post-transcriptional regulation. We identified a new post-transcriptional mechanism, which involves nuclear bodies called paraspeckles. Major components of paraspeckles including the long noncoding RNA Neat1, which is the structural component, and its major protein partners, as well as the number of paraspeckles, follow a circadian pattern in pituitary cells. Paraspeckles are known to retain within the nucleus RNAs containing inverted repeats of Alu sequences. We showed that a reporter gene in which these RNA duplex elements were inserted in the 3'-UTR region displayed a circadian expression. Moreover, circadian endogenous mRNA associated with paraspeckles lost their circadian pattern when paraspeckles were disrupted. This work not only highlights a new paraspeckle-based post-transcriptional mechanism involved in circadian gene expression but also provides the list of all mRNA associated with paraspeckles in the nucleus of pituitary cells.
28060532	Bipolar disorder is characterized by repeated episodes of mania and depression, and can be understood as pathological complex system behaviour involving cognitive, affective and psychomotor disturbance. Accurate prediction of episode transitions in the long-term pattern of mood changes in bipolar disorder could improve the management of the disorder by providing an objective early warning of relapse. In particular, circadian activity changes measured via actigraphy may contain clinically relevant signals of imminent systemic dysregulation. In this study, we propose a mathematical index to investigate the correlation between apparently irregular circadian activity rhythms and critical transitions in episodes of bipolar disorder. Not only does the proposed index illuminate the effects of pharmacological and psychological therapies in control over the state, but it also provides a framework to understand the dynamic (or state-dependent) control strategies. Modelling analyses using our new approach suggest that key clinical goals are minimizing side effects of mood stabilizers as well as increasing the efficiency of other therapeutic strategies.
28060525	A range of evidence suggests that human reward functioning is partly driven by the endogenous circadian system, generating 24-hour rhythms in behavioural measures of reward activation. Reward functioning is multifaceted but literature to date is largely limited to measures of self-reported positive mood states. The aim of this study was to advance the field by testing for hypothesised diurnal variation in previously unexplored components of psychological reward: 'wanting', liking, and learning using subjective and behavioural measures. Risky decision making (automatic Balloon Analogue Risk Task), affective responsivity to positive images (International Affective Pictures System), uncued self-reported discrete emotions, and learning-contingent reward (Iowa Gambling Task) were measured at 10.00 hours, 14.00 hours, and 19.00 hours in a counterbalanced repeated measures design with 50 healthy male participants (aged 18-30). As hypothesised, risky decision making (unconscious 'wanting') and ratings of arousal towards positive images (conscious wanting) exhibited a diurnal waveform with indices highest at 14.00 hours. No diurnal rhythm was observed for liking (pleasure ratings to positive images, discrete uncued positive emotions) or in a learning-contingent reward task. Findings reaffirm that diurnal variation in human reward functioning is most pronounced in the motivational 'wanting' components of reward.
28060253	N6-Methyladenosine (m6A) modifications of RNA are diverse and ubiquitous amongst eukaryotes. They occur in mRNA, rRNA, tRNA, and microRNA. Recent studies have revealed that these reversible RNA modifications affect RNA splicing, translation, degradation, and localization. Multiple physiological processes, like circadian rhythms, stem cell pluripotency, fibrosis, triglyceride metabolism, and obesity are also controlled by m6A modifications. Immunoprecipitation/sequencing, mass spectrometry, and modified northern blotting are some of the methods commonly employed to measure m6A modifications. Herein, we present a northeastern blotting technique for measuring m6A modifications. The current protocol provides good size separation of RNA, better accommodation and standardization for various experimental designs, and clear delineation of m6A modifications in various sources of RNA. While m6A modifications are known to have a crucial impact on human physiology relating to circadian rhythms and obesity, their roles in other (patho)physiological states are unclear. Therefore, investigations on m6A modifications have immense possibility to provide key insights into molecular physiology.
28055288	Circadian preference toward eveningness has been associated with increased risk for mental health problems both in early adolescence and in adulthood. However, in late adolescence, when circadian rhythm naturally shifts to later, its significance for mental health is not clear. Accordingly, we studied how circadian rhythm estimated both by self-reported chronotype and by actigraph-defined midpoint of sleep was associated with self-reported psychiatric problems based on Youth Self Report (YSR). The study builds on a community cohort born in 1998, Helsinki, Finland. At age 17 years (mean age = 16.9, SD = 0.1 years), 183 adolescents (65.6% of the invited) participated in the study. We used the shortened version of the Horne-Östberg morningness-eveningness Questionnaire to define the chronotype, and actigraphs to define the naturally occur circadian rhythm over a 4 to 17 days' period (mean nights N = 8.3, SD = 1.8). The Achenbach software was used to obtain T-score values for YSR psychiatric problem scales. The analyses were adjusted for important covariates including gender, socioeconomic status, body mass index, pubertal maturation, mother's licorice consumption during pregnancy, and actigraph-defined sleep duration and quality. Eveningness was associated with higher scores in rule-breaking behavior and conduct problems (as assessed either by midpoint of sleep or by self-reported chronotype, p-values <0.05), attention deficit/hyperactivity problems (by self-reported chronotype, p-values <0.05), with affective problems (by midpoint of sleep and by self-reported chronotype, p-values <0.05) and somatic complaints (by self-reported chronotype, p-values <0.05), as compared to circadian tendency toward morningness. Our results suggest that the association between eveningness and externalizing problem behavior, present in children and younger adolescents, is also present in late adolescence when circadian rhythms shift toward evening.
28055282	Significant questions remain unanswered regarding the genetic versus environmental contributions to racial/ethnic differences in sleep and circadian rhythms. We addressed this question by investigating the association between diurnal preference, using the morningness-eveningness questionnaire (MEQ), and genetic ancestry within the Baependi Heart Study cohort, a highly admixed Brazilian population based in a rural town. Analysis was performed using measures of ancestry, using the Admixture program, and MEQ from 1,453 individuals. We found an association between the degree of Amerindian (but not European of African) ancestry and morningness, equating to 0.16 units for each additional percent of Amerindian ancestry, after adjustment for age, sex, education, and residential zone. To our knowledge, this is the first published report identifying an association between genetic ancestry and MEQ, and above all, the first one based on ancestral contributions within individuals living in the same community. This previously unknown ancestral dimension of diurnal preference suggests a stratification between racial/ethnic groups in an as yet unknown number of genetic polymorphisms.
28054361	Plants generate rhythmic metabolism during the repetitive day/night cycle. The circadian clock produces internal biological rhythms to synchronize numerous metabolic processes such that they occur at the required time of day. Metabolism conversely influences clock function by controlling circadian period and phase and the expression of core-clock genes. Here, we show that AKIN10, a catalytic subunit of the evolutionarily conserved key energy sensor sucrose non-fermenting 1 (Snf1)-related kinase 1 (SnRK1) complex, plays an important role in the circadian clock. Elevated AKIN10 expression led to delayed peak expression of the circadian clock evening-element GIGANTEA (GI) under diurnal conditions. Moreover, it lengthened clock period specifically under light conditions. Genetic analysis showed that the clock regulator TIME FOR COFFEE (TIC) is required for this effect of AKIN10. Taken together, we propose that AKIN10 conditionally works in a circadian clock input pathway to the circadian oscillator.
28053647	The analysis of circadian leaf movement rhythms is a simple yet effective method to study effects of treatments or gene mutations on the circadian clock of plants. Currently, leaf movements are analysed using time lapse photography and subsequent bioinformatics analyses of leaf movements. Programs that are used for this purpose either are able to perform one function (i.e. leaf tip detection or rhythm analysis) or their function is limited to specific computational environments. We developed a leaf movement analysis tool-PALMA-that works in command line and combines image extraction with rhythm analysis using Fast Fourier transformation and non-linear least squares fitting.We validated PALMA in both simulated time series and in experiments using the known short period mutant sensitivity to red light reduced 1 (srr1-1). We compared PALMA with two established leaf movement analysis tools and found it to perform equally well. Finally, we tested the effect of reduced iron conditions on the leaf movement rhythms of wild type plants. Here, we found that PALMA successfully detected period lengthening under reduced iron conditions.	PALMA correctly estimated the period of both simulated and real-life leaf movement experiments. As a platform-independent console-program that unites both functions needed for the analysis of circadian leaf movements it is a valid alternative to existing leaf movement analysis tools.	
28052921	A molecular circadian oscillator resides in neurons of the cerebral cortex, but its role is unknown. Using the Cre-LoxP method, we have here abolished the core clock gene Arntl in those neurons. This mouse represents the first model carrying a deletion of a circadian clock component specifically in an extrahypothalamic cell type of the brain. Molecular analyses of clock gene expression in the cerebral cortex of the Arntl conditional knockout mouse revealed disrupted circadian expression profiles, whereas clock gene expression in the suprachiasmatic nucleus was still rhythmic, thus showing that Arntl is required for normal function of the cortical circadian oscillator. Daily rhythms in running activity and temperature were not influenced, whereas the resynchronization response to experimental jet-lag exhibited minor though significant differences between genotypes. The tail-suspension test revealed significantly prolonged immobility periods in the knockout mouse indicative of a depressive-like behavioral state. This phenotype was accompanied by reduced norepinephrine levels in the cerebral cortex. Our data show that Arntl is required for normal cortical clock function and further give reason to suspect that the circadian oscillator of the cerebral cortex is involved in regulating both circadian biology and mood-related behavior and biochemistry.
28052040	Retinoid-related orphan receptor α (RORα) is a nuclear receptor, which regulates inflammation and immune responses, lipid metabolism and circadian rhythm. Although RORα suppresses breast tumor invasion, it is unknown whether RORα is dysregulated in gastric cancer leading to cellular survival. Therefore, we hypothesize that RORα is dysfunctional in gastric carcinoma and this causes decreased apoptosis in gastric cancer cells. To test this hypothesis, we employed human gastric cancer tissues with different stages to determine RORα expression, as well as in vitro human gastric cancer cells to determine how RORα is reduced during apoptosis. We found that the expression of RORα was reduced in gastric tissues with cancer, and this correlated with increased TNM stages. The mechanisms underlying RORα reduction is due to the reduced activation of AMP-activated protein kinase (AMPK), as a selective AMPK activator AICAR increased RORα activation and level in human gastric cancer cells. Furthermore, AICAR treatment increased RORα recruitment on the promoters of tumor suppressor genes (i.e., FBXM7, SEMA3F and p21) leading to apoptosis in human gastric cancer cells. Taken together, RORα reduction occurs in gastric cancer leading to the survival of tumor cells, which is attenuated by AMPK. Therefore, both RORα and AMPK are potential targets for the intervention and therapy in gastric carcinoma.
28050554	Gene expression is known to be a stochastic phenomenon. The stochastic gene expression rate is thought to be altered by topological change of chromosome and/or by chromatin modifications such as acetylation and methylation. Changes in mechanical properties of chromosome/chromatin by soluble factors, mechanical stresses from the environment, or metabolites determine cell fate, regulate cellular functions, or maintain cellular homeostasis. Circadian clock, which drives the expression of thousands of genes with 24-hour rhythmicity, has been known to be indispensable for maintaining cellular functions/homeostasis. During the last decade, it has been demonstrated that chromatin also undergoes modifications with 24-hour rhythmicity and facilitates the fine-tuning of circadian gene expression patterns. In this review, we cover data which suggests that chromatin structure changes in a circadian manner and that NAD+ is the key metabolite for circadian chromatin remodeling. Furthermore, we discuss the relationship among circadian clock, NAD+ metabolism, and aging/age-related diseases. In addition, the interventions of NAD+ metabolism for the prevention and treatment of aging and age-related diseases are also discussed.

28049212	Lipopolysaccharide (LPS) induces hyperthermia accompanied by various other systemic inflammatory symptoms. The rodents exposed to repeated cold (RC) stress according to a specific schedule are useful as experimental models for autonomic imbalance or fibromyalgia. It is now proven that RC-stressed mice exhibit tolerance to LPS, we examined thermal responses to LPS challenge in RC-stressed mice by monitoring core temperature using the telemetry system. Systemic administration of LPS caused bimodal hyperthermic responses in RC-stressed and unstressed mice. The magnitude of the LPS-induced hyperthermia was greater in RC-stressed mice than in unstressed mice. The RC stress-induced enhancement of hyperthermic responses to LPS was abolished by pretreatment with diclofenac, which is a cyclooxygenase (COX) inhibitor. LPS did not significantly increase COX-2 protein levels in the lung or hypothalamus of RC-stressed or unstressed mice. RC stress did not alter baseline serum corticosterone levels or their increases in response to LPS challenge. These results suggest that RC stress enhances the susceptibility of mice to LPS challenge, leading to greater prostanoid-dependent hyperthermia, which might contribute to tolerance to LPS in RC-stressed mice.
28049127	Morning symptoms are common in chronic obstructive pulmonary disease (COPD). Many COPD patients consider the morning as the most troublesome part of the day, in which they experience more symptoms and physical activity limitations.To systematically report evidence of the association between morning symptoms and physical activity in COPD patients, a literature search was conducted using relevant MESH terms and text words in PubMed, Embase, Web of Science, COCHRANE, CINAHL and PsycINFO. Quality of the articles was assessed with validated checklists.Eight studies were included. Morning symptoms were present in 39.8-94.4%. In 37.0-90.6% of all COPD patients, there was an association between physical activity and morning symptoms. However, causality could not be proved. Morning symptoms were associated with a sedentary lifestyle (p<0.05). Treatment in line with the guidelines improved the degree of activity limitations due to morning symptoms (p<0.0001).Across all disease stages, COPD patients experience morning symptoms which are negatively associated with physical activity. Physicians should consider morning symptoms as a treatment goal. Pharmacotherapy may improve the degree of activity limitations due to morning symptoms. More objective research should focus on symptoms, activity limitations and physical inactivity of COPD patients, especially in the morning.
28045699	Sleep problems are common but often neglected in older adults, particularly in the context of cancer. Underlying mechanisms are poorly understood and interventions frequently lack a clear scientific basis.The objective of this report was to examine scientific content presented at a National Institutes of Health-sponsored U13 "Bedside to Bench" conference using a qualitative and iterative review procedure. Analysis of current scientific issues regarding sleep in older adults with cancer is needed to direct nurse scientists and clinicians toward research opportunities.	A multistep review procedure for the analysis/synthesis of knowledge gaps and research opportunities was undertaken by oncology nurse scientists in attendance.	Conceptual problems in this area include the lack of standard sleep terminology and absence of an overarching conceptual model. Methodological problems are inconsistent sleep/napping measurement and complex operational challenges in designing comprehensive yet feasible studies in older adults. Knowledge gaps in basic and clinical science relate to cellular and molecular mechanisms that underlie sleep and circadian rhythm disturbances, contribution of sleep to adverse outcomes, and impact of disturbed sleep during hospitalization and the transition from hospital to home.	Focused and interdisciplinary research that advances conceptual and operational understanding of biological and behavioral determinants of sleep health in the aging cancer population can lead to more effective, safe, and targeted interventions for those with cancer-related sleep-circadian disturbances.	Research that addresses current conceptual, methodological, and physiological issues can lead to more effective, safe, and targeted care for older adults with cancer-related sleep-circadian disturbances.	
28043186	Oral propranolol has been recently approved for infantile hemangiomas (IHs), but potential side effects stay a challenge. We sought to make an additional assessment on oral propranolol safety for this indication.Prospective study included 108 infants consecutively treated for IHs at the University Children's Hospital Tirsova, Belgrade from January 2010 to December 2013. Propranolol was administered orally at a daily dose of 0.5 mg/kg and doubled every 48 hours in the absence of side effects until reaching the maximum dose of 2 mg/kg daily. Systolic and diastolic blood pressure and heart rate were measured every 48 hours with clinical observation. Heart rate was monitored by standard electrocardiogram (ECG) and 48-hour Holter ECG.	Statistically significant, but asymptomatic decreases in systolic blood pressure and heart rate recorded by Holter ECG were observed during the first doubling of dose and then remained stable. Arrhythmias were not detected. Despite mild sleep disturbance observed in 31% of infants in the hospital milieu, Holter monitoring indicated circadian rhythm maintenance.	Oral propranolol for IHs does not remarkably affect heart rhythm including circadian variations throughout hospital initiation. Therefore, there is no necessity for Holter monitoring in additional safety assessment.	
28043031	Hepatocellular cancer (HCC) is the sixth most common cancer and liver fibrosis is strongly associated with HCC. Treatment options are limited, and preventive strategies should be developed. An important step in the beginning of liver fibrosis is a strong inflammatory response. 5-HT7 is the last recognized member of the serotonin receptor family and is expressed in both central nerve system and peripheral system and have a lot of functions like learning, memory, smooth muscular relaxation, in the control of circadian rhythms and thermoregulation, pain and migraine, schizophrenia, anxiety, cognitive disturbances, and even inflammation.We therefore examined the biochemical, histopathological and molecular effects of the 5-HT7 receptor agonist and antagonist on inflammatory liver fibrogenesis in animal models of progressive cirrhosis: a mouse model induced by carbon tetrachloride (CCl4) and in Hep3b cells.	5-HT7 expression was observed in the liver in vivo and in vitro in CCl4-induced damage. 5-HT7 receptor agonist but not the antagonist reduced liver markers in mice and in Hep3b cells in carbon tetrachloride (CCl4) induced damage. 5-HT7 agonist, but not antagonist, protected liver tissue from oxidative stress in fibrosis. 5-HT7 agonist but not antagonist induces anti-inflammatory, anti-fibrinotic and anti-cytokine features in liver fibrosis in vivo and in vitro.	5-HT7 receptors have modulatory function and are an up-and-coming pharmacological target in the inflammatory fibrotic process. 5-HT7 receptor agonist LP-44 showed significant hepatoprotective effects against liver fibrosis, and LP-44 might become a useful therapeutic target for chronic liver inflammation and fibrosis.	
28042611	Light exposure and sleep timing are two factors that influence inter-individual variability in the timing of the human circadian clock. The aim of this study was to quantify the degree to which evening light exposure predicts variance in circadian timing over and above bedtime alone in preschool children. Participants were 21 children ages 4.5-5.0 years (4.7 ± 0.2 years; 9 females). Children followed their typical sleep schedules for 4 days during which time they wore a wrist actigraph to assess sleep timing and a pendant light meter to measure minute-by-minute illuminance levels in lux. On the 5th day, children participated in an in-home dim-light melatonin onset (DLMO) assessment. Light exposure in the 2 h before bedtime was averaged and aggregated across the 4 nights preceding the DLMO assessment. Mean DLMO and bedtime were 19:22 ± 01:04 and 20:07 ± 00:46, respectively. Average evening light exposure was 710.1 ± 1418.2 lux. Children with later bedtimes (lights-off time) had more delayed melatonin onset times (r=0.61, p=0.002). Evening light exposure was not independently associated with DLMO (r=0.32, p=0.08); however, a partial correlation between evening light exposure and DLMO when controlling for bedtime yielded a positive correlation (r=0.46, p=0.02). Bedtime explained 37.3% of the variance in the timing of DLMO, and evening light exposure accounted for an additional 13.3% of the variance. These findings represent an important step in understanding factors that influence circadian phase in preschool-age children and have implications for understanding a modifiable pathway that may underlie late sleep timing and the development of evening settling problems in early childhood.
28042033	The master clock in the suprachiasmatic nucleus synchronizes peripheral clocks via humoral and neural signals in mammals. Insulin is thought to be a critical Zeitgeber (synchronizer) for peripheral clocks because it induces transient clock gene expression in cultured cells. However, the extent to which fluctuations in feeding-dependent endogenous insulin affect the temporal expression of clock genes remains unclear. We therefore investigated the temporal expression profiles of clock genes in the peripheral tissues of mice fed for 8 h during either the daytime (DF) or the nighttime (NF) for one week to determine the involvement of feeding cycle-dependent endogenous insulin rhythms in the circadian regulation of peripheral clocks. The phase of circulating insulin fluctuations was reversed in DF compared with NF mice, although those of circulating corticosterone fluctuations and nocturnal locomotor activity were identical between these mice. The reversed feeding cycle affected the circadian phases of Per1 and Per2 gene expression in the liver and not in heart, lung, white adipose and skeletal muscle tissues. On the other hand, injected exogenous insulin significantly induced Akt phosphorylation in the heart and skeletal muscle as well as the liver, and significantly induced Per1 and Per2 gene expression in all examined tissues. These findings suggest that feeding cycles and feeding cycle-dependent endogenous insulin fluctuations are not dominant entrainment signals for peripheral clocks other than the liver, although exogenous insulin might reset peripheral oscillators in mammals.
28041661	An intrinsic daily physiological rhythm called circadian rhythm has been indicated to affect the immune system and its related diseases. Immune tolerance development is closely associated with the onset of immunological disorders. However, the effect of circadian rhythm in the mechanisms of immune tolerance development has not yet been fully understood.The purpose of this study was to investigate the effects of circadian rhythm disruption on the development of immune tolerance by the perturbation of light environment, using a mouse model of neonatally induced cutaneous tolerance.	Mice were kept under constant light (LL) or light-dark (LD) conditions, and hapten was applied at 2days after birth. Six weeks later, hapten was reapplied to abdominal skin, followed by hapten application to ear skin 5days later.	The ear-swelling responses and cell infiltration into inflamed skin significantly increased in LL mice compared with those in LD mice. Interestingly, the percentage and the number of Foxp3+-regulatory T cells notably decreased in inflamed skin and draining lymph nodes of LL mice compared with that in LD mice. Loss-of-function mutation of a key circadian gene, Bmal1, also exacerbated the ear-swelling responses and cell infiltration into inflamed skin in mice.	These results suggest that circadian rhythm may be implicated in immune tolerance development in allergic inflammation.	
28038815	Clinical studies using serum cardiac biomarkers to investigate a circadian variation in acute myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients reperfused by primary percutaneous coronary intervention (PPCI) have produced mixed results. We aimed to investigate this phenomenon using acute MI size measured by cardiovascular magnetic resonance (CMR).Patient-level data was obtained from 4 randomized controlled trials investigating the MI-limiting effects of cardioprotective therapies in this pooled analysis. The primary analysis was performed in those patients with no pre-infarct angina; duration of ischemia >60min and <360min; Thrombolysis In Myocardial Infarction (TIMI) flow pre-PPCI ≤1; TIMI flow post-PPCI 3; and no collateral flow.	169 out of 376 patients with CMR data met the inclusion criteria for the primary analysis. A 24-hour circadian variation in acute MI size as a % of the area-at-risk (%AAR), after adjusting for confounders, was observed with a peak and nadir MI size in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively (difference from the average MI size 5.2%, 95%CI 1.1-9.4%; p=0.013). This was associated with a non-significant circadian variation in left ventricular ejection fraction (LVEF) (difference from the average LVEF 5.9%, 95%CI -0.6-2.2%, p=0.073). There was no circadian variation in MI size or LVEF in the whole cohort.	We report a circadian variation in acute MI size assessed by CMR in a subset of STEMI patients treated by PPCI, with the largest and smallest MI size occurring in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively.	
28035516	To determine the level of cell-free DNA (cfDNA), Septin 9 (SEPT9) and tumor markers (CEA, AFP, CA19-9, TPA, CA72-4). Plasma samples were collected four times a day (06:00, 12:00, 18:00, 24:00) from 9 patients with CRC (5 stage I-II, 4 stage III-IV), from one with colorectal adenoma and from one healthy control. CfDNA was isolated, quantified and bisulfite-converted. CfDNA and methylated SEPT9 were determined by RT-PCR. Plasma levels of conventional tumor markers were also measured. The lowest cfDNA concentrations were observed at 24:00 and 18:00 in stage I-III patients. In stage IV samples low cfDNA level (mean 48.2 ng/ml) were observed at several time points (6:00, 12:00, 18:00). The highest cfDNA levels were measured at 6:00 and 12:00 in CRC I-III stages and at 24:00 in stage IV samples (78.65 ng/ml). Higher in-day differences were found in stage II (43-48%) than in stage I samples (22%). Interestingly, the highest SEPT9 methylation level was found at 24:00 in most CRC cases, in contrast to the cfDNA levels. At 24:00, all cancer and adenoma cases were positive for SEPT9 methylation. At other time points (6:00, 12:00, 18:00) only 77.7% of CRC samples showed SEPT9 positivity. Stage I samples were SEPT9 positive only at 24:00. CEA and CA19-9 levels displayed correlation with the amount of cfDNA in case of late stage cases. Daytime activity can influence SEPT9 positivity in cases with low concentration of cfDNA. Thus, it may improve screening sensitivity by collecting samples earlier in the morning.
28035185	Nociception is one of the most complex senses that is affected not only by external stimulation but also internal conditions. Previous studies have suggested that circadian rhythm is important in modulating nociception. REV-ERBα knock-out (KO) mice have disrupted circadian rhythm and altered mood-related phenotypes. In this study, we examined the role of REV-ERBα in inflammatory nociception. We found that the nociceptive sensitivity of KO mice was partially enhanced in mechanical nociception. However, this partial alteration was independent of the circadian rhythm. Taken together, deletion of REV-ERBα induced a mild change in mechanical nociceptive sensitivity but this alteration was not dependent on the circadian rhythm.
28034487	Circadian rhythm-dependent cell cycle progression produces daily variations in radiosensitivity. This literature review aims to summarise the data on whether radiotherapy outcomes differ depending on administration time. A literature search was conducted on Ovid Medline, Embase, Cochrane Central Register of Controlled Trials and PubMed using key words such as 'radiotherapy', 'circadian rhythm', 'treatment outcome' and 'survival'. Articles evaluating the correlation between radiotherapy time and outcomes in cancer patients were included and relevant information was extracted. Nine studies met the inclusion criteria. Four investigated lung cancer patients undergoing stereotactic radiosurgery for brain metastases, with one study observing improved local control and survival in patients treated in the morning. Another two studies with breast and cervical cancer patients observed that the prevalence of toxicities was higher in afternoon and morning cohorts, respectively. Two studies in head and neck cancer patients found trends indicating morning patients experienced less oral mucositis. Increased toxicities and biochemical failure rates were associated with evening treatment in prostate cancer patients. As inconsistencies in the literature exist regarding the time dependency of radiotherapy outcomes, further investigation is warranted.

28031787	Using an automated cell counting technique developed previously (Case et al., Ecology and Evolution 2014; 4: 3494), we explore the lifespan effects of lac-1, a ceramide synthase gene paralogous to lag-1 in Neurospora crassa in conjunction with the band bd (ras-1) gene. We find that the replicative lifespan of a lac-1KObd double mutants is short, about one race tube cycle, and this double mutant lacks a strong ~21-hr clock cycle as shown by race tube and fluorometer analysis of fluorescent strains including lac-1KO . This short replicative lifespan phenotype is contrasted with a very long estimated chronological lifespan for lac-1KObd double mutants from 247 to 462 days based on our regression analyses on log viability, and for the single mutant lac-1KO, 161 days. Both of these estimated lifespans are much higher than that of previously studied WT and bd single mutant strains. In a lac-1 rescue and induction experiment, the expression of lac-1+ as driven by a quinic acid-dependent promoter actually decreases the median chronological lifespan of cells down to only 7 days, much lower than the 34-day median lifespan found in control bd conidia also grown on quinic acid media, which we interpret as an effect of balancing selection acting on ceramide levels based on previous findings from the literature. Prior work has shown phytoceramides can act as a signal for apoptosis in stressed N. crassa cells. To test this hypothesis of balancing selection on phytoceramide levels, we examine the viability of WT, lag-1KObd, and lac-1KObd strains following the dual stresses of heat and glycolysis inhibition, along with phytoceramide treatments of different dosages. We find that the phytoceramide dosage-response curve is altered in the lag-1KObd mutant, but not in the lac-1KObd mutant. We conclude that phytoceramide production is responsible for the previously reported longevity effects in the lag-1KObd mutant, but a different ceramide may be responsible for the longevity effect observed in the lac-1KObd mutant.
28031289	Circadian deficits in Huntington's disease (HD) are recapitulated in both fragment (R6/2) and full-length (Q175) mouse models of HD. Circadian rhythms are regulated by the suprachiasmatic nuclei (SCN) in the hypothalamus, which are primarily entrained by light detected by the retina. The SCN receives input from intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin, but also receive input from rods and cones. In turn, ipRGCs mediate a range of non-image forming responses to light including circadian entrainment and the pupillary light response (PLR). Retinal degeneration/dysfunction has been described previously in R6/2 mice. We investigated, therefore, whether or not circadian disruption in HD mice is due to abnormalities in retinal photoreception. We measured the expression of melanopsin, rhodopsin and cone opsin, as well as other retinal markers (tyrosine hydroxylase, calbindin, PKCα and Brna3), in R6/2 and Q175 mice at different stages of disease. We also measured the PLR as a 'readout' for ipRGC function and a marker of light reception by the retina. We found that the PLR was attenuated in both lines of HD mice. This was accompanied by a progressive downregulation of cone opsin and melanopsin expression. We suggest that disease-related changes in photoreception by the retina contribute to the progressive dysregulation of circadian rhythmicity and entrainment seen in HD mice. Colour vision is abnormal in HD patients. Therefore, if retinal deficits similar to those seen in HD mice are confirmed in patients, specifically designed light therapy may be an effective strategy to improve circadian dysfunction.
28031015	Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing. First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, various physiological effects of melatonin are reviewed, including detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Given these physiological effects, potential benefits of melatonin use are discussed, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications.
28030993	Incremental markings in dental enamel suggest that the circadian clock may influence the molecular underpinnings orchestrating enamel formation. The aim of this study was to investigate whether the genes and microRNAs (miRNAs) oscillate in a circadian pattern during tooth and enamel development.Comparative gene and miRNA expression profiling of the first mandibular molar tooth germ isolated at different time-points during the light and night period was performed using microarrays and validated using real-time RT-PCR. Bioinformatic analysis was carried out using Ingenuity Pathway Analysis (IPA), and TargetScan software was used in order to identify computationally predicted miRNA-mRNA target relationships.	In total, 439 genes and 32 miRNAs exhibited significantly different (p < 0.05) levels of expression in the light phase compared with the night phase tooth germs. Genes involved in enamel formation, i.e. Amelx, Ambn, Amtn, and Odam, oscillated in a circadian pattern. Furthermore, the circadian clock genes, in particular Clock and Bmal1, oscillated in mouse molar tooth germ during 24-h intervals. The expression of Clock and Bmal1 was inversely correlated with the expression of miR-182 and miR-141, respectively.	MiRNAs, including miR-182 and miR-141, are involved in the control of peripheral circadian rhythms in the developing tooth by regulating the expression of genes coding for circadian transcription factors such as CLOCK and BMAL1. Regulation of circadian rhythms may be important for enamel phenotype, and the morphology of dental enamel may vary between individuals due to differences in circadian profiles.	
28029289	OBJECTIVE To determine effects of diurnal variation and anesthetic agents on intraocular pressure (IOP) in Syrian hamsters (Mesocricetus auratus). ANIMALS 90 healthy adult Syrian hamsters (45 males and 45 females). PROCEDURES IOP was measured with a rebound tonometer. In phase 1, IOP was measured in all hamsters 3 times during a 24-hour period (7 am, 3 pm, and 11 pm). In phase 2, hamsters were assigned to 5 groups (18 animals [9 males and 9 females]/group). Each group received an anesthetic agent or combination of anesthetic agents (ketamine hydrochloride, xylazine hydrochloride, diazepam, ketamine-diazepam [KD], or ketamine-xylazine [KX] groups) administered via the IP route. The IOP was measured before (time 0 [baseline]) and 10, 30, 60, 90, 120, and 150 minutes after administration of drugs. RESULTS Mean ± SD IOP values were 2.58 ± 0.87 mm Hg, 4.46 ± 1.58 mm Hg, and 5.96 ± 1.23 mm Hg at 7 am, 3 pm, and 11 pm, respectively. Mean baseline IOP was 6.25 ± 0.28 mm Hg, 6.12 ± 0.23 mm Hg, 5.75 ± 0.64 mm Hg, 5.12 ± 1.40 mm Hg, and 4.50 ± 1.30 mm Hg for the ketamine, xylazine, diazepam, KD, and KX groups, respectively. A significant decrease in IOP, compared with baseline IOP, was detected in only the KX group at 30, 60, and 90 minutes after drug administration. CONCLUSIONS AND CLINICAL RELEVANCE Maximum IOP in Syrian hamsters was detected at night. The ketamine-xylazine anesthetic combination significantly decreased IOP in Syrian hamsters.
28028599	Women of child-bearing age are the population at greatest risk for depression. The stress experienced during pregnancy and the associated antidepressant treatments can both affect fetal development. Fluoxetine (FLX) is among the most common antidepressants used by pregnant women. We have previously demonstrated that perinatal exposure to FLX can alter expression of circadian rhythms in adulthood. Here, we examine the combined effects of maternal stress during pregnancy and perinatal exposure to the antidepressant FLX on the circadian behavior of mice as adults.Mouse dams were exposed to chronic unpredictable stress (embryonic (E) day 7 to E18), FLX (E15 to postnatal day 12), a combination of both stress and FLX, or were left untreated. At 2 months of age, male offspring were placed in recording chambers and circadian organization of wheel running rhythms and phase shifts to photic and non-photic stimuli were assessed.	Mice exposed to prenatal stress (PS) had smaller light-induced phase delays. Mice exposed to perinatal FLX required more days to re-entrainment to an 8-h phase advance of their light-dark cycle. Mice subjected to either perinatal FLX or to PS had larger light-induced phase advances and smaller phase advances to 8-OH-DPAT. FLX treatment partially reversed the effect of PS on phase shifts to late-night light exposure and to 8-OH-DPAT.	Our results suggest that, in mice, perinatal exposure to either FLX, or PS, or their combination, leads to discernible, persistent changes in their circadian systems as adults.	
28027933	A phenolic acid decarboxylase (padC) regulator, PadR and its homologs proteins belong to the PadR family. Despite the growing numbers of the PadR family members and their various roles in bacteria, such as detoxifications, drug transports and circadian rhythms, biochemical and biophysical studies of the PadR family are very limited. Thus, a ligand-induced regulatory mechanism of the PadR family transcription factors remains to be elucidated. Here, we report a crystal structure of a Bacteroides fragilis PadR-like protein, BF2549 and revealed its interaction with putative operator DNA and ligand molecules. Comparative structural and primary sequence analyses provide a PadR-specific motif that is conserved in the PadR family but deviated from the MarR family. Furthermore, putative ligand binding sites are observed in the BF2549 structure. Finally, a homology-based structure model of BF2549 and 29-mer dsDNA propose regulatory mechanisms of the PadR family in transcriptional derepression.
28027684	Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm is associated with the cortisol stress response in children. Since alterations in cortisol stress responses have been associated with mental and physical health, this study investigated whether the cortisol circadian rhythm is associated with cortisol stress responses in 6-year-old children. To this end, 149 normally developing children (Mage = 6.09 years; 70 girls) participated in an innovative social evaluative stress test that effectively provoked increases in cortisol. To determine the cortisol stress response, six cortisol saliva samples were collected and two cortisol stress response indices were calculated: total stress cortisol and cortisol stress reactivity. To determine children's cortisol circadian rhythm eight cortisol circadian samples were collected during two days. Total diurnal cortisol and diurnal cortisol decline scores were calculated as indices of the cortisol circadian rhythm. Hierarchical regression analyses indicated that higher total diurnal cortisol as well as a smaller diurnal cortisol decline, were both uniquely associated with higher total stress cortisol. No associations were found between the cortisol circadian rhythm indices and cortisol stress reactivity. Possible explanations for the patterns found are links with children's self-regulatory capacities and parenting quality.
28027301	Oscillations occur in a wide variety of cellular processes, for example in calcium and p53 signaling responses, in metabolic pathways or within gene-regulatory networks, e.g. the circadian system. Since it is of central importance to understand the influence of perturbations on the dynamics of these systems a number of experimental and theoretical studies have examined their robustness. The period of circadian oscillations has been found to be very robust and to provide reliable timing. For intracellular calcium oscillations the period has been shown to be very sensitive and to allow for frequency-encoded signaling. We here apply a comprehensive computational approach to study the robustness of period and amplitude of oscillatory systems. We employ different prototype oscillator models and a large number of parameter sets obtained by random sampling. This framework is used to examine the effect of three design principles on the sensitivities towards perturbations of the kinetic parameters. We find that a prototype oscillator with negative feedback has lower period sensitivities than a prototype oscillator relying on positive feedback, but on average higher amplitude sensitivities. For both oscillator types, the use of Michaelis-Menten instead of mass action kinetics in all degradation and conversion reactions leads to an increase in period as well as amplitude sensitivities. We observe moderate changes in sensitivities if replacing mass conversion reactions by purely regulatory reactions. These insights are validated for a set of established models of various cellular rhythms. Overall, our work highlights the importance of reaction kinetics and feedback type for the variability of period and amplitude and therefore for the establishment of predictive models.
28025809	The human orexin/hypocretin receptors (hOX1R and hOX2R) are G protein-coupled receptors (GPCRs) that mediate the diverse functions of the orexin/hypocretin neuropeptides. Orexins/hypocretins produced by neurons in the lateral hypothalamus stimulate their cognate GPCRs in multiple regions of the central nervous system to control sleep and arousal, circadian rhythms, metabolism, reward pathways, and other behaviors. Dysfunction of orexin/hypocretin signaling is associated with human disease, and the receptors are active targets in a number of therapeutic areas. To better understand the molecular mechanism of the orexin/hypocretin neuropeptides, high-resolution three-dimensional structures of hOX1R and hOX2R are critical. We have solved high-resolution crystal structures of both human orexin/hypocretin receptors bound to high-affinity antagonists. These atomic structures have elucidated how different small molecule antagonists bind with high potency and selectivity, and have also provided clues as to how the native ligands may associate with their receptors. The orexin/hypocretin receptor coordinates, now available to the broader academic and drug discovery community, will facilitate rational design of new therapeutics that modulate orexin/hypocretin signaling in humans.
28025546	In 2013, the World Health Organization (WHO) called for joint surveillance of population salt and iodine intakes using urinary analysis. 24-h urine collection is considered the gold standard for salt intake assessment, but there is an emerging consensus that casual urine sampling can provide comparable information for population-level surveillance. Our review covers the use of the urinary sodium concentration (UNaC) and the urinary iodine concentration (UIC) from casual urine samples to estimate salt intakes and to partition the sources of iodine intakes. We reviewed literature on 24-h urinary sodium excretion (UNaE) and UNaC and documented the use of UNaC for national salt intake monitoring. We combined information from our review of urinary sodium with evidence on urinary iodine to assess the appropriateness of partitioning methods currently being adapted for cross-sectional survey analyses. At least nine countries are using casual urine collection for surveillance of population salt intakes; all these countries used single samples. Time trend analyses indicate that single UNaC can be used for monitoring changes in mean salt intakes. However; single UNaC suffers the same limitation as single UNaE; i.e., an estimate of the proportion excess salt intake can be biased due to high individual variability. There is evidence, albeit limited, that repeat UNaC sampling has good agreement at the population level with repeat UNaE collections; thus permitting an unbiased estimate of the proportion of excess salt intake. High variability of UIC and UNaC in single urine samples may also bias the estimates of dietary iodine intake sources. Our review concludes that repeated collection, in a sub-sample of individuals, of casual UNaC data would provide an immediate practical approach for routine monitoring of salt intake, because it overcomes the bias in estimates of excess salt intake. Thus we recommend more survey research to expand the evidence-base on predicted-UNaE from repeat casual UNaC sampling. We also conclude that the methodology for partitioning the sources of iodine intake based on the combination of UIC and UNaC measurements in casual urine samples can be improved by repeat collections of casual data; which helps to reduce regression dilution bias. We recommend more survey research to determine the effect of regression dilution bias and circadian rhythms on the partitioning of dietary iodine intake sources.
28025460	The cardiovascular prognosis of heart failure with preserved ejection fraction (HFpEF) has been shown to be similar to that of heart failure with reduced ejection fraction (HFrEF). It is unknown which factors predict cardiovascular outcome in HFpEF. We tested the hypothesis that the abnormal pattern of circadian blood pressure (BP) rhythm known as the riser BP pattern is associated with adverse outcomes in HFpEF.Methods and Results:We performed a prospective, observational cohort study of hospitalized HF patients who underwent ambulatory BP monitoring (ABPM). Five hundred and sixteen hospitalized HF patients (age, 69±13 years; male, n=321 [62%]; female, n=195 [38%]) were followed up for a median 20.9 months. The composite outcome consisting of all-cause mortality and cardiovascular events was observed in 220 patients. On Kaplan-Meier analysis, the riser BP pattern subgroup had a significantly higher incidence of the composite outcome than the other subgroups of HFpEF patients (HR, 3.01; 95% CI: 1.54-6.08, P<0.01), but not the HFrEF patients.The riser BP pattern was found to be a novel predictor of cardiovascular outcome in HFpEF patients.	
28025148	Previous studies have shown that circadian clock genes are expressed in mammalian testes; however, it remains unclear if the expression patterns of these genes are cyclic. Furthermore, it is unknown whether Leydig cells, the primary androgen secreting cells in the testis, play a role in the rhythmicity of circadian clock and steroidogenic-related gene transcription. Here, we examine the circadian clock of mouse Leydig cells, and the link to steroidogenic-related gene transcription. We confirm, via sampling over a full circadian time (CT) period, a lack of circadian rhythmicity in mouse testes in comparison with the robust gene expression cycling of circadian clock genes in mouse livers. Immunofluorescence imaging of mouse testes collected at CT0 and CT12 show that the BMAL1 protein is exclusively expressed in mouse Leydig cells, and clearly linked to the circadian oscillation. Furthermore, dexamethasone treatment synchronized the expression of several of these canonical circadian clock and steroidogenic-related genes. Bioinformatic analyses revealed the presence of several circadian clock-related sequence motifs in the promoters of these steroidogenic-related genes. Our results suggest mouse Leydig cells may contain a functional circadian oscillator and the circadian clockwork in mouse Leydig cells regulates steroidogenic-related gene transcription by binding to the E-box, RORE, and D-box motifs in their promoters. However, additional research is required to determine the specific molecular mechanisms involved.
28018987	Evidence from previous studies suggests that greater sleep pressure, in the form of EEG-based slow waves, accumulates in specific brain regions that are more active during prior waking experience. We sought to quantify the number and coherence of EEG slow waves in subjects with mild traumatic brain injury (mTBI).We developed a method to automatically detect individual slow waves in each EEG channel, and validated this method using simulated EEG data. We then used this method to quantify EEG-based slow waves during sleep and wake states in both mouse and human subjects with mTBI. A modified coherence index that accounts for information from multiple channels was calculated as a measure of slow wave synchrony.	Brain-injured mice showed significantly higher theta:alpha amplitude ratios and significantly more slow waves during spontaneous wakefulness and during prolonged sleep deprivation, compared to sham-injured control mice. Human subjects with mTBI showed significantly higher theta:beta amplitude ratios and significantly more EEG slow waves while awake compared to age-matched control subjects. We then quantified the global coherence index of slow waves across several EEG channels in human subjects. Individuals with mTBI showed significantly less EEG global coherence compared to control subjects while awake, but not during sleep. EEG global coherence was significantly correlated with severity of post-concussive symptoms (as assessed by the Neurobehavioral Symptom Inventory scale).	Taken together, our data from both mouse and human studies suggest that EEG slow wave quantity and the global coherence index of slow waves may represent a sensitive marker for the diagnosis and prognosis of mTBI and post-concussive symptoms.	
28017879	Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior. These endogenous rhythms dampen with age and thus compromise temporal coordination. Feeding-fasting patterns are an external cue that profoundly influence the robustness of daily biological rhythms. Erratic eating patterns can disrupt the temporal coordination of metabolism and physiology leading to chronic diseases that are also characteristic of aging. However, sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse these chronic diseases in experimental models. In humans, epidemiological studies have shown erratic eating patterns increase the risk of disease, whereas sustained feeding-fasting cycles, or prolonged overnight fasting, is correlated with protection from breast cancer. Therefore, optimizing the timing of external cues with defined eating patterns can sustain a robust circadian clock, which may prevent disease and improve prognosis.
28017732	Epigenetic modifications in reproductive tissues have predominantly focused on pathological conditions, such as ovarian and uterine cancers. The contribution of DNA methylation and histone acetylation to the timing and control of fertility is not well described. Siberian hamsters provide an important model to investigate the relatively short-term regulation of fertility (e.g. estrous) as well as long-term timing of breeding (e.g. seasonal). Recent work has shown that DNA methyltransferase 3a (dnmt3a) expression is associated with reproductive involution. Here, the objectives were to identify the impact of photoperiod on hdac1-3 expression in hamster testicular, ovarian and uterine tissue. Then, we assessed the effect of E2P4 and estrous cycling on hdac1-3 expression in uterine tissue. Testicular expression of hdac1 was significantly reduced, whereas hdac3 increased in reproductively photoregressed male hamsters; hdac2 expression did not significantly change across photoperiod conditions. There was no significant photoperiodic effect on ovarian expression of hdac1-3. Uterine expression of hdac3 expression was greater in long day hamsters; exposure to short days significantly reduced uterine hdac2 expression. Ovariectomized hamsters administered a single bolus injection of oil were found to have elevated uterine hdac2 compared to E2P4 treated females 12h and 24h post injection. Uterine hdac1-3 expression was relatively constant across the estrous cycle. Altogether these data indicate tissue-dependent photoperiodic regulation of hdac1-3 expression and that E2P4 may inhibit uterine hdac2 over long-term breeding cycles.
28017731	The hypothalamic-pituitary-gonadal (HPG) axis, with gonadotropin-releasing hormone (GnRH) initiating the endocrine cascade, regulates testosterone secretion. Testosterone, through its pleiotropic effects, plays a crucial role in coordinating morphology, physiology and behavior in a reproductive context. The concentration of circulating testosterone, however, varies over the course of the day and in response to other internal or external stimuli, potentially making it difficult to relate testosterone sampled at one time point with traits of interest. Many researchers now utilize the administration of exogenous GnRH to elicit a standardized stimulation of testosterone secretion. However, it has remained unclear if and how this exogenously stimulated activation of the HPG axis is related with endogenously regulated testosterone that is capable of influencing testosterone related traits. Repeated measures of a hormone can uncover consistent individual variation in hormonal differences at the HPG axis level, variation that potentially stems from underlying genetic variation in a population experiencing identical environmental cues. Thus, we asked, using the house sparrow (Passer domesticus), how daily endogenous variation in testosterone profiles relates to GnRH-induced testosterone secretion. Further, we explore the relationship between endogenous daily testosterone peaks and GnRH-induced testosterone with badge size, a morphological trait related with status within a social group. We found that GnRH-induced testosterone levels reflect a highly repeatable hormonal phenotype that is strongly correlated with nighttime testosterone levels. The results demonstrate the usefulness of GnRH-induced testosterone in studies aimed at understanding individual variation and selection on endogenously regulated testosterone levels and the potential importance of nighttime testosterone levels to physiology and behavior.
28017681	Neurodegeneration of hippocampal structures is implicated in Alzheimer's disease (AD). Patients with AD exhibit 'sundown syndrome' featuring mood swings and anxiety. Although there are studies demonstrating circadian rhythm disruption associated with sundown phenomenon, the mechanisms underlying the emotional disturbances remain elusive. In the present study, we examined the relationship between subiculum (a key hippocampal output structure) and anxiety. Our study demonstrates that bilateral ventral subicular lesion (VSL) leads to anxiogenic behavior. In the elevated plus maze test, VSL rats made less number of entries into the open arms and spent significantly more time in the closed arms. Similarly, in the light-dark exploration test, VSL rats spent significantly more time in the dark chamber and made fewer entries into the light chamber. VSL also produced significant neurodegeneration in the paraventricular, suprachiasmatic and dorsomedial nuclei of the hypothalamus. Exposing VSL rats to a short photoperiod regime (SPR; 06/18h light-dark cycle) for 21days ameliorated the anxiety-like behavior. VSL rats on SPR also exhibited increased food consumption and higher core body temperature. Our study supports the hypothesis that the ventral subiculum regulates anxiety-like behavior and that SPR helps in the alleviation of such behavior. Even though the mechanisms underlying anxiolytic effects of light-dark cycle manipulation are yet to be elucidated, such non-pharmacological strategies can help to mitigate anxiety-like behavior. A proper understanding of the effectiveness of photoperiod manipulation will help in developing strategies in the management of emotional disturbances associated with affective and neurodegenerative disorders including AD.
28017605	The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip-/- mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.
28013579	Millions of people worldwide are working at times that overlap with the normal time for sleep. Sleep problems related to the work schedule may mediate the well-established relationship between shift work and increased risk for disease, occupational errors and accidents. Yet, our understanding of causality and the underlying mechanisms that explain this relationship is limited. We aimed to assess the consequences of night-shift work for sleep and to examine whether night-shift work-induced sleep disturbances may yield electrophysiological markers of impaired maintenance of the waking brain state. An experimental model developed in rats simulated a 4-day protocol of night-work in humans. Two groups of rats underwent 8-h sessions of enforced ambulation, either at the circadian time when the animal was physiologically primed for wakefulness (active-workers, mimicking day-shift) or for sleep (rest-workers, mimicking night-shift). The 4-day rest-work schedule induced a pronounced redistribution of sleep to the endogenous active phase. Rest-work also led to higher electroencephalogram (EEG) slow-wave (1-4 Hz) energy in quiet wakefulness during work-sessions, suggesting a degraded waking state. After the daily work-sessions, being in their endogenous active phase, rest-workers slept less and had higher gamma (80-90 Hz) activity during wake than active-workers. Finally, rest-work induced an enduring shift in the main sleep period and attenuated the accumulation of slow-wave energy during NREM sleep. A comparison of recovery data from 12:12 LD and constant dark conditions suggests that reduced time in NREM sleep throughout the recorded 7-day recovery phase induced by rest-work may be modulated by circadian factors. Our data in rats show that enforced night-work-like activity during the normal resting phase has pronounced acute and persistent effects on sleep and waking behavior. The study also underscores the potential importance of animal models for future studies on the health consequences of night-shift work and the mechanisms underlying increased risk for diseases.
28013051	The daily variations in circulating fatty acid (FA) contents and lipid metabolism have been well documented. However, whether long chain polyunsaturated FA (PUFA) contents and expression of genes involved in their de novo synthesis exhibit daily rhythms are yet unknown. We conducted the present study to investigate the daily variations in PUFA contents in plasma and liver of pigs. Moreover, diurnal expression of genes encode fatty acid desaturases and elongases, which are key enzymes catalyzed de novo synthesis of long chain PUFA, were also explored. The results showed that long chain PUFA contents in plasma and liver both exhibited diurnal rhythms. Diurnal variations were also observed in mRNA expression of FASD1 (Delta 5-desaturase), FASD2 (Delta 6-desaturase), ELOVL5 (fatty acid elongase 5) and ELOVL2 in liver, with an unexpectedly high level at night. Moreover, our results showed a similarity between the diurnal patterns of FASD1, FASD2, ELOVL2, ELOVL5 and Period 2. These results indicated a high activity of the desaturase-elongase pathway at night in pigs. These findings have important physiological and pathophysiological implications, since long chain PUFA are essential for cell function and closely involved in the development of metabolic syndrome.
28012806	Throughout the industrialized world, nearly one in five employees works some form of nontraditional shift. Such shift work is associated with numerous negative health consequences, ranging from cognitive complaints to cancer, as well as diminished quality of life. Furthermore, a substantial percentage of shift workers develop shift work disorder, a circadian rhythm sleep disorder characterized by excessive sleepiness, insomnia, or both as a result of shift work. In addition to adverse health consequences and diminished quality of life at the individual level, shift work disorder incurs significant costs to employers through diminished workplace performance and increased accidents and errors. Nonetheless, shift work will remain a vital component of the modern economy. This article reviews seminal and recent literature regarding shift work, with an eye toward real-world application in clinical and organizational settings.
28012425	Intensive care unit patients typically exhibit pathologic wakefulness, poor quality of daytime sleep, nocturnal sleep fragmentation, and sleep patterns that feature the absence of slow wave sleep and rapid eye movement. This article offers a review of the existing literature examining circadian desynchronization in critically ill patients, highlighting contributing factors identified by scholars, and circadian abnormalities observed in these patients. It discusses potential implications for clinical practice and suggests avenues of future research. Elucidating the role of circadian rhythms in the management of critical illness can guide future chronotherapeutic approaches and optimize patient outcomes.
28011880	In several species caloric restriction (CR) extends life span. In this paper we integrate data from studies on CR and other sources to articulate the hypothalamic deregulation hypothesis by which estrogen receptor-alpha (ER-α) signaling in the hypothalamus and limbic system affects life span under the stress of CR in mammals. ER-α is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the arcuate nucleus (ARN), preoptic area (POA), ventromedial nucleus (VMN), antero ventral periventricular nucleus (AVPV), paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus (SCN). Estradiol signaling via ER-α is essential in basal level functioning of reproductive cycle, sexually receptive behaviors, physiological stress responses, as well as sleep cycle, and other nonsexual behaviors. When an organism is placed under long-term CR, which introduces an external stress to this ER-α signaling, the reduction of ER-α expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-α in the hypothalamus and limbic system that affect normal endocrine functioning.
28010116	Circadian rhythms are a critical part of the body's homeostatic mechanisms. These rhythms repeat with a cycle-length of approximately 24 h and are generated by a transcriptional-translational feedback loop. These rhythms are critical for proper behavioral, physiological, and molecular functions. CHRONO, a novel circadian clock gene, forms a complex with other clock proteins and modulates the circadian machinery. CHRONO also interacts with histone deacetylase (HDAC) to modulate the epigenetic status of the transcriptional regulation. Chrono knockout mice display a longer period of circadian behavior and an elevated stress response. This paper reviews the molecular function of CHRONO with a focus on epigenetic regulation and speculates on the possible function of CHRONO in physiological processes. Key messages Chrono is a circadian clock gene whose transcription exhibits a robust circadian oscillation. CHRONO is a repressor of circadian transcriptional/translational feedback loops. CHRONO may function to link epigenetic control mechanisms to stress responses.
28008257	A woman was diagnosed with non-24-hour sleep-wake syndrome and depressive symptoms. Her depressive symptoms did not respond to standard doses of several antidepressants or mood stabilizers. Furthermore, her sleep-wake cycle remained non-entrained despite treatment with a melatonin-related drug, vitamin B12, and phototherapy. Ultimately, her sleep-wake rhythm was restored to a 24-hour pattern with a low dose of valproic acid, and her depressive symptoms tended to improve as a result of synchronization without antidepressants. Low-dose valproic acid appears to be one of the effective means of entraining circadian rhythms in patients with non-24-hour sleep-wake syndrome, which in turn likely improves associated depressive symptoms.
28008157	Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control.
28007935	Organisms use circadian clocks to generate 24-h rhythms in gene expression. However, the clock can interact with other pathways to generate shorter period oscillations. It remains unclear how these different frequencies are generated. Here, we examine this problem by studying the coupling of the clock to the alternative sigma factor sigC in the cyanobacterium Synechococcus elongatus Using single-cell microscopy, we find that psbAI, a key photosynthesis gene regulated by both sigC and the clock, is activated with two peaks of gene expression every circadian cycle under constant low light. This two-peak oscillation is dependent on sigC, without which psbAI rhythms revert to one oscillatory peak per day. We also observe two circadian peaks of elongation rate, which are dependent on sigC, suggesting a role for the frequency doubling in modulating growth. We propose that the two-peak rhythm in psbAI expression is generated by an incoherent feedforward loop between the clock, sigC and psbAI Modelling and experiments suggest that this could be a general network motif to allow frequency doubling of outputs.
28007926	The circadian clock plays a role in many biologic processes, yet very little is known about its role in metabolism of drugs and carcinogens. The purpose of this study was to define the impact of circadian rhythms on benzo-a-pyrene (BaP) metabolism in the mouse mammary gland and develop a circadian in vitro model for investigating changes in BaP metabolism resulting from cross-talk between the molecular clock and aryl hydrocarbon receptor. Female 129sv mice (12 weeks old) received a single gavage dose of 50 mg/kg BaP at either noon or midnight, and mammary tissues were isolated 4 or 24 hours later. BaP-induced Cyp1a1 and Cyp1b1 mRNA levels were higher 4 hours after dosing at noon than at 4 hours after dosing at midnight, and this corresponded with parallel changes in Per gene expression. In our in vitro model, we dosed MCF10A mammary cells at different times after serum shock to study how time of day shifts drug metabolism in cells. Analysis of CYP1A1 and CYP1B1 gene expression showed the maximum enzyme-induced metabolism response 12 and 20 hours after shock, as determined by ethoxyresorufin-O-deethylase activity, metabolism of BaP, and formation of DNA-BaP adducts. The pattern of PER-, BMAL-, and aryl hydrocarbon receptor-induced P450 gene expression and BaP metabolism was similar to BaP-induced Cyp1A1 and Cyp1B1 and molecular clock gene expression in mouse mammary glands. These studies indicate time-of-day exposure influences BaP metabolism in mouse mammary glands and describe an in vitro model that can be used to investigate the circadian influence on the metabolism of carcinogens.
28007541	The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.
28006027	For animals living in temperate latitudes, seasonal changes in day length are an important cue for adaptations of their physiology and behavior to the altered environmental conditions. The suprachiasmatic nucleus (SCN) is known as the central circadian clock in mammals, but may also play an important role in adaptations to different photoperiods. The SCN receives direct light input from the retina and is able to encode day-length by approximating the waveform of the electrical activity rhythm to the duration of daylight. Changing the overall waveform requires a reorganization of the neuronal network within the SCN with a change in the degree of synchrony between the neurons; however, the underlying mechanisms are yet unknown. In the present study we used PER2::LUC bioluminescence imaging in cultured SCN slices to characterize network dynamics on the single-cell level and we aimed to provide evidence for a role of modulations in coupling strength in the photoperiodic-induced phase dispersal. Exposure to long photoperiod (LP) induced a larger distribution of peak times of the single-cell PER2::LUC rhythms in the anterior SCN, compared to short photoperiod. Interestingly, the cycle-to-cycle variability in single-cell period of PER2::LUC rhythms is also higher in the anterior SCN in LP, and is positively correlated with peak time dispersal. Applying a new, impartial community detection method on the time series data of the PER2::LUC rhythm revealed two clusters of cells with a specific spatial distribution, which we define as dorsolateral and ventromedial SCN. Post hoc analysis of rhythm characteristics of these clusters showed larger cycle-to-cycle single-cell period variability in the dorsolateral compared to the ventromedial cluster in the anterior SCN. We conclude that a change in coupling strength within the SCN network is a plausible explanation to the observed changes in single-cell period variability, which can contribute to the photoperiod-induced phase distribution.
28004075	Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. Circadian rhythm is controlled by the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clocks in various tissues. More importantly, the central clock can integrate photic/nonphotic signals to generate rhythmic outputs, and then drive the slave oscillators in peripheral tissues through neuroendocrine and behavioral signals. Human reproductive activities, as some other physiological functions, are controlled by the biological clocks. Accumulating lines of epidemiological and genetic evidence indicate that disruption of circadian clock can be directly involved in multiple pathological processes, including infertility. In this review, we mainly discuss the presence of a circadian clock in reproductive tissues and its roles in follicles development, ovulation, spermatogenesis, fertilization and embryo implantation, etc. As the increased shift work and assisted reproductive technologies possibly disrupt circadian rhythmicity to impact reproduction, the importance of circadian rhythms should be highlighted in the regulation of reproductive process.
28000948	To obtain clues to the link between the molecular mechanism of circadian and photoperiod clocks, we cloned two circadian clock genes, period (per) and timeless (tim) from the moth Sesamia nonagrioides, which undergoes facultative diapause controlled by photoperiod. Sequence analysis revealed a high degree of conservation among the compared insects fοr both genes. We also investigated the expression patterns of per and tim in brains of larvae growing under 16L:8D (long days), constant darkness (DD) and 10L:14D (short days) conditions by qPCR assays. The results showed that mRNA accumulations encoding both genes exhibited diel oscillations under different photoperiods. The oscillation of per and tim mRNA, under short-day photoperiod differed from long-day. The difference between long-day and short-day conditions in the pattern of mRNA levels of per and tim appears to distinguish photoperiodic conditions clearly and both genes were influenced by photoperiod in different ways. We infer that not all photoperiodic clocks of insects interact with circadian clocks in the same fashion. Our results suggest that transcriptional regulations of the both clock genes act in the diapause programing in S. nonagrioides. The expression patterns of these genes are affected by photoperiod but runs with 24 h by entrainment to daily environmental cues.
28000102	Pharmacokinetic/pharmacodynamic modeling and simulation can aid clinical drug development by dynamically integrating key system- and drug-specific information into predictive profiles. In this study, we propose a methodology to predict pharmacokinetic/pharmacodynamic profiles of sinogliatin (HMS-5552, RO-5305552), a novel glucokinase activator to treat diabetes mellitus, for first-in-patient (FIP) studies.Initially, pharmacokinetic/pharmacodynamic profiles of sinogliatin and another glucokinase activator (US2) previously acquired from healthy subjects were fitted using Model A incorporating an indirect response mechanism. The pharmacokinetic/pharmacodynamic profiles of US2 in patients with type 2 diabetes mellitus (T2DM) were then fitted using Model B incorporating circadian rhythm and food effects after thoughtful research on the difference between healthy subjects and T2DM patients. The differences in results between the two US2 modeling populations were used to scale the values of the pharmacodynamic parameters and refine the pharmacodynamic model of sinogliatin, which was then utilized to project pharmacokinetic/pharmacodynamic profiles of sinogliatin in T2DM patients after an 8-day simulated treatment. Results showed that the projected pharmacokinetic/pharmacodynamic values of five parameters were within 70-130% of values fitted from observed clinical data while the other two remaining projected parameters were within a twofold error. Population pharmacokinetic/pharmacodynamic analysis conducted for sinogliatin also suggested that age and sex were significantly correlated to pharmacokinetic/pharmacodynamic characteristics. Additionally, Model B was combined with a glycosylated hemoglobin (HbA1c) compartment to form Model C, which was then used to project serum HbA1c levels in patients after a 1-month simulated treatment of sinogliatin. The predicted HbA1c changes were nearly identical to observed clinical values (0.82 vs. 0.78%).	Model-based drug development methods utilizing a learn-research-confirm cycle may accurately project pharmacokinetic/pharmacodynamic profiles of new drugs in FIP studies.	
27999821	Background. Spinal cord injury (SCI) leads to bowel dysfunction. Electroacupuncture (EA) may improve bowel function. Objective. To assess EA on daily rhythmicity of intestinal movement and circadian rhythmicity of colonic Per2 expression in rats with SCI. Methods. Rats were randomized to the sham, SCI, and SCI+EA groups. EA was performed at bilateral Zusanli point (ST36) during daytime (11:00-11:30) for 14 days following SCI. Intestinal transit and daily rhythmicity of intestinal movement were assessed. Circadian rhythmicity of colonic Per2 expression was assessed by real-time RT-PCR. Results. EA shortened the stool efflux time and increased the dry fecal weight within 24 h in SCI rats. Daily rhythmicity of intestinal movements was unaffected by SCI. The expression of colonic Per2 peaked at 20:00 and the nadir was observed at 8:00 in the SCI and sham groups. In the SCI+EA group, colonic Per2 expression peaked at 12:00 and 20:00, and the nadir was observed at 8:00. Conclusion. SCI did not change the circadian rhythmicity of colonic Per2 expression in rats, and daily intestinal movement rhythmicity was retained. EA changed the daily rhythmicity of intestinal movement and the circadian rhythmicity of colonic Per2 expression in rats with SCI, increasing Per2 expression shortly after EA treatment.
27999812	In order to characterize the toxic response of zebra fish (Danio rerio) to Deltamethrin (DM), behavior strength (BS) and muscle AChE activity of zebra fish were investigated. The results showed that the average values of both BS and AChE activity showed a similarly decreased tendency as DM concentration increased, which confirmed the dose-effect relationship, and high and low levels of AChE and BS partly matched low and high levels of exposure concentrations in self-organizing map. These indicated that AChE and BS had slight different aspects of toxicity although overall trend was similar. Behavior activity suggested a possibility of reviving circadian rhythm in test organisms after exposure to the chemical in lower concentration (0.1 TU). This type of rhythm disappeared in higher concentrations (1.0 TU and 2.0 TU). Time series trend analysis of BS and AChE showed an evident time delayed effect of AChE, and a 2 h AChE inhibition delay with higher correlation coefficients (r) in different treatments was observed. It was confirmed that muscle AChE inhibition of zebra fish is a factor for swimming behavior change, though there was a 2 h delay, and other factors should be investigated to illustrate the detailed behavior response mechanism.
27999288	Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.
27999181	Plants have the ability to respond to seasonal environmental variations by monitoring day length to initiate flowering. The transition from vegetative to the reproductive stage is the critical developmental switch in flowering plants to ensure optimal fitness and/or yield. It has been previously reported that B-BOX32 (BBX32) has the potential to increase grain yield when ectopically expressed in soybean. In the present study, we performed a detailed molecular characterization of the Arabidopsis B-box domain gene BBX32 We showed that the circadian clock in Arabidopsis regulates BBX32 and expressed in the early morning. To understand the molecular mechanism of BBX32 regulation, we performed a large-scale yeast two-hybrid screen and identified CONSTANS-LIKE 3 (COL3)/BBX4 as one of its interacting protein partners. Using different genetic and biochemical assays, we have validated this interaction and shown that COL3 targets FT in the presence of BBX32 to regulate the flowering pathway. Based on these findings, we hypothesized that this BBX32-COL3 module could be an additional regulatory mechanism affecting the reproductive development in Arabidopsis that could be translated to crops for increased agricultural productivity.
27999088	The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs.
27998755	Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are impaired in rodents that have been rendered circadian-arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS-arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally-arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3h after light onset (ZT03) or 2h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing.
27998697	The choroid plexuses (CPs) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF). In recent years, novel functions have been attributed to this tissue such as in immune and chemical surveillance of the central nervous system, brain development, adult neurogenesis and circadian rhythm regulation. Sex hormones (SH) are widely recognized as modulators in several neurodegenerative diseases, and there is evidence that estrogens and androgens regulate several fundamental biological functions in the CPs. Therefore, SH are likely to affect the composition of the CSF impacting on brain homeostasis. This review will look at implications of the CPs' sex-related specificities.
27998295	Severe mental illness (SMI) is common, chronic and difficult to treat. Sleep and circadian dysfunctions are prominent correlates of SMI, yet have been minimally studied in ways that reflect the complexity of the sleep problems experienced. Prior treatment studies have been disorder-focused-they have treated a specific sleep problem in a specific diagnostic group. However, real life sleep and circadianproblems are not so neatly categorized, particularly in SMI where features of insomnia overlap with hypersomnia, delayed sleep phase and irregular sleep-wake schedules. Accordingly, the aim of this studyprotocol is to test the hypothesis that a Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) will improve functional impairment, disorder-focused symptoms and sleep and circadian functioning. Participants across DSM diagnoses and across common sleep and circadian problems are eligible. The elements of TranS-C are efficacious across SMI in research settings with research-based providers. The next step is to test TranS-C in a community setting. Accordingly, this study is being conducted within Alameda County Behavioral Health Care Services (ACBHCS), the Community Mental Health Centre (CMHC) for Alameda County.120 adults diagnosed with SMI and sleep and circadian dysfunction within ACBHCS will be randomly allocated to TranS-C (n = 60) or 6-months of Usual Care followed by Delayed Treatment with TranS-C (UC-DT; n = 60). TranS-C is modularized and delivered across eight to twelve 50-minute, weekly, individual sessions. All participants will be assessed before and immediately following treatment and again 6 months later. Primary analysis will examine whether TranS-C significantly improves functional impairment, disorder-specific symptoms and sleep and circadian functioning, relative to UC-DT. Exploratory analysis will examine whether improvements in sleep and circadian functioning predict reduction in functional impairment and disorder-specific symptoms, and whether the intervention effects are mediated by improved sleep and circadian functioning and moderated by previously reported risk factors (demographics, symptom severity, medications, psychiatric and medical comorbidity).	This trial tests an important and understudied mechanism-dysregulated sleep and circadian rhythms-in SMI, a novel transdiagnostic treatment approach, in a community setting so as to contribute to the goal of bridging the gap between research and practice.	
27997888	Ras dexamethasone-induced protein (RASD1) is a member of Ras superfamily of small GTPases. RASD1 regulates various signaling pathways involved in iron homeostasis, growth hormone secretion, and circadian rhythm. However, RASD1 function in oocyte remains unknown.Using immunohistochemistry, immunofluorescence, and quantitative real-time RT-PCR, RASD1 expression in mouse ovary and RASD1 role in oocyte maturation-related gene expression, spindle formation, and chromosome alignment were analyzed. RNAi microinjection and time-lapse video microscopy were used to examine the effect of Rasd1 knockdown on oocyte maturation.	RASD1 was highly detected in oocytes transitioning from primordial to secondary follicles. Rasd1 was highly expressed in germinal vesicle (GV), during GV breakdown, and in metaphase I (MI) stage as oocytes mature, and its expression was significantly downregulated in MII stage. With knockdown of Rasd1, maturation in GV oocytes was arrested at MI stage, showing disrupted meiotic spindling and chromosomal misalignment. In addition, Obox4 and Arp2/3, engaged in MI-MII transition and cytokinesis, respectively, were misregulated in GV oocytes by Rasd1 knockdown.	These findings suggest that RASD1 is a novel factor in MI-MII oocyte transition and may be involved in regulating the progression of cytokinesis and spindle formation, controlling related signaling pathways during oocyte maturation.	
27997348	Disturbance of the circadian rhythm has been associated with disease states, such as metabolic disorders, depression and cancer. Quantification of the circadian markers such as melatonin and cortisol critically depend on reliable and reproducible analytical methods. Previously, melatonin and cortisol were primarily analyzed separately, mainly using immunoassays.Here we describe the validation and application of a high-throughput liquid chromatography in combination with mass spectrometry (LC-MS/MS) method for the combined analysis of melatonin and cortisol in plasma and saliva. The LC-MS/MS method was validated according to international validation guidelines. We used this method to analyze total plasma, free plasma (as obtained by equilibrium dialysis) and saliva melatonin and cortisol in healthy adults.	Validation results for plasma and saliva melatonin and cortisol were well within the international validation criteria. We observed no difference between saliva collected by passive drooling or Salivette. Moreover, we noted a significant difference in saliva vs. free plasma melatonin. We observed on average 36% (95% CI: 4%-60%) higher salivary melatonin levels in comparison to free plasma melatonin, suggestive of local production of melatonin in the salivary glands.	The novel outcome of this study is probably due to the high precision of our LC-MS/MS assay. These outcomes illustrate the added value of accurate and sensitive mass spectrometry based methods for the quantification of neuroendocrine biomarkers.	
27997334	Kisspeptin is crucial for the generation of the circadian-gated preovulatory gonadotrophin-releasing hormone (GnRH)-LH surge in female rodents, with expression in the anteroventral periventricular nucleus (AVPV) peaking in the late afternoon of pro-oestrus. Given kisspeptin expression is established before puberty, the aim of the present study was to investigate kisspeptin and clock gene rhythms during the neonatal period. Anterior and posterior hypothalami were collected from C57BL/6J mice on Postnatal Days (P) 5, 15 and 25, at six time points across 24h, for analysis of gene expression by reverse transcription-quantitative polymerase chain reaction. Expression of aryl hydrocarbon receptor nuclear translocator-like gene (Bmal1) and nuclear receptor subfamily 1, group D, member 2 (Rev-erbα) in the anterior hypothalamus (containing the suprachiasmatic nucleus) was not rhythmic at P5 or P15, but Bmal1 expression exhibited rhythmicity in P25 females, whereas Rev-erbα expression was rhythmic in P25 males. KiSS-1 metastasis-suppressor (Kiss1) expression did not exhibit time-of-day variation in the anterior (containing the AVPV) or posterior (containing the arcuate nucleus) hypothalami in female and male mice at P5, P15 or P25. The data indicate that the kisspeptin circadian peak in expression observed in the AVPV of pro-oestrous females does not manifest at P5, P15 or P25, likely due to inadequate oestrogenic stimuli, as well as incomplete development of clock gene rhythmicity before puberty.
27997226	Hepatocellular carcinoma (HCC) is the major threat to human health, and disruption of circadian clock genes is implicated in hepatocarcinogenesis. This study examined the dysregulation of metallothioneins and circadian genes in achieved human HCC (n = 24), peri-HCC tissues (n = 24) as compared with normal human livers (n = 36). Total RNA was extracted and reverse transcribed. Real-time RT-qPCR was performed to determine the expression of genes of interest. The results demonstrated the downregulation of metallothionein-1 (MT-1), MT-2, and metal transcription factor-1 (MFT-1) in human HCC as compared with Peri-HCC and normal tissues. MTs are a biomarker for HCC and have typical circadian rhythms; the expression of major circadian clock genes was also determined. HCC produced a dramatic decrease in the expression of core clock genes, circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein 1 (Bmal1), and decreased the expression of the clock feedback control genes, Periods (Per1, Per2) and Cryptochromes (Cry1, Cry2). On the other hand, the expression of clock target genes nuclear orphan receptor factor protein (Nr1d1) and D-box-binding protein (Dbp) was upregulated as compared with Peri-HCC and normal livers. Peri-HCC also had mild alterations in these gene expressions. In summary, the present study clearly demonstrated the dysregulation of MTs and circadian clock genes in human HCC, which could provide the information of targeting MT and circadian clock in HCC management.
27997028	Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus, a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol [EtOH]) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether EtOH has similar effects on circadian regulation during adolescence.General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12-hour light, 12-hour dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of EtOH (1.5 g/kg, i.p.) or equal volume saline 15 minutes prior to a 30-minute light pulse at Zeitgeber Time 14 (2 hours into the dark phase) and then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age-group received injections but no light pulse prior to DD.	While adults showed the expected decrease in photic phase-delays induced by acute EtOH, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude.	Collectively, our results indicate that adolescent mice are less sensitive to the effect of EtOH on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults.	
27996309	ABSRACT Exposure to artificial light at night (ALAN) has been reported to be associated with various pathological changes including sleep deprivation, circadian rhythm disruption, and melatonin suppression with increase in various cancers such as breast or prostate cancers. In this study, we sought to elucidate the association between ALAN and prostate cancer in 27 districts within Gwangju City and urban and rural areas from South Jeolla Province in South Korea. We analyzed the correlation between ALAN and the incidence of a range of cancers by Poisson regression analysis, after adjustment for confounding risk factors, such as smoking, drinking, obesity, stress, air pollution (particulate matter <10 μm in diameter), urbanization (proportion of urbanized area), and the cancer screening rate. Interestingly, the incidence of prostate cancer was significantly associated with ALAN (risk ratio = 1.02, p = 0.0369) and urbanization (risk ratio = 1.06, p = 0.0055). In particular, comparing the prostate cancer incidence at 25% and 75% level of ALAN, the risk ratio was 1.726 (12.6 over 7.3, respectively). No significant association was observed between ALAN and other cancers, including stomach, esophageal, liver, pancreatic, laryngeal, lung and tracheal, bladder, and brain and central nervous system cancers, as well as lymphoma and multiple myeloma. In conclusion, this study shows that a high incidence of prostate cancer may be independently associated with light pollution and urbanization, which represent significant factors in the rapid process of industrialization of South Korea.
27996307	Human genetic studies have implicated specific genes that constitute the molecular clock in the manifestation of bipolar disorder (BD). Among the clock genes involved in the control system of circadian rhythms, CLOCK 3111 T/C and Period3 (PER3) influence core psychopathological features of mood disorders, such as patterns of sleep, rest, and activity, diurnal preference, cognitive performances after sleep loss, age at the onset of the illness, and response to antidepressant treatment. Furthermore, several studies pointed out that bipolar symptomatology is associated with dysfunctions in white matter (WM) integrity, suggesting these structural alterations as a possible biomarker of the disorder. We hypothesise that CLOCK and PER3 polymorphisms could be potential factors affecting WM microstructure integrity in bipolar patients. The relationship between these clock genes and DTI measures of WM integrity in a sample of 140 (53 M; 87 F) patients affected by BD type I was studied. Tract-based spatial statistics analyses on DTI measures of WM integrity were performed for each clock gene polymorphism, between the genetic groups. We accounted for the effect of nuisance covariates known to influence WM microstructure: age, sex, lithium treatment, age at the onset of the illness, and the number of illness episodes. We found that compared to T homozygotes, CLOCK C carriers showed a widespread increase of the mean diffusivity in several WM tracts. Compared with PER35/5 homozygotes, PER34/4 homozygotes showed significantly increased radial diffusivity and reduced fractional anisotropy in several brain WM tracts. No significant difference was observed between heterozygotes and the other subgroups. Altogether, this pattern of results suggests WM disruption in CLOCK C carrier and in PER34 homozygotes. Sleep promotes myelination and oligodendrocyte precursor cell proliferation and associates with higher expression of genes coding for phospholipid synthesis and myelination in oligodendrocytes. These clock genes play a pivotal role in maintaining circadian rhythms and the sleep-wake cycle. Thus, it may be suggested that CLOCK rs1801260*C and PER34/4 influence myelination processes by regulating sleep quality and quantity.
27995565	Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.
27995329	In this exploratory case-control study, we investigated basal cortisol regulation in 5-16-year-old children, 3-6 months following PICU (paediatric intensive care) admission. This was nested within a study of child psychological and cognitive function; 47 children were assessed alongside 56 healthy controls. Saliva samples were collected three times per day (immediately after waking, waking +30 min, and waking +12 h) over two consecutive weekdays. In addition, data on posttraumatic stress symptoms were ascertained from 33 PICU admitted children using the Impact of Events Scale-8 (IES-8). Primary analysis revealed no significant differences in basal cortisol concentrations between PICU discharged children and healthy controls (p > 0.05). Secondary analysis in the PICU group identified a significant positive association between posttraumatic stress symptoms and evening (waking +12 h) cortisol concentrations (p = 0.004). However, when subject to multivariate analysis, evening cortisol was a modest independent predictor of IES-8 scores, relative to the presence of septic illness and poor pre-morbid health. We conclude that paediatric critical illness does not appear to result in marked perturbations to basal cortisol at 3-6 month following discharge. There was evidence of a link between evening cortisol and symptoms of PTSD, but this was not a robust effect and requires further elucidation.
27992627	Recent studies found that the concentration of amyloid-β (Aβ) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of Aβ kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied.To determine the association between Aβ kinetics, age, amyloid levels, and the Aβ day/night pattern in humans.	We measured Aβ concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of Aβ40 and Aβ42 were measured.	Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine.	The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid Aβ concentrations and Aβ turnover rates.	Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in Aβ concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: Aβ40, -7.42 pM; P < .001; Aβ42, -3.72 pM; P < .001). Amyloid deposition diminished day/night amplitude and linear increase of Aβ42 but not of Aβ40. Increased age diminished day/night amplitude of both Aβ40 and Aβ42. After controlling for amyloid deposition, amplitude of Aβ40 was positively associated with production rates (r = 0.42; P < .001), while the linear rise was associated with turnover rates (r = 0.28; P < .05). The amplitude and linear rise of Aβ42 were both associated with turnover (r = -0.38; P < .001) and production (r = 0.238; P < .05) rates.	Amyloid deposition is associated with premature loss of normal Aβ42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on Aβ42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night Aβ patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.	
27992553	Light is a powerful entrainer of circadian clocks in almost all eukaryotic organisms promoting synchronization of internal circadian rhythms with external environmental light-dark (LD) cycles. In mammals, the circadian system is organized in a hierarchical manner, in which a central pacemaker in the suprachiasmatic nucleus (SCN) synchronizes oscillators in peripheral tissues. Recent evidence demonstrates that photoentrainment of the SCN proceeds via signaling from a subpopulation of retinal ganglion cells (RGCs) which are melanopsin-expressing and intrinsically photosensitive (ipRGCs). However, it is still unclear whether photoentrainment of peripheral clocks is mediated exclusively by the ipRGC system or if signaling from RGCs that do not express melanopsin also plays a role. Here we have used genetic "silencing" of ipRGC neurotransmission in mice to investigate whether this photoreceptive system is obligatory for the photoentrainment of peripheral circadian clocks. Genetic silencing of ipRGC neurotransmission in mice was achieved by expression of tetanus toxin light chain in melanopsin-expressing cells (Opn4::TeNT mouse line). Rhythms of the clock gene Period 2 in various peripheral tissues were measured by crossbreeding Opn4::TeNT mice with PER2 luciferase knock-in mice (mPER2Luc). We found that in Opn4::TeNT mice the pupillary light reflex, light modulation of activity, and circadian photoentrainment of locomotor activity were severely impaired. Furthermore, ex vivo cultures from Opn4::TeNT, mPER2Luc mice of the adrenal gland, cornea, lung, liver, pituitary and spleen exhibited robust circadian rhythms of PER2::LUC bioluminescence. However, their peak bioluminescence rhythms were not aligned to the projected LD cycles indicating their lack of photic entrainment in vivo. Finally, we found that the circadian rhythm in adrenal corticosterone in Opn4::TeNT mice, as monitored by in vivo subcutaneous microdialysis, was desynchronized from environmental LD cycles. Our findings reveal a non-redundant role of ipRGCs for photic entrainment of peripheral tissues, highlighting the importance of this photoreceptive system for the organismal adaptation to daily environmental LD cycles.
27992087	Glutamate phase shifts the circadian clock in the mammalian suprachiasmatic nucleus (SCN) by activating NMDA receptors. Tissue-type plasminogen activator (tPA) gates phase shifts by activating plasmin to generate m(ature) BDNF, which binds TrkB receptors allowing clock phase shifts. Here, we investigate phase shifting in tPA knockout (tPA-/- ; B6.129S2-Plattm1Mlg /J) mice, and identify urokinase-type plasminogen activator (uPA) as an additional circadian clock regulator. Behavioral activity rhythms in tPA-/- mice entrain to a light-dark (LD) cycle and phase shift in response to nocturnal light pulses with no apparent loss in sensitivity. When the LD cycle is inverted, tPA-/- mice take significantly longer to entrain than C57BL/6J wild-type (WT) mice. SCN brain slices from tPA-/- mice exhibit entrained neuronal activity rhythms and phase shift in response to nocturnal glutamate with no change in dose-dependency. Pre-treating slices with the tPA/uPA inhibitor, plasminogen activator inhibitor-1 (PAI-1), inhibits glutamate-induced phase delays in tPA-/- slices. Selective inhibition of uPA with UK122 prevents glutamate-induced phase resetting in tPA-/- but not WT SCN slices. tPA expression is higher at night than the day in WT SCN, while uPA expression remains constant in WT and tPA-/- slices. Casein-plasminogen zymography reveals that neither tPA nor uPA total proteolytic activity is under circadian control in WT or tPA-/- SCN. Finally, tPA-/- SCN tissue has lower mBDNF levels than WT tissue, while UK122 does not affect mBDNF levels in either strain. Together, these results suggest that either tPA or uPA can support photic/glutamatergic phase shifts of the SCN circadian clock, possibly acting through distinct mechanisms.

27991858	During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.	The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.	A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.	
27990327	This review summarizes recent developments relevant to the treatment of circadian rhythm sleep-wake disorders. The clinical practice guidelines for the treatment of intrinsic circadian rhythm sleep-wake disorders is described, followed by recent treatment studies for delayed sleep-wake phase disorder, non-24 hour sleep-wake disorder, irregular sleep-wake disorder and shift work. New methods to estimate circadian phase, including home saliva collection to estimate the dim light melatonin onset, circadian questionnaires and general rules to guide light and exogenous melatonin treatments are described. New developments in light treatment are detailed, including light flashes during sleep and wearable light devices. Substances such as caffeine and alcohol, and devices such as electronic tablets are also considered for their potential to shift circadian timing. Finally, an update on melatonin supplements in the US is discussed, along with the controversy surrounding the use of melatonin supplements in patients with prediabetes or diabetes.
27988807	Light is the strongest synchronizer controlling circadian rhythms. The intensity and duration of light change throughout the year, thereby influencing body weight, food preferences, and melatonin secretion in humans and animals. Although the expression of clock genes has been examined using human samples, it currently remains unknown whether bright light during the daytime affects the expression of these genes in humans. Therefore, we herein investigated the effects of bright light exposure during the daytime on clock gene expression in the hair follicular and root cells of the human scalp. Seven healthy men (20.4 ± 2.2 years old; 172.3 ± 5.8 cm; 64.3 ± 8.5 kg; BMI 21.7 ± 3.1 kg/m2, mean ± SD) participated in this study. Subjects completed 3-day experimental sessions twice in 1 month during which they were exposed to bright and dim light conditions. The mRNA expression of Per1-3, Cry1-2, Rev-erb-α (Nr1d1), Rev-erb-β (Nr1d2), and Dec1 was analyzed using branched DNA probes. No significant changes were observed in the expression of Per1, Per2, Per3, Cry1, Cry2, Rev-erb-α (Nr1d1), or Dec1 following exposure to bright light conditions. However, the expression of Rev-erb-β (Nr1d2) tended to be stronger under bright light than dim light conditions. These results suggest that the bright light stimulus did not influence the expression of clock genes in humans. Long-lasting bright light exposure during the daytime may be required to change the expression of clock genes in humans.
27987529	Melatonin is synthesized in the pineal gland and controls circadian rhythm of peripheral adipose tissue, resulting in changes in body weight. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms of circadian rhythm-mediated proliferation in adipose tissue is still limited. Here, we showed that melatonin (20 mg/kg/d) promoted circadian and proliferation processes in white adipose tissue. The circadian amplitudes of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1, P<.05) and circadian locomotor output cycles kaput (Clock, P<.05), period 2 (Per2, P<.05), cyclin E (P<.05), and c-Myc (P<.05) were directly increased by melatonin in adipose tissue. Melatonin also promoted cell cycle and increased cell numbers (P<.05), which was correlated with the Clock expression (P<.05). Further analysis demonstrated that Clock bound to the E-box elements in the promoter region of c-Myc and then directly stimulated c-Myc transcription. Moreover, Clock physically interacted with histone deacetylase 3 (HDAC3) and formed a complex with c-Myc to promote adipocyte proliferation. Melatonin also attenuated circadian disruption and promoted adipocyte proliferation in chronic jet-lagged mice and obese mice. Thus, our study found that melatonin promoted adipocyte proliferation by forming a Clock/HDAC3/c-Myc complex and subsequently driving the circadian amplitudes of proliferation genes. Our data reveal a novel mechanism that links circadian rhythm to cell proliferation in adipose tissue. These findings also identify a new potential means for melatonin to prevent and treat sleep deprivation-caused obesity.
27987432	Molecular processes involved in photosystem II adaptation of woody species to diurnal changes in light and temperature conditions are still not well understood. Regarding this, here we investigated differences between young and mature leaves of common fig (Ficus carica L.) in photosynthetic performance as well as accumulation of the main photosynthetic proteins: light harvesting complex II, D1 protein and Rubisco large subunit. Investigated leaf types revealed different adjustment mechanisms to keep effective photosynthesis. Rather stable diurnal accumulation of light harvesting complex II in mature leaves enabled efficient excitation energy utilization (negative L-band) what triggered faster D1 protein degradation at high light. However, after photoinhibition, greater accumulation of D1 during the night enabled them faster recovery. So, the most photosynthetic parameters, as the maximum quantum yield for primary photochemistry, electron transport and overall photosynthetic efficiency in mature leaves successfully restored to their initial values at 1a.m. Reduced connectivity of light harvesting complexes II to its reaction centers (positive L-band) in young leaves increased dissipation of excess light causing less pressure to D1 and its slower degradation. Decreased electron transport in young leaves, due to reduced transfer beyond primary acceptor QA- most probably additionally induced degradation of Rubisco large subunit what consequently led to the stronger decrease of overall photosynthetic efficiency in young leaves at noon.
27981774	Previous studies have shown that elderly patients (age ≥65 years) are less likely to be admitted to the intensive care unit following a rapid response team call and have high hospital mortality rates. This study has shown that elderly patients have a significantly higher probability of being admitted to an intensive care unit following a rapid response team call at night than during the day. However, at no time are they at greater risk than younger patients of incomplete vital sign recording, a failure to escalate care for acute deterioration or mortality.
27981356	In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.
27980711	The C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice. In hearts from male C57BL/6J.YA/J and C57BL/6J mice, orchidectomy (ORX) affected in a strictly strain-specific fashion the expression a subset of genes showing enrichment for functional categories, including that of circadian rhythms and cardiac contractility. We further tested whether: (1) there were strain-specific differences in cardiac circadian rhythms; (2) strain-dependent differences in the effects of ORX on contractility genes translated into differences in cardiac functions; and (3) differential contractility responses occurred preferentially at times when circadian rhythms also showed strain-specific differences.In hearts from the two above strains, we (1) profiled the expression levels of 15 circadian genes at 4-h intervals across a 24 h period; (2) tested the effects of either ORX or androgen replacement on expression of cardiac contractility genes, and that of ORX on myocardial functional reserve; and (3) verified whether the effects of MSY variants on cardiac contractility-related responses showed synchronicity with differences in circadian rhythms.	Among the 15 tested circadian genes, a subset of them were affected by strain (and thus the genetic origin of MSY), which interacted with the amplitude of their peak of maximal expression at 2:00 PM. At that same time-point, ORX decreased (and androgen supplementation increased) the expression of three contractility-related genes, and decreased myocardial relaxation reserve in C57BL/6J.YA/J, but not in C57BL/6J mice. These effects were not detected at 10:00 AM, i.e., at another time-point when circadian genes showed no strain-specific differences.	The results indicate that in mice, androgens have activational effects on cardiac circadian rhythms, contractile gene expression, and myocardial functional reserve. All effects occurred preferentially at the same time of the day, but varied as a function of the genetic origin of MSY. Androgens may therefore be necessary but not sufficient to impart male-specific characteristics to some particular cardiac functions, with genetic material from MSY being one other necessary factor to fully define their range of actions.	
27980224	Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending.
27979876	Circadian clocks regulate much of behavior and physiology, but the mechanisms by which they do so remain poorly understood. While cyclic gene expression is thought to underlie metabolic rhythms, little is known about cycles in cellular physiology. We found that Drosophila insulin-producing cells (IPCs), which are located in the pars intercerebralis and lack an autonomous circadian clock, are functionally connected to the central circadian clock circuit via DN1 neurons. Insulin mediates circadian output by regulating the rhythmic expression of a metabolic gene (sxe2) in the fat body. Patch clamp electrophysiology reveals that IPCs display circadian clock-regulated daily rhythms in firing event frequency and bursting proportion under light:dark conditions. The activity of IPCs and the rhythmic expression of sxe2 are additionally regulated by feeding, as demonstrated by night feeding-induced changes in IPC firing characteristics and sxe2 levels in the fat body. These findings indicate circuit-level regulation of metabolism by clock cells in Drosophila and support a role for the pars intercerebralis in integrating circadian control of behavior and physiology.
27979046	Blunted nighttime blood pressure (BP) dipping is prognostic of cardiovascular morbidity and mortality. Patients with coronary heart disease (CHD) are often characterized by a blunted nighttime BP dipping pattern. The present study compared the effects of 2 behavioral intervention programs, aerobic exercise (EX) and stress management (SM) training, with a usual care (UC) control group on BP dipping in a sample of CHD patients.This was a secondary analysis of a randomized, controlled trial with allocation concealment and blinded outcome assessment in 134 patients with stable CHD and exercise-induced myocardial ischemia. Nighttime BP dipping was assessed by 24-hour ambulatory BP monitoring, at prerandomization baseline and after 16 weeks of one of the following treatments: usual medical care; UC plus supervised aerobic EX for 35 minutes, 3 times per week; UC plus weekly 1.5-hour sessions of SM training.	The EX and SM groups exhibited greater improvements in systolic BP dipping (P=.052) and diastolic BP dipping (P=.031) compared with UC. Postintervention systolic BP percent-dipping means were 12.9% (SE=1.5) for SM, 11.1% (SE=1.4) for EX, and 8.6% (SE=1.4) for UC. Postintervention diastolic BP percent-dipping means were 13.3% (SE=1.9) for SM, 14.1% (SE=1.8) for EX, and 8.8% (1.8) for UC.	For patients with stable CHD, EX or SM training resulted in improved nighttime BP dipping compared with usual medical care. These favorable effects of healthy lifestyle modifications may help reduce the risk of adverse clinical events.	
27977405	The objective of this study was to compare the analysis of 17-hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) in serum with analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) on dried blood spot samples (DBSS) for monitoring therapy in children with congenital adrenal hyperplasia (CAH), and to investigate differences in 17-OHP values during the day.Fourteen children (8 females), median age 4.2 (0.3-16.0) years, were studied. Serum samples and DBSS were drawn before hydrocortisone dosing.	17-OHP by LC-MS/MS in DBSS were highly correlated to 17-OHP by RIA in serum, r=0.956, p<0.01. A total of 26 three-time-point series were investigated. Using only the afternoon 17-OHP values to determine the hydrocortisone doses would have led to overdosing seven times and underdosing six times.	Good agreement was demonstrated between 17-OHP determination by RIA in serum and LC-MS/MS on DBSS. Multiple 17-OHP measurements per day are required to ensure sufficient hydrocortisone dose adjustment.	
27976750	Background  Disruption of rhythms in activity and rest occur in many diseases, and provide an important indicator of healthy physiology and behaviour. However, outside the field of sleep and circadian rhythm research, these rhythmic processes are rarely measured due to the requirement for specialised resources and expertise. Until recently, the primary approach to measuring activity in laboratory rodents has been based on voluntary running wheel activity. By contrast, measuring sleep requires the use of electroencephalography (EEG), which involves invasive surgical procedures and time-consuming data analysis. Methods Here we describe a simple, non-invasive system to measure home cage activity in mice based upon passive infrared (PIR) motion sensors. Careful calibration of this system will allow users to simultaneously assess sleep status in mice. The use of open-source tools and simple sensors keeps the cost and the size of data-files down, in order to increase ease of use and uptake. Results In addition to providing accurate data on circadian activity parameters, here we show that extended immobility of >40 seconds provides a reliable indicator of sleep, correlating well with EEG-defined sleep (Pearson's r >0.95, 4 mice).  Conclusions Whilst any detailed analysis of sleep patterns in mice will require EEG, behaviourally-defined sleep provides a valuable non-invasive means of simultaneously phenotyping both circadian rhythms and sleep. Whilst previous approaches have relied upon analysis of video data, here we show that simple motion sensors provide a cheap and effective alternative, enabling real-time analysis and longitudinal studies extending over weeks or even months. The data files produced are small, enabling easy deposition and sharing. We have named this system COMPASS - Continuous Open Mouse Phenotyping of Activity and Sleep Status. This simple approach is of particular value in phenotyping screens as well as providing an ideal tool to assess activity and rest cycles for non-specialists.
27975357	There would be no life without light. The rotation of the earth around its axis has introduced the development of biological clocks in all living subjects regulating all functions of the body. The rhythms best described are the 24-hour/circadian and the seasonal rhythms. The rhythmic composition around the body clock has great impact on health and disease, both in diagnostics and treatment. Nowadays, bright light, e.g. in seasonal affective disorder, can be regarded as a drug, being even more effective than selective serotonin reuptake inhibitors.
27974202	In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network.
27974043	The Germanwings Flight 9525 crash has brought the sensitive subject of airline pilot mental health to the forefront in aviation. Globally, 350 million people suffer from depression-a common mental disorder. This study provides further information on this important topic regarding mental health especially among female airline pilots. This is the first study to describe airline pilot mental health-with a focus on depression and suicidal thoughts-outside of the information derived from aircraft accident investigations, regulated health examinations, or identifiable self-reports, which are records protected by civil aviation authorities and airline companies.This is a descriptive cross-sectional study via an anonymous web-based survey administered between April and December 2015. Pilots were recruited from unions, airline companies, and airports via convenience sampling. Data analysis included calculating absolute number and prevalence of health characteristics and depression scores.	One thousand eight hundred thirty seven (52.7%) of the 3485 surveyed pilots completed the survey, with 1866 (53.5%) completing at least half of the survey. 233 (12.6%) of 1848 airline pilots responding to the Patient Health Questionnaire 9 (PHQ-9), and 193 (13.5%) of 1430 pilots who reported working as an airline pilot in the last seven days at time of survey, met depression threshold-PHQ-9 total score ≥ 10. Seventy-five participants (4.1%) reported having suicidal thoughts within the past two weeks. We found a significant trend in proportions of depression at higher levels of use of sleep-aid medication (trend test z = 6.74, p < 0.001) and among those experiencing sexual harassment (z = 3.18, p = 0.001) or verbal harassment (z = 6.13, p < 0.001).	Hundreds of pilots currently flying are managing depressive symptoms perhaps without the possibility of treatment due to the fear of negative career impacts. This study found 233 (12.6%) airline pilots meeting depression threshold and 75 (4.1%) pilots reporting having suicidal thoughts. Although results have limited generalizability, there are a significant number of active pilots suffering from depressive symptoms. We recommend airline organizations increase support for preventative mental health treatment. Future research will evaluate additional risk factors of depression such as sleep and circadian rhythm disturbances.	
27966533	Arabidopsis adapts to elevated temperature by promoting stem elongation and hyponastic growth through a temperature-responsive transcription factor PIF4. Here we show that the evening-expressed clock component TOC1 interacts with and inactivates PIF4, thereby suppressing thermoresponsive growth in the evening. We find that the expression of PIF4 target genes show circadian rhythms of thermosensitivity, with minimum responsiveness in the evening when TOC1 level is high. Loss of function of TOC1 and its close homologue PRR5 restores thermosensitivity in the evening, whereas TOC1 overexpression causes thermo insensitivity, demonstrating that TOC1 mediates the evening-specific inhibition of thermoresponses. We further show that PIF4 is required for thermoadaptation mediated by moderately elevated temperature. Our results demonstrate that the interaction between TOC1 and PIF4 mediates the circadian gating of thermoresponsive growth, which may serve to increase fitness by matching thermoresponsiveness with the day-night cycles of fluctuating temperature and light conditions.
27966269	To compare the long-term effect on circadian photoentrainment and sleep in patients implanted with neutral and blue-blocking intraocular lenses 1 year after cataract surgery.Randomized, controlled trial involving 67 patients with age-related cataract. Intervention was cataract surgery with implantation of either a neutral or a blue-blocking intraocular lens (IOL). Main outcome was activation of the intrinsically photosensitive retinal ganglion cells (ipRGC) measured by chromatic pupillometry. The circadian rhythm was analysed by 24-hr melatonin profiles and actigraphy; the latter was also used to determine objective sleep quality. The Pittsburgh Sleep Quality Index determined subjective sleep quality.	One year after surgery, peak melatonin concentration was 3.3 pg/ml (95% CI, 2-5.5) corresponding to 50% lower for the participants allocated to blue-blocking IOLs compared with participants allocated to neutral IOLs. Compared with preoperative levels, the ipRGC response had increased by 13.7% (95% confidence interval [CI], 3.2-22.6) 1 year after surgery. Objective sleep quality was also improved as the time of wakefulness after sleep onset had improved by 5 min (95% CI, 1-10) for the entire population while sleep efficiency had increased by two percentage points (95% CI, 0.42-3.65) although exclusively, for the participants allocated to blue-blocking IOLs.	Blue-blocking IOLs increased sleep efficiency but lowered nocturnal melatonin secretion compared with neutral IOLs. Cataract surgery improved the response of ipRGCs and sleep quality. However, the effect of cataract surgery on sleep quality may be unrelated to circadian photoentrainment.	
27964860	To characterize the patterns of light exposure and physical activity level and assess their relationship with sleep quality and depressive symptoms in adults with delayed sleep-wake phase disorder (DSWPD).42 DSWPD (22 female, mean age 34.5 y) and 26 (±4 years) age-and-sex-matched controls (12 female, mean age 33.4 y) underwent seven days of light and activity monitoring.	Individuals with DSWPD had significantly delayed bed times and wake times, but similar sleep duration compared to controls. Subjective sleep quality (Pittsburgh Sleep Quality Index (PSQI)) was poorer in DSWPDs compared to controls. Those with DSWPD had significantly more activity and light exposure late at night (2:00-4:00) and significantly less activity and light exposure in the morning (8:00-11:00). Total 24 h levels of light and activity were not significantly different between DSWPD and controls. However, the DSWPD group had significantly more light exposure than controls 22 h after waking, during their sleep period. Later light exposure correlated with higher depression scores [Beck Depression Index (BDI)] and poorer sleep quality (PSQI).	The light exposure patterns observed in DSWPD likely contribute to and perpetuate the chronically delayed sleep and wake phase in these patients. In addition, increased light exposure during the sleep period may also contribute to the poor sleep quality and mood disorders that are common in these individuals.	
27960079	In this issue of Cancer Cell, Kettner et al. identify the disruption of normal circadian rhythmicity as an independent risk factor for hepatocellular carcinoma (HCC) in experimental animals and reveal opposing roles for the nuclear receptors FXR and CAR in disease progression from non-alcoholic fatty liver disease (NAFLD) to HCC.
27959943	To characterize the 24-h habitual-position intraocular pressure (IOP) patterns of optic disc phenotypes (ODPs) in untreated normal-tension glaucoma (NTG) and the relationships between nocturnal IOP elevation and various clinical factors.Prospective, cross-sectional, observational study.	Eighty-two NTG patients with focal ischemic (FI) ODP and 82 age- and disease severity-matched NTG patients with myopic glaucomatous (MG) ODP were recruited prospectively over 3 years. The IOP was recorded 11 times over a 24-hour (h) period by a single ophthalmologist using a hand-held tonometer (TonoPen®XL). A cosinor model was used to describe the 24-h IOP rhythm. Associations between nocturnal IOP elevation and both ocular and demographic variables were evaluated using the generalized estimating equation (GEE).	Mean habitual-position IOP was significantly higher during nighttime than daytime in the FI group (16.44 vs. 14.23 mmHg, P < 0.001), but not in the MG group (15.91 vs. 15.70 mmHg, P = 0.82). The FI group also exhibited a significantly higher peak IOP during sleeping hours (P = 0.01) and lower trough IOP during the 24-h period than the MG group (P < 0.01). The MG group showed a significantly higher peak IOP during waking hours than the FI group (P < 0.01). Therefore, 24-h IOP fluctuation range was significantly higher in the FI group than the MG group (P = 0.013). In the FI group, peak habitual-position IOP and the highest frequency of IOP peaks occurred during sleeping hours (12 AM-6 AM). By contrast, IOP peaks in the MG group occurred during morning hours (8 AM-12 PM). The FI group showed an overall nocturnal acrophase in habitual-position IOP, with 45 patients (54.9%) having a nocturnal acrophase; 10 (12.2%), a diurnal acrophase; and 27 (32.9%), no evident acrophase. By contrast, the MG group showed no evident peak in habitual-position IOP, with 9 patients (10.9%) having a nocturnal acrophase; 43 (52.4%), a diurnal acrophase; and 30 (36.6%), no evident acrophase. In multivariate modeling using the GEE, ODP (P < 0.001) and spherical equivalent (SE, P = 0.001) were independently associated with nocturnal IOP elevation.	Based on 24-h habitual-position IOP data, FI is associated with significant nocturnal IOP elevation, while no such nocturnal IOP elevation is observed in MG ODP. In untreated NTG, there are also significant differences in the 24-h IOP pattern between FI and MG ODPs.	
27957809	Ecological interactions between flowers and pollinators are all about timing. Flower opening/closing and scent emissions are largely synchronized with pollinator activity, and a circadian clock regulates these rhythms. However, whether the circadian clock increases a plant's reproductive success by regulating these floral rhythms remains untested. Flowers of Nicotiana attenuata, a wild tobacco, diurnally and rhythmically open, emit scent and move vertically through a 140° arc to interact with nocturnal hawkmoths. We tethered flowers to evaluate the importance of flower positions for Manduca sexta-mediated pollinations; flower position dramatically influenced pollination. We examined the pollination success of phase-shifted flowers, silenced in circadian clock genes, NaZTL, NaLHY, and NaTOC1, by RNAi. Circadian rhythms in N. attenuata flowers are responsible for altered seed set from outcrossed pollen.
27956169	Diapause (also known as dormancy) is a state of arrested development induced by photoperiod or temperature that allows insects to survive adverse environmental conditions. By regulating diapause induction, the circadian clock is involved in short-day-induced winter diapause but whether this is also the case in long-day (LD)-induced summer diapause remains unknown. The cabbage beetle Colaphellus bowringi could enter summer diapause under LD conditions. However, a non-photoperiodic-diapause (NPD) strain of this species, which was developed in our laboratory by artificial selection, could not enter diapause under LD photoperiod. Therefore, we identified circadian clock genes in this species and measured differences in their expression between a high diapause (HD) strain and the NPD strain to investigate the potential relationship between circadian clock genes and summer diapause induction in C. bowringi. We successfully cloned eight circadian clock genes and obtained intact ORFs of four; cryptochrome2, double-time, shaggy and vrille. Phylogenetic trees and sequence alignment analyses indicated that these circadian clock genes were conserved across insect taxa. The quantitative real-time PCR indicated that clock, cycle, period, timeless, cryptochrome2, and vrille were differentially expressed between HD and NPD strains reared under LD photoperiod during the diapause induction phase. These findings suggest the potential relationship between circadian clock genes and LD-regulated summer diapause induction in C. bowringi.
27943459	Neural stem cells (NSCs) are immature precursors of the central nervous system (CNS), with self-renewal and multipotential differentiation abilities. Their proliferation and differentiation are dynamically regulated by hormonal and local factors. Alteration in neurogenesis is associated with many neurological disorders. Increasing evidence suggests that modulation of NSCs can be a promising therapeutic approach for neural injury and neurodegenerative disorders. Melatonin, a pineal gland-derived hormone, regulates the neuroimmuno-endocrine axis and is functionally important to the circadian rhythm, tumour suppression and immunity. In the CNS, melatonin exerts neuroprotective effects in many diseases, such as Parkinson's disease, Alzheimer's disease and ischaemic brain injury. Emerging evidence suggests that it might also mediate such protective action by influencing proliferation and differentiation of NSCs. In this article, we review the current literature concerned with effects of melatonin on NSCs in different physiological and pathological conditions.

27942033	Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as "repressilator" as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.
27941970	Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.
27941666	Diurnal mood variations are one of the core symptoms in depression, and total sleep deprivation (SD) can induce rapid, short-lasting clinical improvement in depressed patients. Here, we investigated if differential sleep pressure conditions impact on subjective mood levels in young women with major depressive disorder (MDD) without sleep disturbances, and in healthy controls. Eight healthy and eight MDD women underwent 40-h SD (high sleep pressure) and 40-h multiple NAP (low sleep pressure) protocols under constant routine conditions during which subjective mood was assessed every 30-min. MDD women rated overall significantly worse mood than controls, with minimal values for both groups during the biological night (ca. 4 a.m.), under high and low sleep pressure conditions. During SD, nighttime mood ratings in MDD women were lower than in controls and partially recovered during the second day of SD, but never attained control levels. The degree of this diurnal time-course in mood under SD correlated positively with sleep quality in MDD women. Our data indicate that MDD women without sleep disturbances did not exhibit a SD-induced antidepressant response, suggesting that the mood enhancement response to sleep deprivation might be related to the co-existence of sleep disturbances, which is an association that remains to be fully established.
27941611	Diapause is a common biological phenomenon that occurs in many organisms, including fish, insects, and nematodes. In the silkworm (Bombyx mori), diapause generally occurs in the egg stage. Treatment with O₂, HCl, or other compounds can prevent egg diapause. Here, we characterized the transcriptomic responses of newly laid eggs treated with O₂ or HCl. Digital gene expression analysis showed that 610 genes in O₂-treated eggs and 656 in HCl-treated eggs were differentially expressed. Of these, 343 genes were differentially expressed in both treatments. In addition to trehalases, sorbic acid dehydrogenases, and some enzymes involved in the carbohydrate metabolism, we also identified heat shock proteins, cytochrome P450, and GADD45, which are related to stress tolerance. Gene ontology enrichment analysis showed differentially expressed genes in O₂-treated eggs were involved in oxidoreductase activity as well as in binding, catalytic, and metabolic processes. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the pathways for ribosome biogenesis, spliceosome, and circadian rhythm were significantly enriched in HCl-treated eggs. The reliability of the data was confirmed by qRT-PCR analysis. Our results improved the understanding of the mechanism of diapause blocking in silkworm eggs treated with O₂ or HCl and identified novel molecular targets for future studies.
27941174	Adipokines have been implicated in obesity, insulin resistance and sleep regulation. However, the role of chemerin and progranulin, two recently described adipokines, in the context of sleep remains unclear. The aim of this study was to compare nocturnal serum chemerin and progranulin levels between overweight/obese and normal-weight adolescents and to assess variations by sex, across different sleep stages and in relation to glucose metabolism.The study sample included 34 overweight/obese and 32 normal-weight adolescents from secondary schools and the Leipzig Research Center for Civilization Diseases (LIFE) Child study cohort. We obtained longitudinal serum adipokine levels during in-laboratory polysomnography followed by an oral glucose tolerance test.	Overweight/obese adolescents had significantly higher mean nocturnal serum chemerin area under the curve (AUC) levels (348.2±133.3 vs. 241.7±67.7 vs. ng/mL×h, p<0.001) compared to normal-weight controls. In detail, higher chemerin AUC levels in obese/overweight subjects were exclusively due to increased levels in females. No overall difference for serum progranulin AUC was found between the groups. However, when assessing sex-specific levels, serum progranulin AUC levels were ~30% higher in overweight/obese males compared to overweight/obese females. Of note, nocturnal serum chemerin and progranulin AUC did not exhibit a correlation with markers of glucose metabolism or sleep stages.	Collectively, we report a sexual dimorphism in nocturnal progranulin and chemerin levels, which may help explain underlying differences in energy balance and body composition between males and females in the context of obesity.	
27940615	Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core "social behavior network" (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural "hotspots" in the SBN that relate to avian affiliative behavior, as well as neural "hotspots" that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus-caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential "hotspots" for the modulation of affiliation, aggression, and parental care.
27940169	Aging is a complex and multifactorial biological process that leads to the progressive deterioration of physiological systems, including the circadian system. In addition, oxidative stress has been associated with the aging of the normal brain and the development of late-onset neurodegenerative diseases. Even though, functional weakening of circadian rhythms and antioxidant function has been observed during aging, the mechanisms by which the circadian system signaling and oxidative stress are interrelated have not yet been elucidated. The objectives of this study were to evaluate the consequences of aging on the temporal organization of the antioxidant defense system and oxidative status as well as to analyze the endogenous clock activity, in the hippocampus of aged rats.Young adults (3-month-old) or older (22-month-old) male Holtzman rats were maintained under constant darkness conditions, during 15days before the sacrifice. Levels of catalase (CAT) and glutathione peroxidase (GPx) mRNA and activity, reduced glutathione (GSH), lipoperoxidation (LPO) and BMAL1 protein were analyzed in hippocampus samples isolated every 4h during a 24-h period. Locomotor activity was recorded during 20days before the experiment.	Our results show that aging modifies temporal patterns of CAT and GPx expression and activity in the hippocampus in a different way. On the one hand, it abolishes the oscillating CAT expression and specific enzymatic activity while, on the other, it increases the mesor of circadian GPx activity rhythm (p<0.01). Additionally, we observed increased GSH (p<0.05) and reduced LPO (p<0.01) levels in the hippocampus of aged rats. Moreover, the nocturnal locomotor activity was reduced in the older animals in comparison to the young adult rats (p<0.01). Interestingly, the 22month-old animals became arrhythmic and showed a marked fragmentation as well as a significant decline in daily locomotor activity when they were maintained under constant darkness conditions (p<0.05). Aging also abolished circadian rhythms of the core clock BMAL1 protein.	The loss of temporal organization of the antioxidant enzymes activity, the oxidative status and the cellular clock machinery could result in a temporally altered antioxidant defense system in the aging brain. Learning about how aging affects the circadian system and the expression of genes involved in the antioxidant defense system could contribute to the design of new strategies to improve the quality of life of older people and also to promote a healthy aging.	

27938913	Circadian rhythm disruption has been associated with increased risk of ischemic stroke (IS). Daylight saving time (DST) transitions disrupt circadian rhythms and shifts the pattern of diurnal variation in stroke onset, but effects on the incidence of IS are unknown.Effects of 2004-2013 DST transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during two weeks prior to and two weeks after the index week.	Hospitalizations for IS increased during the first two days (Relative Risk 1.08; CI 1.01-1.15, P = 0.020) after transition, but difference was diluted when observing the whole week (RR 1.03; 0.99-1.06; P = 0.069). Weekday-specific increase was observed on the second day (Monday; RR 1.09; CI 1.00-1.90; P = 0.023) and fifth day (Thursday; RR 1.11; CI 1.01-1.21; P = 0.016) after transition. Women were more susceptible than men to temporal changes during the week after DST transitions. Advanced age (>65 years) (RR 1.20; CI 1.04-1.38; P = 0.020) was associated with increased risk during the first two days, and malignancy (RR 1.25; CI 1.00-1.56; P = 0.047) during the week after DST transition.	DST transitions appear to be associated with an increase in IS hospitalizations during the first two days after transitions but not during the entire following week. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant comorbidities.	
27936340	Both oxidative stress and morning surge (MS) of blood pressure (BP) were found to be closely related with cardiovascular and cerebrovascular diseases. We investigated the association between MS of BP and oxidative stress in newly diagnosed hypertensive patients.We prospectively included 237 newly diagnosed hypertensive patients in the present study (mean age: 51.6 ± 11.7 years). The patients were classified according to the extent of the sleep-through surge as follows: the top decile of sleep-through surge (>47.2 mmHg, n = 27; EMShigh group), versus all others (n = 210, EMSlow group). Total antioxidant capacity (TAC) and total oxidant status (TOS) levels were determined by using an automated measurement method. The oxidative stress index (OSI) was calculated as the ratio of TOS to TAC. Serum paraoxonase 1 (PON-1) activity was measured spectrophotometrically.	Patients in EMShigh group were found to have higher hs-CRP, TOS, and OSI values and lower TAC and PON-1 values (p < 0.01, for all). MS of BP was associated with hs-CRP, PON-1, TOS, TAC, and OSI levels in bivariate analysis. Multivariate linear regression analysis showed that MS of BP was significantly associated with PON-1(β = -0.206, p < 0.001), OSI (β = 0.602, p < 0.001) and hs-CRP (β = 0.210, p < 0.001).	Present study shows that OSI is increased and antioxidant PON-1 activity is decreased in patients with enhanced MS of BP. There is a close association between high MS of BP and oxidative stress markers in newly diagnosed hypertensive patients.	
27936113	Delirium is characterized by disturbances in circadian rhythm. Melatonin regulates our circadian rhythm. Our aim was to compare preoperative cerebrospinal fluid (CSF) melatonin levels in patients with and without postoperative delirium.Prospective cohort study with hip fracture patients ≥ 65 years who were acutely admitted to the hospital for surgical treatment and received spinal anaesthesia. CSF was collected after cannulation, before administering anaesthetics. Melatonin was measured by radioimmunoassay (RIA). Data on delirium was obtained from medical and nursing records. Nurses screened every shift for delirium using the Delirium Observation Screening Scale (DOSS). If the DOSS was ≥3, a psychiatrist was consulted to diagnose possible delirium using the DSM-IV criteria. At admission, demographic data, medical history, and information on functional and cognitive status was obtained.	Seventy-six patients met the inclusion criteria. Sixty patients were included in the analysis. Main reasons for exclusion were technical difficulties, insufficient CSF or exogenous melatonin use. Thirteen patients (21.7%) experienced delirium during hospitalisation. Baseline characteristics did not differ between patients with and without postoperative delirium. In patients with and without postoperative delirium melatonin levels were 12.88 pg/ml (SD 6.3) and 11.72 pg/ml (SD 4.5) respectively, p-value 0.47. No differences between patients with and without delirium were found in mean melatonin levels in analyses stratified for cognitive impairment or age.	Preoperative CSF melatonin levels did not differ between patients with and without postoperative delirium. This suggests that, if disturbances in melatonin secretion occur, these might occur after surgery due to postoperative inflammation.	
27935605	There are many ganglion cell types and subtypes in our retina that carry color information. These have appeared at different times over the history of the evolution of the vertebrate visual system. They project to several different places in the brain and serve a variety of purposes allowing wavelength information to contribute to diverse visual functions. These include circadian photoentrainment, regulation of sleep and mood, guidance of orienting movements, detection and segmentation of objects. Predecessors to some of the circuits serving these purposes presumably arose before mammals evolved and different functions are represented by distinct ganglion cell types. However, while other animals use color information to elicit motor movements and regulate activity rhythms, as do humans, using phylogenetically ancient circuitry, the ability to appreciate color appearance may have been refined in ancestors to primates, mediated by a special set of ganglion cells that serve only that purpose. Understanding the circuitry for color vision has implications for the possibility of treating color blindness using gene therapy by recapitulating evolution. In addition, understanding how color is encoded, including how chromatic and achromatic percepts are separated is a step toward developing a complete picture of the diversity of ganglion cell types and their functions. Such knowledge could be useful in developing therapeutic strategies for blinding eye disorders that rely on stimulating elements in the retina, where more than 50 different neuron types are organized into circuits that transform signals from photoreceptors into specialized detectors many of which are not directly involved in conscious vision.
27933514	Experimental studies have revealed that hypoglycaemia can result in morphological changes in electrocardiographic repolarisation in subjects with type 1 diabetes. However, the influence of spontaneous nocturnal hypoglycaemia on repolarisation morphology in a 'real life' situation is not clear.Adults with type 1 diabetes (n = 11) underwent continuous glucose monitoring with a subcutaneous sensor and digital 12-lead ECG recording for three nights. T-wave morphology was analysed with custom-made software during both hypoglycaemia (glucose <3.5 mmol/l at least 20 min) from ten consecutive heart beats in the middle of the deepest hypoglycaemia and from a control nonhypoglycaemic period (glucose ≥5.0 mmol/l) from the same recording.	In the comparison of 10 hypoglycaemia-control pairs, heart rate (65 ± 12 beats/min during normoglycaemia versus 85 ± 19 beats/min during hypoglycaemia, p = 0.028) increased and the QTc interval (439 ± 5 vs. 373 ± 5 ms, respectively, p = 0.025) decreased significantly during hypoglycaemia. The spatial QRS-T angle (TCRT) was reduced, and the roughness of the T-wave loop (T-E) increased significantly (p = 0.037 for both) in the patients during hypoglycaemia.	In adults with type 1 diabetes, spontaneous nocturnal hypoglycaemia results in morphological changes and increased heterogeneity of global cardiac repolarisation. These changes may contribute to the risk of 'dead in bed' syndrome encountered in young individuals with type 1 diabetes.	
27933073	This paper presents a discovery: the change of the outline shape of mistletoe (Viscum album ssp. album) berries in vivo and in situ during ripening. It was found that a plant organ that is usually considered to merely increase in size actually changes shape in a specific rhythmic fashion. We introduce a new approach to chronobiological research on a macro-phenotypic scale to trace changes over long periods of time (with a resolution from hours to months) by using a dynamic form-determining parameter called Lambda (λ). λ is known in projective geometry as a measure for pertinent features of the outline shapes of egg-like forms, so called path curves. Ascertained circadian changes of form were analyzed for their correlation with environmental factors such as light, temperature, and other weather influences. Certain weather conditions such as sky cover, i.e., sunshine minutes per hour, have an impact on the amplitude of the daily change in form. The present paper suggests a possible supplement to established methods in chronobiology, as in this case the dynamic of form-change becomes a measurable feature, displaying a convincing accordance between mathematical rule and plant shape.
27931190	Clock genes are considered to be the molecular core of biological clock in vertebrates and they are directly involved in the regulation of daily rhythms in vertebrate tissues such as skeletal muscles. Fish myotomes are composed of anatomically segregated fast and slow muscle fibers that possess different metabolic and contractile properties. To date, there is no report on the characterization of the circadian clock system components of slow muscles in fish.In the present study, the molecular clock components (clock, arntl1/2, cry1/2/3, cry-dash, npas2, nr1d1/2, per1/2/3, rorα and tim genes) and their daily transcription levels were characterized in slow and fast muscles of Chinese perch (Siniperca chuatsi). Among the 15 clock genes, nrld2 and per3 had no daily rhythmicity in slow muscles, and cry2/3 and tim displayed no daily rhythmicity in fast muscles of the adult fish. In the slow muscles, the highest expression of the most clock paralogs occurred at the dark period except arntl1, nr1d1, nr1d2 and tim. With the exception of nr1d2 and tim, the other clock genes had an acrophase at the light period in fast muscles. The circadian expression of the myogenic regulatory factors (mrf4 and myf5), mstn and pnca showed either a positive or a negative correlation with the transcription pattern of the clock genes in both types of muscles.	It was the first report to unravel the molecular clock components of the slow and fast muscles in vertebrates. The expressional pattern differences of the clock genes between the two types of muscle fibers suggest that the clock system may play key roles on muscle type-specific tissue maintenance and function.	
27929128	The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (<0.1 lux), rather than completely dark nights, permits expression of an altered circadian waveform wherein mice in light/dark/light/dark (LDLD) cycles "bifurcate" their rhythms into two rest and activity intervals per 24 h. Secondly, this bifurcated state enables mice to adopt stable activity rhythms under 15 or 30 h days (LDLD T15/T30), well beyond conventional limits of entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.
27929109	The circadian clock governs virtually all processes in the human body, including sleep-wake behaviour. Circadian misalignment describes the off-set between sleep-wake cycles and clock-regulated physiology. This strain is predominantly caused by external (societal) demands including shift work, early school start times and fast travels across time zones. Sleeping at the 'wrong' internal time can jeopardise health and safety, and we therefore need a good quantification of this phenomenon. Here, we propose a novel method to quantify the mistiming of sleep-wake rhythms and demonstrate its versatility in day workers and shift workers. Based on a single time series, our Composite Phase Deviation method unveils distinct, subject- and schedule-specific geometries ('islands and pancakes') that illustrate how modern work times interfere with sleep. With increasing levels of circadian strain, the resulting shapes change systematically from small, connected forms to large and fragmented patterns. Our method shows good congruence with published measures of circadian misalignment (i.e., Inter-daily Stability and 'Behavioural Entrainment'), but offers added value as to its requirements, e.g., being computable for sleep logs and questionnaires. Composite Phase Deviations will help to understand the mechanisms that link 'living against the clock' with health and disease on an individual basis.
27928822	ZPR1 proteins belong to the C4-type of zinc finger coordinators known in animal cells to interact with other proteins and participate in cell growth and proliferation. In contrast, the current knowledge regarding plant ZPR1 proteins is very scarce. Here, we identify a novel potato nuclear factor belonging to this family and named StZPR1. StZPR1 is specifically expressed in photosynthetic organs during the light period, and the ZPR1 protein is located in the nuclear chromatin fraction. From modelling and experimental analyses, we reveal the StZPR1 ability to bind the circadian DNA cis motif 'CAACAGCATC', named CIRC and present in the promoter of the clock-controlled double B-box StBBX24 gene, the expression of which peaks in the middle of the day. We found that transgenic lines silenced for StZPR1 expression still display a 24 h period for the oscillation of StBBX24 expression but delayed by 4 h towards the night. Importantly, other BBX genes exhibit altered circadian regulation in these lines. Our data demonstrate that StZPR1 allows fitting of the StBBX24 circadian rhythm to the light period and provide evidence that ZPR1 is a novel clock-associated protein in plants necessary for the accurate rhythmic expression of specific circadian-regulated genes.
27927713	Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease.Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess-treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets.	We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens. Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renal Egr1, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart.	A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.	
27925286	We have previously shown that endochondral ossification is finely regulated by the Clock system expressed in chondrocytes during postnatal skeletogenesis. Here we show a sophisticated modulation of bone resorption and bone mass by the Clock system through its expression in bone-forming osteoblasts. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Period1 (Per1) were expressed with oscillatory rhythmicity in the bone in vivo, and circadian rhythm was also observed in cultured osteoblasts of Per1::luciferase transgenic mice. Global deletion of murine Bmal1, a core component of the Clock system, led to a low bone mass, associated with increased bone resorption. This phenotype was recapitulated by the deletion of Bmal1 in osteoblasts alone. Co-culture experiments revealed that Bmal1-deficient osteoblasts have a higher ability to support osteoclastogenesis. Moreover, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]-induced receptor activator of nuclear factor κB ligand (Rankl) expression was more strongly enhanced in both Bmal1-deficient bone and cultured osteoblasts, whereas overexpression of Bmal1/Clock conversely inhibited it in osteoblasts. These results suggest that bone resorption and bone mass are regulated at a sophisticated level by osteoblastic Clock system through a mechanism relevant to the modulation of 1,25(OH)2 D3 -induced Rankl expression in osteoblasts. © 2017 American Society for Bone and Mineral Research.
27925052	Night eating syndrome (NES) is characterized by caloric intake ≥ 25% of total daily after dinner and/or by two or more weekly nocturnal awakenings accompanied by food ingestion. Causes of NES are not entirely clear and seem to involve a desynchronization between the circadian rhythms of food ingestion and sleep, resulting in a delayed pattern of food intake. Estimates of the prevalence of NES in the general population are around 1.5%, and although much higher frequencies have been described in obese individuals, a causal relationship between NES and obesity is not clearly established. Since the first NES reports, several treatment modalities have been proposed, although, in many cases, the evidence is still insufficient and there is no consensus on the ideal approach. In order to conduct a critical review of proposed treatments for NES since its original description, a systematic search of articles published in journals indexed in Medline/Pubmed database in the period 1955-2015 was performed. Seventeen articles addressing non-pharmacological and pharmacological therapies met the selection criteria. Based on the articles analyzed, we conclude that serotonergic agents and psychological interventions, particularly cognitive behavioral therapy, have been shown to be effective for the treatment of NES. A combination of non-pharmacological and pharmacological therapies must be considered in future studies on the treatment of these patients.
27924279	KaiC, a core protein of the cyanobacterial circadian clock, is rhythmically autophosphorylated and autodephosphorylated with a period of approximately 24 h in the presence of two other Kai proteins, KaiA and KaiB. In vitro experiments to investigate the KaiC phosphorylation cycle consume considerable time and effort. To automate the fractionation, quantification, and evaluation steps, we developed a suite consisting of an automated sampling device equipped with an 8-channel temperature controller and accompanying analysis software. Eight sample tables can be controlled independently at different temperatures within a fluctuation of ±0.01°C, enabling investigation of the temperature dependency of clock activities simultaneously in a single experiment. The suite includes an independent software that helps users intuitively conduct a densitometric analysis of gel images in a short time with improved reliability. Multiple lanes on a gel can be detected quasi-automatically through an auto-detection procedure implemented in the software, with or without correction for lane 'smiling.' To demonstrate the performance of the suite, robustness of the period against temperature variations was evaluated using 32 datasets of the KaiC phosphorylation cycle. By using the software, the time required for the analysis was reduced by approximately 65% relative to the conventional method, with reasonable reproducibility and quality. The suite is potentially applicable to other clock or clock-related systems in higher organisms, relieving users from having to repeat multiple manual sampling and analytical steps.
27923457	The brain is considered a major site for microRNA (miRNA) expression; as evidenced by several studies reporting microarray data of different brain substructures. The hypothalamus is among the brain regions that plays a crucial role in integrating signals from other brain nuclei as well as environmental, hormonal, metabolic and neuronal signals from the periphery in order to deliver an adequate response. The hypothalamus controls vital functions such as reproduction, energy homeostasis, water balance, circadian rhythm and stress. These functions need a high neuronal plasticity to adequately respond to physiological, environmental and psychological stimuli that could be limited to a specific temporal period during life or are cyclic events. In this context, miRNAs constitute major regulators and coordinators of gene expression. Indeed, in response to specific stimuli, changes in miRNA expression profiles finely tune specific mRNA targets to adequately fit to the immediate needs through mainly the modulation of neuronal plasticity.
27923445	Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels.Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels.	There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p<0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females.	This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise.	
27923220	The circadian clock is rhythmically expressed in blood vessels, but the interaction between the circadian clock and disturbed blood flow remains unclear. We examined the relationships between BMAL1 and CLOCK and 2 regulators of endothelial function, AKT1 and endothelial nitric oxide synthase (eNOS), in vascular regions of altered blood flow. We found that the aortic arch from WT mice exhibited reduced sensitivity to acetylcholine (Ach)-mediated relaxation relative to the thoracic aorta. In Clock-mutant (mut) mice the aorta exhibited a reduced sensitivity to Ach. In WT mice, the phosphorylated forms of eNOS and AKT were decreased in the aortic arch, while BMAL1 and CLOCK expression followed a similar pattern of reduction in the arch. In conditions of surgically induced flow reduction, phosphorylated-eNOS (serine 1177) increased, as did p-AKT in the ipsilateral left common carotid artery (LC) of WT mice. Similarly, BMAL1 and CLOCK exhibited increased expression after 5 days in the remodeled LC. eNOS expression was increased at 8 p.m. versus 8 a.m. in WT mice, and this pattern was abolished in mut and Bmal1-KO mice. These data suggest that the circadian clock may be a biomechanical and temporal sensor that acts to coordinate timing, flow dynamics, and endothelial function.
27922614	Circadian clocks are endogenous timekeeping networks that allow organisms to align their physiology with their changing environment and to perform biological processes at the most relevant times of the day and year. Initial feedback-loop models of the oscillator have been enriched by emerging evidence highlighting the increasing variety of factors and mechanisms that contribute to the generation of rhythms. In this Review, we consider the two major input pathways that connect the circadian clock of the model plant Arabidopsis thaliana to its environment and discuss recent advances in understanding of how transcriptional, post-translational and post-transcriptional mechanisms contribute to clock function.
27922612	Endogenous biological rhythms with approximately 24-h periodicity are generated by the circadian clock, in which clock genes coordinate with one another and form a transcriptional-translational negative feedback loop. The precision of the circadian clock is further regulated by multiple post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation and SUMOylation. Here, we review current understanding of the regulatory mechanisms of the core clock proteins by PTMs in the mammalian circadian clock.
27922611	The mammalian molecular clock comprises a complex network of transcriptional programs that integrates environmental signals with physiological pathways in a tissue-specific manner. Emerging technologies are extending knowledge of basic clock features by uncovering their underlying molecular mechanisms, thus setting the stage for a 'systems' view of the molecular clock. Here we discuss how recent data from genome-wide genetic and epigenetic studies have informed the understanding of clock function. In addition to its importance in human physiology and disease, the clock mechanism provides an ideal model to assess general principles of dynamic transcription regulation in vivo.
27922609	Metabolic cycles result from the partitioning of oxidative and reductive metabolism into rhythmic phases of gene expression and oscillating post-translational protein modifications. Relatively little is known about how these switches in gene expression are controlled, although recent studies have suggested that transcription itself may play a central role. This review explores the molecular basis of the metabolic and gene-expression oscillations in the yeast Saccharomyces cerevisiae, as well as how they relate to other biological time-keeping mechanisms, such as circadian rhythms.
27922568	Depression is often associated with disruptions in sleep and circadian rhythms. We aimed to confirm these relationships via actigraphic assessment in a large, population-based sample and test whether sex moderates these relationships.A total of 418 participants (age = 35-85 years, mean [standard deviation] = 57.04 [11.47]) completed questionnaires and 1 week of actigraphy, used to calculate sleep and rest-activity statistics including mesor (mean activity level), amplitude (height of rhythm), and acrophase (time of day that rhythm peaks).	Depressive symptoms, assessed via Center for Epidemiologic Studies Depression Scale, were associated with disrupted sleep and rest-activity rhythms. Furthermore, men demonstrated longer sleep onset latency (SOL, B = -13.28, p < .001), longer wake time after sleep onset (B = -6.26, p < .01), lower sleep efficiency (B = 5.91, p < .001), and lower total sleep time (TST, B = 33.16, p < .001) than women. Sex moderated the relationship between depression and SOL, TST, mesor, and amplitude; sex-stratified models revealed that higher depression scores were associated with greater SOL (B = 1.05, p < .001) and less TST (B = -0.87, p < .10) for women with higher depressive symptoms, but lower mesor (B = -1.75, p < .01) and amplitude (B = -1.94, p < .01) for men with higher depressive symptoms.	Depressive symptoms were related to disrupted sleep continuity and rest-activity rhythms in this population-based sample; however, these relationships differed by sex. Women with greater depressive symptoms exhibited difficulty with sleep continuity, whereas men with greater depressive symptoms demonstrated disruption throughout the 24-hour rhythm.	
27920227	The increasing demand for improved agricultural production will require more efficient breeding for traits that maintain yield under heterogeneous environments. The internal circadian oscillator is essential for perceiving and coordinating environmental cues such as day length, temperature, and abiotic stress responses within physiological processes. To investigate the contribution of the circadian clock to local adaptability, we have analyzed circadian period by leaf movement in natural populations of Mimulus guttatus and domesticated cultivars of Glycine max. We detected consistent variation in circadian period along a latitudinal gradient in annual populations of the wild plant and the selectively bred crop, and this provides novel evidence of natural and artificial selection for circadian performance. These findings provide new support that the circadian clock acts as a central regulator of plant adaptability and further highlight the potential of applying circadian clock gene variation to marker-assisted breeding programs in crops.
27920083	Cardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping.Secondary healthcare unit in Copenhagen, Denmark.	24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years.	In this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen.	Primary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF).	Systolic BP dipping increased 2.4% (0.03-4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (-0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study.	We demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined.	EudraCT2012-002136-90; Post-results.	

27920039	Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level. In this review, we introduce some basic concepts underlying periodicity of gene regulation, and then highlight recent genome-wide investigations on the propagation of rhythms across multiple regulatory layers in mammals, all the way from chromatin conformation to protein accumulation.
27918287	Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination- and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, α-calmodulin kinase-II (αCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and αCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages.
27918240	To determine the effect of circadian rhythm on neuromuscular responses and kinematics related to physical tennis performance, after a standardised warm-up, 13 highly competitive male tennis players were tested twice for serve velocity/accuracy (SVA), countermovement vertical jump (CMJ), isometric handgrip strength (IS), agility T-test (AGIL) and a 10-m sprint (10-m RUN). In a randomised, counter-balance order, tennis players underwent the test battery twice, either in the morning (i.e., AM; 9:00 h) and in the afternoon (i.e., PM; 16:30 h). Paired t-tests were used to analyse differences due to time-of-day in performance variables. Comparison of morning versus afternoon testing revealed that SVA (168.5 ± 6.5 vs. 175.2 ± 6.1 km · h-1; P = 0.003; effect size [ES] = 1.07), CMJ (32.2 ± 0.9 vs. 33.7 ± 1.1 cm; P = 0.018; ES = 1.46), AGIL (10.14 ± 0.1 vs. 9.91 ± 0.2 s; P = 0.007; ES = 1.23) and 10-m RUN time (1.74 ± 0.1 vs. 1.69 ± 0.1 s; P = 0.021; ES = 0.67) were significantly blunted during the morning testing. However, IS was not affected by time-of-day (P = 0.891). Thus, tennis performance may be reduced when competing in the morning in comparison to early evening. Therefore, coaches and tennis players should focus on schedule the SVA, power, speed and agility training sessions in the afternoon.
27916575	Precise timing of gene transcription is a fundamental component of many biological rhythms. DNA methylation and histone acetylation are two epigenetic modifications that can affect the probability of gene transcription and RNA expression. Enzymes involved in DNA methylation (dnmts) have been shown to exhibit photoperiodic rhythms in expression in the hypothalamus, which coincide with hypothalamic expression of deiodinase type III (dio3), a gene involved in the photoperiodic regulation of reproduction. It is currently unknown whether enzymes involved in histone deacetylation (hdacs) also vary in response to photoperiod, nor have seasonal changes in the circadian waveforms of methylation and/or acetylation enzymes been examined. The present work documents circadian and photoperiodic changes in dnmts and hdacs in whole hypothalamic dissections obtained from male Siberian hamsters (Phodopus sungorus) after 5-6weeks of exposure to SD. The data indicate that short days (SD) markedly inhibit dnmt3a expression, and that SD inhibition of dnmt3a was evident regardless of the alignment of circadian waveforms. Among hdacs, photoperiodic and circadian changes in expression were only observed in hdac4 expression. Recurrent temporal waveforms in epigenetic enzyme expression may provide molecular inputs to the timing systems that reprogram RNA expression to generate daily and annual phenotypic plasticity.

27915477	Exercise enhances memory function by increasing neurogenesis in the hippocampus, and circadian rhythms modulate synaptic plasticity in the hippocampus. The circadian rhythm-dependent effects of treadmill exercise on memory function in relation with neurogenesis were investigated using mice.The step-down avoidance test was used to evaluate short-term memory, the 8-arm maze test was used to test spatial learning ability, and 5-bromo-2'-deoxyuridine immunofluorescence was used to assess neurogenesis. Western blotting was also performed to assess levels of synaptic plasticity-associated proteins, such as brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphorylated cAMP response element-binding protein, early growth response protein 1, postsynaptic density protein 95, and growth-associated protein 43. The mice in the treadmill exercise at zeitgeber 1 group started exercising 1 hour after sunrise, the mice in the treadmill exercise at zeitgeber 6 group started exercising 6 hours after sunrise, and the mice in the treadmill exercise at zeitgeber 13 group started exercising 1 hour after sunset. The mice in the exercise groups were forced to run on a motorized treadmill for 30 minutes once a day for 7 weeks.	Treadmill exercise improved short-term memory and spatial learning ability, and increased hippocampal neurogenesis and the expression of synaptic plasticity-associated proteins. These effects of treadmill exercise were stronger in mice that exercised during the day or in the evening than in mice that exercised at dawn.	Treadmill exercise improved memory function by increasing neurogenesis and the expression of synaptic plasticity-associated proteins. These results suggest that the memory-enhancing effect of treadmill exercise may depend on circadian rhythm changes.	
27915366	The Leydig cell physiology displays a circadian rhythm driven by a complex interaction of the reproductive axis hormones and circadian system. The final output of this regulatory process is circadian pattern of steroidogenic genes expression and testosterone production. Aging gradually decreases robustness of rhythmic testosterone secretion without change in pattern of LH secretion. Here, we analyzed effect of aging on circadian variation of cAMP and cGMP signaling in Leydig cells. Results showed opposite effect of aging on cAMP and cGMP daily variation. Reduced amplitude of cAMP circadian oscillation was probably associated with changed expression of genes involved in cAMP production (increased circadian pattern of Adcy7, Adcy9, Adcy10 and decreased Adcy3); cAMP degradation (increased Pde4a, decreased Pde8b, canceled rhythm of Pde4d, completely reversed circadian pattern of Pde7b and Pde8a); and circadian expression of protein kinase A subunits (Prkac/PRKAC and Prkar2a). Aging stimulates expression of genes responsible for cGMP production (Nos2, Gucy1a3 and Gucy1b3/GUCYB3) and degradation (Pde5a, Pde6a and Pde6h) but the overall net effect is elevation of cGMP circadian oscillations in Leydig cells. In addition, the expression of cGMP-dependent kinase, Prkg1/PRKG1 is up-regulated. It seems that aging potentiate cGMP- and reduce cAMP-signaling in Leydig cells. Since both signaling pathways affect testosterone production and clockwork in the cells, further insights into these signaling pathways will help to unravel disorders linked to the circadian timing system, aging and reproduction.
27914990	Melanopsin is a non-image forming photoreceptor known to be present in the retina and it is considered to have light regulated tasks among other functions. In the present work, melanopsin presence in human lens epithelial cells as well as in human lens tissue is described for the first time. Moreover, studying the concentration of melatonin and its synthesising enzyme AANAT proved a clear link between melanopsin activation and the suppression of melatonin synthesis. Melanopsin sensitivity to specific wavelength (465-480 nm, blue) was confirmed after making temporal studies incubating lens epithelial cells under light, red, green, blue and total darkness for 2, 4, 8, 12 h and analysing the concentration of both melatonin and its synthesising enzyme AANAT, discovering that melatonin levels after submitting cells to total darkness are significantly higher to ones submitted to white or specifically blue light (***p < 0.001, n = 6). The involvement of melanopsin in the regulation of melatonin was also determined by using a specific inhibitor AA92593 and by inhibiting melanopsin-induced phospholipase C activation. Under this situation neither AANAT nor melatonin levels changed under light conditions (n = 4, ***p < 0.001). The discovery of melanopsin in the lens opens the possibility of regulating melatonin synthesis with the corresponding implication as an antioxidant substance.
27913791	BMAL1 (brain and muscle ARNT-like protein 1, also known as MOP3 or ARNT3) belongs to the family of the basic helix-loop-helix (bHLH)-PAS domain-containing transcription factors, and is a key component of the molecular oscillator that generates circadian rhythms. Here, we report that BMAL1-deficient cells are significantly more susceptible to infection by two major respiratory viruses of the Paramyxoviridae family, namely RSV and PIV3. Embryonic fibroblasts from Bmal1-/- mice produced nearly 10-fold more progeny virus than their wild type controls. These results were supported by animal studies whereby pulmonary infection of RSV produced a more severe disease and morbidity in Bmal1-/-mice. These results show that BMAL1 can regulate cellular innate immunity against specific RNA viruses.
27913020	With the rapid development of traffic facilities in China, traffic noise pollution is increasingly prominent. This research aims to explore the influences of combined traffic noise on receptors' anxiety. Institute of cancer research mice were exposed to combined traffic noise (CTN) from highway and high-speed railway for 52days, whose day-night equivalent continuous A-weighted sound pressure level (Ldn) was 70dB(A). The impacts of CTN on anxiety were explored by behavior tests and monoamine neurotransmitter assays. The results were in depth discussed in comparison to two previous studies on the impacts of single high-speed railway noise (HSRN) and aircraft noise (AN), but data from the three studies were not merged and statistically compared. No significant differences were shown in the behavioral indicators and the monoamine levels between the experimental and control groups after CTN exposure, indicating no obvious impacts of 70dB(A) CTN on anxiety in mice were found in this study. When Ldn was approximately 70dB(A), CTN had less obvious impacts on anxiety than HSRN and AN, which is mainly related to that both the acoustical parameters of noise events [maximum noise level (LAmax), noise events duration, slope of rise, difference of LAmax from 1-min background equivalent continuous A-weighted sound pressure level] and modified day-night equivalent continuous R-weighted sound pressure level (considering animal auditory sensitivity to different sound frequencies and circadian rhythms) of CTN are smaller than those of HSRN and AN.
27912863	Residence at Zhongshan Station (69°22'24″S, 76°22'40″E) for over 1 year exposes winter-over members to marked changes of light-dark cycle, ranging from the constant daylight of polar days to the constant darkness of polar nights, in addition to geographic and social isolation. This extreme photoperiodic environment may increase the risk of sleep disturbances and circadian desynchrony. The aim of this study was to investigate the circadian rhythm and sleep phase of Chinese winter-over expeditioners at Zhongshan Station.This study was conducted on 17 healthy male participants before departure from Shanghai and during residence at Zhongshan Station for 1 year (before winter, mid-winter, and end of winter). Sequential urine samples over 48 hours were obtained, 6-sulphatoxymelatonin in urine was assessed, and the circadian rhythm was analyzed by a cosine curve-fitting method. Participants' sleep parameters were obtained from wrist actigraphy and sleep logs. Morningness-Eveningness Questionnaire and Seasonal Pattern Assessment Questionnaire were completed.	The acrophase of 6-sulphatoxymelatonin rhythm, sleep onset, sleep offset, and mid-sleep time were delayed significantly (P < .05) in Antarctica relative to departure values. The subjects had greater eveningness preference (P < .05) in mid-winter in Antarctica. The Global Seasonality Score and the prevalence of subsyndromal seasonal affective disorder increased (P < .05) during winter.	Our results indicate that during polar nights Chinese expeditioners experienced the following problems: delayed circadian rhythm and sleep phase, later chronotype, and incidence of subsyndromal seasonal affective disorder. An appropriate combination of artificial bright light during dark winter months and a strict social schedule are recommended in a winter-over station in Antarctica.	
27912106	Due to the limited cognitive and communicative abilities of adults with intellectual disabilities (ID), current treatment options for depression are often limited to lifestyle changes and pharmacological treatment. Bright light therapy (BLT) is an effective intervention for both seasonal and non-seasonal depression in the general population. BLT is an inexpensive, easy to carry out intervention with minimal side effects. However, knowledge on its anti-depressant effect in adults with ID is lacking. Obstacles in realizing a controlled intervention study in this particular study population may have contributed to this lack. To study the effect of BLT on depression in this population, it is necessary to successfully execute a multicenter randomized controlled trial (RCT). Therefore, the study protocol and the management of anticipated obstacles regarding this trial are presented.
27912059	The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.
27911598	The role of thyroid hormones (THs) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice as a result of defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3-/- brain is opposite that of the serum, exhibiting enhanced levels of TH action. Because the brain, particularly the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3-/- mice and determine whether it is associated with hypothalamic abnormalities. Here we show that Dio3-/- mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine (T3) treatment. They also exhibit increased TH action in the hypothalamus, with abnormal expression and T3 sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. The normal to elevated serum levels of leptin, and elevated and repressed expression of Agrp and Pomc, respectively, suggest a profile of leptin resistance. Interestingly, Dio3-/- mice also display elevated locomotor activity and increased energy expenditure. This occurs in association with expanded nighttime activity periods, suggesting a disrupted circadian rhythm. We conclude that DIO3-mediated regulation of TH action in the central nervous system influences multiple critical determinants of energy balance. Those influences may partially compensate each other, with the result likely contributing to the decreased adiposity observed in Dio3-/- mice.
27908540	In recent years, strong evidence has emerged suggesting that insufficient duration, quality, and/or timing of sleep are associated with cardiovascular disease (CVD), and various mechanisms for this association have been proposed. Such associations may be related to endophenotypic features of the sleep homeostat and the circadian oscillator, or may be state-like effects of the environment. Here, we review recent literature on sleep, circadian rhythms and CVD with a specific emphasis on differences between racial/ethnic groups. We discuss the reported differences, mainly between individuals of European and African descent, in parameters related to sleep (architecture, duration, quality) and circadian rhythms (period length and phase shifting). We further review racial/ethnic differences in cardiovascular disease and its risk factors, and develop the hypothesis that racial/ethnic health disparities may, to a greater or smaller degree, relate to differences in parameters related to sleep and circadian rhythms. When humans left Africa some 100,000 years ago, some genetic differences between different races/ethnicities were acquired. These genetic differences have been proposed as a possible predictor of CVD disparities, but concomitant differences in culture and lifestyle between different groups may equally explain CVD disparities. We discuss the evidence for genetic and environmental causes of these differences in sleep and circadian rhythms, and their usefulness as health intervention targets.
27907092	Disruptions to circadian rhythm in mice and humans have been associated with an increased risk of obesity and metabolic syndrome. The gut microbiota is known to be essential for the maintenance of circadian rhythm in the host suggesting a role for microbe-host interactions in the regulation of the peripheral circadian clock. Previous work suggested a role for gut bacterial bile salt hydrolase (BSH) activity in the regulation of host circadian gene expression. Here we demonstrate that unconjugated bile acids, known to be generated through the BSH activity of the gut microbiota, are potentially chronobiological regulators of host circadian gene expression. We utilised a synchronised Caco-2 epithelial colorectal cell model and demonstrated that unconjugated bile acids, but not the equivalent tauro-conjugated bile salts, enhance the expression levels of genes involved in circadian rhythm. In addition oral administration of mice with unconjugated bile acids significantly altered expression levels of circadian clock genes in the ileum and colon as well as the liver with significant changes to expression of hepatic regulators of circadian rhythm (including Dbp) and associated genes (Per2, Per3 and Cry2). The data demonstrate a potential mechanism for microbe-host crosstalk that significantly impacts upon host circadian gene expression.
27906548	To evaluate the involvement of the day-night feeding cycle in the circadian regulation of circulating plasminogen activator inhibitor-1 (PAI-1) concentrations, mice were fed with a diet for eight hours during either daytime (DF) or nighttime (NF) for one week. The reversed feeding cycle did not affect the circadian phases of plasma PAI-1 levels as well as the nocturnal wheel-running activity, although the phase of Pai-1 mRNA expression was significantly advanced for 8.6 hours in the livers of DF, compared with NF mice. The day-night feeding cycle is not a critical Zeitgeber for circadian rhythm of circulating PAI-1.
27904154	Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.
27904104	Objective Hypertension and diurnal blood pressure (BP) variation are widely accepted as risk factors for renal damage. However, the effects of unilateral nephrectomy on BP and its circadian rhythm have not yet been clarified in patients with a compromised renal function, including dialysis patients. Methods We investigated 22 unilateral nephrectomized patients (16 men and 6 women, age: 64.5±14.3 years). The function of the circulating renin-angiotensin system (RAS) (plasma renin activity and plasma angiotensin II) and 24-h ambulatory BP monitoring (ABPM) were evaluated before and after nephrectomy. Daytime and nighttime 24-h ABPM values were determined based on sleep and waking times. Results In non-dialysis patients, the estimated glomerular filtration rate after nephrectomy was significantly lower than that before (before, 62.4±23.2 mL/min/1.73 m2 vs. after, 43.7±16.8 mL/min/1.73 m2; p<0.01). No significant differences were noted in the levels of BPs and circulating RAS before and after nephrectomy. However, the night-to-day (N/D) ratio of systolic BP (SBP) was significantly higher after nephrectomy than before (before, 93.3±6.5% vs. after, 98.4±6.9%; p<0.01), and the patterns of circadian BP rhythm also significantly differed before and after nephrectomy (p=0.022). Namely, the rates of dipper patterns decreased and nondipper and riser patterns increased after nephrectomy. In contrast, in dialysis patients, no significant differences were observed in the N/D ratio of SBP or the patterns of circadian BP rhythm before and after nephrectomy. Conclusion Unilateral nephrectomy affects the circadian rhythm of BP but not absolute values of BP.
27900568	The prevention and correction of hyperphosphatemia are major goals of the treatment of chronic kidney disease (CKD)-bone mineral disorders, and thus, Pi balance requires special attention. Pi balance is maintained by intestinal absorption, renal excretion, and bone accretion. The kidney is mainly responsible for the plasma Pi concentration. In CKD, reduced glomerular filtration rate leads to various Pi metabolism abnormalities, and Pi absorption in the small intestine also has an important role in Pi metabolism. Disturbances in Pi metabolism are mediated by a series of complex changes in regulatory hormones originating from the skeleton, intestine, parathyroid gland, and kidney. In this review, we describe the regulation of type II sodium-dependent Pi co-transporters by the kidney and intestine, including the regulation of Pi transport, circadian rhythm, and the vicious circle between salivary Pi secretion and intestinal Pi absorption in animals with and without CKD.
27900498	Blood pressure is commonly abnormal in parkinsonian disorders, but central hemodynamics and arterial stiffness, well-established predictors of total cardiovascular risk, have rarely been studied in these disorders. 32 patients [27 with idiopathic Parkinson's disease (iPD); 5 with multiple system atrophy (MSA)] and 15 controls matched for cardiac risk factors underwent 24 h-ambulatory blood pressure recordings using an I.E.M. device (Mobil-O-Graph™), measuring peripheral pressure and calculating central pressures and arterial stiffness. Mean augmentation indices corrected for heart rate (AIx@75) were significantly lower and pulse wave velocities were significantly elevated in patients compared to controls. Central systolic blood pressure, cardiac output and daytime total vascular resistance were significantly elevated in patients. Mean nocturnal systolic peripheral blood pressure and nocturnal heart rates were also significantly higher; 56.3% of patients had nocturnal hypertension (80% of the MSA group); 85.2% showed non-dipping. This supports previous findings of reduced vulnerability to systemic atherosclerosis and end-organ damage in treated PD. Yet, hemodynamic abnormalities were common and often remained asymptomatic.
27900440	To explore the circadian rhythm of serum interleukin (IL)-6 in collagen-induced arthritis (CIA) rats and compare the safety and effectiveness of methotrexate (MTX) administered traditionally and via chronotherapy.CIA rat models were immunized with bovine type II collagen. Serum IL-6 levels in normal and CIA rats were measured at 2, 6, 10, 14, 18, or 22 h after the light was turned on (HALO). MTX was administered to 6 HALO/18 HALO experimental groups of Wistar rats once daily according to the IL-6 rhythm. The control groups (positive, negative, and normal) were given MTX or an equal volume of phosphate buffered saline (PBS) once a week simultaneously. Arthritis score, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP) levels in the serum were measured by enzyme-linked immunosorbent assay (ELISA). Histological changes in the ankle joint were analyzed.	After 6 weeks of treatment, arthritis scores in the experimental group were lower than in the control group. The expression of TNF-α, IL-6, and CRP was lower in the 18 HALO group than in the control or 6 HALO groups. Histopathology scores in the experimental groups were lower than in the control group (p < 0.05).	The plasma IL-6 levels in CIA rats were higher than in normal rats and showed significant circadian rhythm. Daily administration of MTX is more potent than weekly administration. The therapeutic index of rheumatoid arthritis (RA) may be improved with MTX therapy based on the IL-6 circadian rhythm.	
27899452	Phosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclin M (CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2BAT), which consists of two cystathionine β-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disc-like homodimer of CNNM2BAT bound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg2+ thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 and CNNM2 activities.
27899042	We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.
27896554	This study investigated the volatile emission from apple (Malus x domestica Borkh., cv. Golden Delicious) foliage that was either intact, mechanically-damaged, or exposed to larval feeding by Pandemis heparana (Denis and Schiffermüller) (Lepidoptera: Tortricidae). Volatiles were collected by closed-loop-stripping-analysis and characterized by gas chromatography-mass spectrometry in three time periods: after 1 h and again 24 and 48 h later. Volatiles for all treatments also were monitored continuously over a 72-h period by the use of proton transfer reaction - time of flight-mass spectrometry (PTR-ToF-MS). In addition, the volatile samples were analyzed by gas chromatography-electroantennographic detection (GC-EAD) using male and female antennae of P. heparana. Twelve compounds were detected from intact foliage compared with 23 from mechanically-damaged, and 30 from P. heparana-infested foliage. Interestingly, six compounds were released only by P. heparana-infested foliage. The emission dynamics of many compounds measured by PTR-ToF-MS showed striking differences according to the timing of herbivory and the circadian cycle. For example, the emission of green leaf volatiles began shortly after the start of herbivory, and increased over time independently from the light-dark cycle. Conversely, the emission of terpenes and aromatic compounds showed a several-hour delay in response to herbivory, and followed a diurnal rhythm. Methanol was the only identified volatile showing a nocturnal rhythm. Consistent GC-EAD responses were found for sixteen compounds, including five aromatic ones. A field trial in Sweden demonstrated that benzyl alcohol, 2-phenylethanol, phenylacetonitrile, and indole lures placed in traps were not attractive to Pandemis spp. adults, but 2-phenylethanol and phenylacetonitrile when used in combination with acetic acid were attractive to both sexes.
27895890	Animal models have become valuable experimental tools for understanding the pathophysiology and therapeutic interventions in cardiovascular disease. Yet to date, few studies document the age- and sex-related differences in arterial pressure, circadian rhythm, and renal function in normotensive mice under basal conditions, across the life span. We hypothesized that mice display similar sex- and age-related differences in arterial pressure and renal function to humans.Mean arterial pressure (MAP) and circadian rhythm of arterial pressure were measured over 3 days via radiotelemetry, in 3- and 5-month-old (adult) and 14- and 18-month-old (aged) FVB/N and in 5-month-old (adult) C57BL/6 male and female normotensive mice. In FVB/N mice, albuminuria from 24-h urine samples as well as body, heart, and kidney weights were measured at each age.	Twenty-four-hour MAP was greater in males than females at 3, 5, and 14 months of age. A similar sex difference in arterial pressure was observed in C57BL/6 mice at 5 months of age. In FVB/N mice, 24-h MAP increased with age, with females displaying a greater increase between 3 and 18 months of age than males, such that MAP was no longer different between the sexes at 18 months of age. A circadian pattern was observed in arterial pressure, heart rate, and locomotor activity, with values for each greater during the active (night/dark) than the inactive (day/light) period. The night-day dip in MAP was greater in males and increased with age in both sexes. Albuminuria was greater in males than females, increased with age in both sexes, and rose to a greater level in males than females at 18 months of age.	Arterial pressure and albuminuria increase in an age- and sex-specific manner in mice, similar to patterns observed in humans. Thus, mice represent a useful model for studying age and sex differences in the regulation of arterial pressure and renal disease. Understanding the mechanisms that underlie the pathophysiology of cardiovascular disease may lead to new and better-tailored therapies for men and women.	
27895820	Synchrony of biological processes with environmental cues developed over millennia to match growth, reproduction and senescence. This entails a complex interplay of genetic, metabolic, chemical, light, hormonal and hedonistic factors across life forms. Sleep is one of the most prominent rhythms where such a match is established. Over the past 100 years or so, it has been possible to disturb the synchrony between sleep-wake cycle and environmental cues. Development of electric lights, shift work and continual accessibility of the internet has disrupted this match. As a result, many non-communicable diseases such as obesity, insulin resistance, type 2 diabetes, coronary artery disease and malignancies have been attributed in part to such disruption. In this presentation a review is made of the origin and evolution of sleep studies, the pathogenic mediators for such asynchrony, clinical evidence and relevance and suggested management options to deal with the disturbances.
27894927	Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.
27893733	It has been proposed that the CLOCK-ARNTL (BMAL1) complex drives circadian transcription of thousands of genes, including Per and Cry family genes that encode suppressors of CLOCK-ARNTL-dependent transcription. However, recent studies demonstrated that 70-80% of circadian-oscillating mRNAs have no obvious rhythms in their de novo transcription, indicating the potential importance of post-transcriptional regulation. Our CLOCK-ChIP-seq analysis identified rhythmic expression of adenosine deaminase, RNA-specific, B1 (Adarb1, also known as Adar2), an adenosine-to-inosine (A-to-I) RNA-editing enzyme. RNA-seq showed circadian rhythms of ADARB1-mediated A-to-I editing in a variety of transcripts. In Adarb1-knockout mice, rhythms of large populations of mRNA were attenuated, indicating a profound impact of ADARB1-mediated A-to-I editing on RNA rhythms. Furthermore, Adarb1-knockout mice exhibited short-period rhythms in locomotor activity and gene expression. These phenotypes were associated with abnormal accumulation of CRY2. The present study identifies A-to-I RNA editing as a key mechanism of post-transcriptional regulation in the circadian clockwork.
27892932	Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD+/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK-BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK-BMAL1-dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.
27891621	Cryptochromes are evolutionarily related to the light-dependent DNA repair enzyme photolyase, serving as major regulators of circadian rhythms in insects and vertebrate animals. There are two types of cryptochromes in the animal kingdom: Drosophila-like CRYs that act as nonvisual photopigments linking circadian rhythms to the environmental light/dark cycle, and vertebrate-like CRYs that do not appear to sense light directly, but control the generation of circadian rhythms by acting as transcriptional repressors. Some animals have both types of CRYs, while others possess only one. Cryptochromes have two domains, the photolyase homology region (PHR) and an extended, intrinsically disordered C-terminus. While all animal CRYs share a high degree of sequence and structural homology in their PHR domains, the C-termini are divergent in both length and sequence identity. Recently, cryptochrome function has been shown to extend beyond its pivotal role in circadian clocks, participating in regulation of the DNA damage response, cancer progression and glucocorticoid signaling, as well as being implicated as possible magnetoreceptors. In this review, we provide a historical perspective on the discovery of animal cryptochromes, examine similarities and differences of the two types of animal cryptochromes and explore some of the divergent roles for this class of proteins.
27890733	The pathophysiological mechanism of J wave in anterior leads (A-leads) and inferolateral leads (L-leads) remains unclear.We investigated the onset mode and circadian distribution of ventricular tachyarrhythmia (VTA) episodes between patients with early repolarization syndrome (ERS) and Brugada syndrome (BrS).	The study enrolled 35 patients with ERS and 52 patients with type 1 BrS with spontaneous ventricular fibrillation who were divided into 4 groups: ERS(A+L) (n = 15), patients with ERS who had a non-type 1 Brugada pattern electrocardiogram in any A-leads (second to fourth intercostal spaces) in control and/or after drug provocation tests; ERS(L) (n = 20), patients with ERS with J wave only in L-leads; BrS(A) (n = 24), patients with BrS without J wave in L-leads; and BrS(A+L) (n = 28), patients with BrS with J wave in L-leads. The onset mode of 206 VTAs obtained from electrocardiograms or implantable cardioverter-defibrillators and the circadian distribution of 352 VTAs were investigated in the 4 groups.	Three groups with J wave in A-leads, ERS(A+L), BrS(A), and BrS(A+L), had higher incidences of nocturnal (63%, 43%, and 47%, respectively) and sudden onset VTAs (67%, 97%, and 86%, respectively) with longer coupling intervals of premature ventricular contractions (388.8, 397.3, and 385.6 ms, respectively) than the ERS(L) group with J wave only in L-leads (25%, P = .0019; 19%, P < .0001; and 330.6 ms, P = .0004, respectively), the last of which mainly displayed VTAs with a short-long-short sequence.	The onset mode of VTAs was different between patients with J wave in A-leads and patients with J wave in only L-leads. The underlying mechanism of J wave may differ between A-leads and L-leads.	
27890490	Chronobiology studies periodic changes in living organisms and it has been proposed as a promising approach to investigate obesity. We analyze the association of the characteristics of the rest-activity rhythms with obesity, cardiorespiratory fitness and metabolic risk in adolescents from nine European countries.1044 adolescents (12.5-17.5 y) were studied. Circadian health was evaluated by actigraphy with accelerometers (Actigraph GT1M). Characteristics of the daytime activity such as fragmentation (intradaily variability), estimated acrophase, and 10 h mean daytime activity index were obtained. Body composition was assessed using Bioelectrical-Impedance-Analysis, skinfold thickness, air-displacement-plethysmography and Dual-energy-X-ray-Absorptiometry. Cardiorespiratory fitness (VO2max) and metabolic risk were studied.	Highly fragmented activity rhythms were associated with obesity and central adiposity (P < 0.05). Obese adolescents had ∼3 times higher odds of having a high fragmentation of daytime activity compared to normal weight adolescents OR (95% CI) = 2.8 (1.170, 6.443). A highly fragmented rhythm was also related to lower cardiorespiratory fitness and higher metabolic risk (P < 0.05) so those adolescents classified as low fitness showed a significantly higher fragmentation of daytime activity than those included in the high fitness group (P < 0.0001). Other characteristics of the rhythms such as smaller 10 h daytime mean activity index and delayed estimated acrophase were also related to obesity and metabolic risk (P < 0.05).	Our results indicate that the daily organization of the rest-activity cycle is more fragmented in obese and less fit adolescents and correlates with higher metabolic risk. This fact reinforces our hypothesis that disturbances in daily rhythms can be considered as sensitive markers of poorer adolescent's health.	
27888766	Up to date, little information is available on effects of circadian rhythm on metal-induced toxicity in fish. In this study, zebrafish were acutely exposed to 0.97mgL-1 cadmium for 12h either at ZT0 (the light intensity began to reached maximum) or at ZT12 (light intensity began to reached minimum) to evaluate the temporal sensitivity of oxidative stress and inflammatory responses in the brain of zebrafish. Profiles of responses of some genes at mRNA, protein and activity levels were different between ZT0 and ZT12 in the normal water. Exposure to Cd induced contrary antioxidant responses and similar inflammatory responses between ZT0 and ZT12. However, the number of inflammatory genes which were up-regulated was significantly greater at ZT12 than at ZT0. And, the up-regulated inflammatory genes were more responsive at ZT12 than at ZT0. At ZT12, antioxidant genes were down-regulated at mRNA, protein and activity levels. Contrarily, antioxidant genes were not affected at mRNA levels but activated at the protein and/or activity levels at ZT0. Reactive oxygen species (ROS) sharply increased and remained relatively stable when fish were exposed to Cd at ZT12 and ZT0, respectively. Positive correlations between ROS levels and mRNA levels of nuclear transcription factor κB (NF-κB) and between mRNA levels of NF-κB and its target genes were observed, suggesting that ROS may play an essential role in regulating the magnitude of inflammatory responses. Taken together, oxidative stress and immunotoxicity in the brain were more serious when fish were exposed to Cd in the evening than in the morning, highlighting the importance of circadian rhythm in Cd-induced neurotoxicity in fish.
27888640	Elevated levels of total cholesterol and low-density lipoprotein play an important role in the development of atheromas and, therefore, in cardiovascular diseases. Cholesterol biosynthesis follows a circadian rhythm and is principally produced at night (between 12:00 am and 6:00 am). The adjustment of hypolipaemic therapy to biologic rhythms is known as chronotherapy. Chronotherapy is based on the idea that medication can have different effects depending on the hour at which it is taken. Statins are one of the most widely used drugs for the prevention of cardiovascular events. In usual clinical practice, statins are administered once per day without specifying the time when they should be taken. It is unknown whether the timing of statin administration is important for clinical outcomes.To critically evaluate and analyse the evidence available from randomised controlled trials regarding the effects of chronotherapy on the effectiveness and safety of treating hyperlipidaemia with statins.	We searched the CENTRAL, MEDLINE, Embase, LILACS, ProQuest Health & Medical Complete, OpenSIGLE, Web of Science Conference Proceedings, and various other resources including clinical trials registers up to November 2015. We also searched the reference lists of relevant reviews for eligible studies.	We included randomised controlled trials (RCTs), enrolling people with primary or secondary hyperlipidaemia. To be included, trials must have compared any chronotherapeutic lipid-lowering regimen with statins and any other statin lipid-lowering regimen not based on chronotherapy. We considered any type and dosage of statin as eligible, as long as the control and experimental arms differed only in the timing of the administration of the same statin. Quasi-randomised studies were excluded.	We used the standard methodological procedures expected by Cochrane. We extracted the key data from studies in relation to participants, interventions, and outcomes for safety and efficacy. We calculated odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Using the GRADE approach, we assessed the quality of the evidence and we used the GRADEpro Guideline Development Tool to import data from Review Manager to create 'Summary of findings' tables.	This review includes eight RCTs (767 participants analysed in morning and evening arms). The trials used different lipid-lowering regimens with statins (lovastatin: two trials; simvastatin: three trials; fluvastatin: two trials; pravastatin: one trial). All trials compared the effects between morning and evening statin administration. Trial length ranged from four to 14 weeks. We found a high risk of bias in the domain of selective reporting in three trials and in the domain of incomplete outcome data in one trial of the eight trials included. None of the studies included were judged to be at low risk of bias.None of the included RCTs reported data on cardiovascular mortality, cardiovascular morbidity, incidence of cardiovascular events, or deaths from any cause. Pooled results showed no evidence of a difference in total cholesterol (MD 4.33, 95% CI -1.36 to 10.01), 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence), low-density lipoprotein cholesterol (LDL-C) levels (MD 4.85 mg/dL, 95% CI -0.87 to 10.57, 473 participants, five trials, mean follow-up 9 weeks, low-quality evidence), high-density lipoprotein cholesterol (HDL-C) (MD 0.54, 95% CI -1.08 to 2.17, 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence) or triglycerides (MD -8.91, 95% CI -22 to 4.17, 510 participants, five trials, mean follow-up 9 weeks, low-quality evidence) between morning and evening statin administration.With regard to safety outcomes, five trials (556 participants) reported adverse events. Pooled analysis found no differences in statins adverse events between morning and evening intake (OR 0.71, 95% CI 0.44 to 1.15, 556 participants, five trials, mean follow-up 9 weeks, low-quality evidence).	Limited and low-quality evidence suggested that there were no differences between chronomodulated treatment with statins in people with hyperlipidaemia as compared to conventional treatment with statins, in terms of clinically relevant outcomes. Studies were short term and therefore did not report on our primary outcomes, cardiovascular clinical events or death. The review did not find differences in adverse events associated with statins between both regimens. Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration. Further high-quality trials with longer-term follow-up are needed to confirm the results of this review.	
27888171	Telehealth solutions can improve the safety of ambulatory chemotherapy, contributing to the maintenance of patients at their home, hence improving their well-being, all the while reducing health care costs. There is, however, need for a practicable multilevel monitoring solution, encompassing relevant outputs involved in the pathophysiology of chemotherapy-induced toxicity. Domomedicine embraces the delivery of complex care and medical procedures at the patient's home based on modern technologies, and thus it offers an integrated approach for increasing the safety of cancer patients on chemotherapy.The objective was to evaluate patient compliance and clinical relevance of a novel integrated multiparametric telemonitoring domomedicine platform in cancer patients receiving multidrug chemotherapy at home.	Self-measured body weight, self-rated symptoms using the 19-item MD Anderson Symptom Inventory (MDASI), and circadian rest-activity rhythm recording with a wrist accelerometer (actigraph) were transmitted daily by patients to a server via the Internet, using a dedicated platform installed at home. Daily body weight changes, individual MDASI scores, and relative percentage of activity in-bed versus out-of-bed (I<O) were computed. Chemotherapy was administered according to the patient medical condition. Compliance was evaluated according to the proportions of (1) patient-days with all data available (full) and (2) patient-days with at least one parameter available (minimal). Acceptability was assessed using the Whole Systems Demonstrator Service User Technology Acceptability Questionnaire. Linear discriminant analysis was used to identify the combination of parameters associated with subsequent unplanned hospitalization.	A total of 31 patients (males: 55% [17/31]; World Health Organization Performance Status=0: 29% (9/31); age range: 35-91 years) participated for a median of 58 days (38-313). They received a total of 102 chemotherapy courses (64.7% as outpatients). Overall full compliance was 59.7% (522/874), with at least one data available for 830/874 patient-days (95.0%), during the 30-day per-protocol span. Missing data rates were similar for each parameter. Patients were altogether satisfied with the use of the platform. Ten toxicity-related hospitalizations occurred in 6 patients. The combination of weighted circadian function (actigraphy parameter I<O), body weight change, and MDASI scores predicted for ensuing emergency hospitalization within 3 days, with an accuracy of 94%.	Multidimensional daily telemonitoring of body weight, circadian rest-activity rhythm, and patient-reported symptoms was feasible, satisfactory, and clinically relevant in patients on chemotherapy. This domomedicine platform constitutes a unique tool for the further development of safe home-based chemotherapy administration.	
27888113	Circadian rhythms are the approximate 24h biological cycles that function to prepare an organism for daily environmental changes. Circadian rhythms unquestionably play critical roles in metabolic homeostasis and the exercise has emerged as a strong non-photic time cue or zeitgeber in animal models and humans. Numerous studies about the effects of exercise on the citrate synthase activity have been published. Citrate is used to assess energy production or expenditure because it is a substrate of the Krebs Cycle, a cycle for oxidative energy production.We tested the existence of a rhythmic urinary citrate excretion in a rat model that is made to exercise at six different points during the day.	The data obtained by the enzyme assays were fitted to a mathematical model (Fourier series), showing for the first time, the existence of a distinct ultradian rhythm in the urinary citrate excretion. The aerobic exercise led to the increase in the period length of the ultradian rhythm and raised the acrophase value of the urinary citrate excretion. Therefore, the urinary citrate excretion pattern changed after exercise, showing a clear circadian rhythm fitted to the mathematical model.	The citrate urine samples could provide accurate data for ranking an individual's metabolic status. Using exercise to maintain the circadian clock at an appropriate phase and amplitude might be effective to prevent cardiometabolic disease development.	
27887821	The relationship between sleep disorders and Internet addiction has been little work. Given the importance of these disorders, we felt it appropriate to make a synthesis of available data and to establish causality or accountability between Internet addiction and the onset of sleep disorders.A literature review was then performed. We selected scientific articles in English and French, published between 1987 and 2016 by consulting the databases Medline, Embase, PsycINFO and Google Scholar. The words used alone or in combination are as follows: addiction, dependence, Internet, behavioral addiction, sleep.	A computer screen light inhibits melatonin secretion and acts as a real external desynchronizer circadian rhythm resulting in a withdrawal syndrome or syndrome sleep phase delay when the stress of social awakening is suppressed.	We assume here that the specific treatment of addictive disorders have an influence on sleep disorders.	
27885322	Depression is often diagnosed using the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria. We propose how certain lifestyle choices and non-modifiable factors can predict the development of depression. We identified 10 cause categories (hits or "blows" to the brain) and theorize that four or more active hits could trigger a depression episode. Methods. A sample of 4271 participants from our community-based program (70% female; ages 17-94 years) was assessed at baseline and at the eighth week of the program using a custom test. Ten cause categories were examined as predictors of depression are (1) Genetic, (2)Developmental, (3)Lifestyle, (4)Circadian Rhythm, (5)Addiction, (6)Nutrition, (7)Toxic, (8)Social/Complicated Grief, (9)Medical Condition, and (10)Frontal Lobe. Results. The relationship between the DSM-5 score and a person having four hits categories in the first program week showed a sensitivity of 89.98 % (95% CI: 89.20 % - 90.73%), specificity 48.84% (CI 45.94-51.75) and Matthew Correlation Coefficient (MCC) .41 . For the eight-week test, the results showed a sensitivity 83.6% (CI 81.9-85.5), specificity 53.7% (CI 51.7-55.6) and MCC .38. Overall, the hits that improved the most from baseline after the eighth week were: Nutrition (47%), Frontal lobe (36%), Addiction (24%), Circadian rhythm (24%), Lifestyle (20%), Social (12%) and Medical (10%). Conclusions. The Nedley four-hit hypothesis seems to predict a depressive episode and correlates well with the DSM-5 criteria with good sensitivity and MCC but less specificity. Identifying these factors and applying lifestyle therapies could play an important role in the treatment of depressed individuals.
27885090	Daily rhythmic changes are found in cellular events in cell cycle, DNA repair, apoptosis and angiogenesis in both normal and tumour tissue, as well as in enzymatic activity and drug metabolism. In this paper, we hypothesize that circadian rhythms need to be considered in radiation protection and optimization in personalized medicine, especially for paediatric care. The sensitivity of the eye lens to ionizing radiation makes the case for limiting damage to the lens epithelium by planning medical radio-imaging procedures for the afternoon, rather than the morning. Equally, the tumour and normal tissue response to radiotherapy is also subject to diurnal variation enabling optimization of time of treatment.
27885007	A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
27885006	Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer's disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.
27885003	The last 20 years have seen the rapid evolution of our understanding of the molecular genes and networks that enable almost all forms of life to generate 24-hour-or circadian-rhythms. One finding has been particularly exciting: that the molecular circadian clock resides in almost all of the cells of the body and that the clock regulates the timing of many cellular and signaling pathways associated with multiple disease states. Such advances represent a new frontier for medicine: circadian medicine.
27884951	We present clinical, electroencephalographic and low-resolution electromagnetic tomography data that support combined treatment with insulin and a monoamine oxidase inhibitor in a patient with type 1 diabetes. We suggest that brain imaging data can identify a subgroup of patients who are likely to benefit from an insulin regimen and monoamine oxidase inhibition to improve glycaemic control, cardiovascular function, normalize the circadian rhythm and restore perception of glycaemic awareness.

27884699	Cell adhesion molecules (CAMs) play essential roles in the central nervous system, where some families are involved in synaptic development and function. These synaptic adhesion molecules (SAMs) are involved in the regulation of synaptic plasticity, and the formation of neuronal networks. Recent findings from studies examining the consequences of sleep loss suggest that these molecules are candidates to act in sleep regulation. This review highlights the experimental data that lead to the identification of SAMs as potential sleep regulators, and discusses results supporting that specific SAMs are involved in different aspects of sleep regulation. Further, some potential mechanisms by which SAMs may act to regulate sleep are outlined, and the proposition that these molecules may serve as molecular machinery in the two sleep regulatory processes, the circadian and homeostatic components, is presented. Together, the data argue that SAMs regulate the neuronal plasticity that underlies sleep and wakefulness.
27884645	Circadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions.RNA was extracted from normal and OA-affected human knee cartilage (n = 14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the transforming growth factor beta (TGF-β) pathway.	NR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-β signaling pathway.	The CR pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-β signaling, which is a central pathway in cartilage homeostasis.	
27884543	Molecular clocks allow an organism to track time of day, providing the means to anticipate and respond to the daily changes within the environment. In mammals the molecular clock consists of a network of proteins that form auto-regulatory feedback loops that drive rhythms in physiology and behavior. In recent times the extent to which the molecular clock controls key metabolic and immune pathways has begun to emerge. For example, the main clock protein BMAL1 has been linked to mitochondrial metabolism, mitochondrial dynamics and various host defense pathways. The molecular clock may function to integrate daily metabolic changes driven by feeding-fasting to immune function and output. Understanding how the clock intersects with metabolic pathways within immune cells to affect immune phenotypes will have broad implications for the management of metabolic, inflammatory and infectious diseases.
27883893	Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD.We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD.	DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles.	Our results indicate that cycles of DNA methylation contribute to the regulation of BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.	
27883226	The expression patterns of clock-controlled genes (ccgs) are regulated by circadian rhythm, which is a major regulatory and physiological mechanism tied to the solar day. Disruptions in circadian rhythm contribute to the development of cardiovascular diseases, cancer, metabolic syndromes, and aging. It has been reported that bone remodeling is also regulated by circadian rhythm. However, the molecular mechanism by which the circadian gene Clock regulates bone remodeling has yet to be elucidated. Here, we show that Clock mutant mice exhibit a significant reduction in bone density as well as increased apoptosis. Protein disulfide isomerase family A member 3 (PDIA3) is a 1,25-dihydroxy-vitamin D3 [1α,25(OH)2D3] receptor that can regulate bone formation and apoptosis. Using luciferase and ChIP assays, we confirmed that Pdia3 is a ccg. Clock activates Pdia3 transcription by binding the E-box promoter, and transcription is decreased in ClockΔ19 mutant mice. Forced expression of Pdia3 or of Clock completely rescues the osteogenic disorders found in the mutant background and inhibits apoptosis in vivo and in vitro. Furthermore, ablation of PDIA3 via RNA interference completely blocks the compensatory effect of forced expression of Clock in osteoblasts. Our results demonstrate that the core circadian gene Clock regulates bone formation via transcriptional control of 1,2,5(OH)2D3 receptor PDIA3. © 2016 American Society for Bone and Mineral Research.
27883065	Light at night disrupts the circadian clock and causes serious health problems in the modern world. Here, we show that newly developed four-package light-emitting diodes (LEDs) can provide harmless lighting at night. To quantify the effects of light on the circadian clock, we employed the concept of circadian illuminance (CIL). CIL represents the amount of light weighted toward the wavelengths to which the circadian clock is most sensitive, whereas visual illuminance (VIL) represents the total amount of visible light. Exposure to 12 h:12 h cycles of white LED light with high and low CIL values but a constant VIL value (conditions hereafter referred to as CH/CL) can entrain behavioral and molecular circadian rhythms in flies. Moreover, flies re-entrain to phase shift in the CH/CL cycle. Core-clock proteins are required for the rhythmic behaviors seen with this LED lighting scheme. Taken together, this study provides a guide for designing healthful white LED lights for use at night, and proposes the use of the CIL value for estimating the harmful effects of any light source on organismal health.
27882399	The Epworth Sleepiness Scale (ESS) is frequently used to determine daytime sleepiness in patients with sleep-disordered breathing. It is still unclear whether different levels of alertness induced by the circadian rhythm influence ESS score.The aim of this study is to investigate the influence of circadian rhythm-dependent alertness on ESS performance.	In a monocentric prospective noninterventional observation study, 97 patients with suspected sleep-disordered breathing were investigated with respect to daytime sleepiness in temporal relationship to polysomnographic examination and treatment. The Karolinska Sleepiness Scale (KSS) and the Stanford Sleepiness Scale (SSS) served as references for the detection of present sleepiness at three different measurement times (morning, noon, evening), prior to and following a diagnostic polysomnography night as well as after a continuous positive airway pressure (CPAP) titration night (9 measurements in total). The KSS, SSS, and ESS were performed at these times in a randomized order.	The KSS and SSS scores revealed a circadian rhythm-dependent curve with increased sleepiness at noon and in the evening. Following a diagnostic polysomnography night, the scores were increased compared to the measurements prior to the night. After the CPAP titration night, sleepiness in the morning was reduced. KSS and SSS reflect the changes in alertness induced by the circadian rhythm. The ESS score war neither altered by the intra-daily nor by the inter-daily changes in the level of alertness.	According to the present data, the ESS serves as a reliable instrument to detect the level of daytime sleepiness independently of the circadian rhythm-dependent level of alertness.	
27881993	Sugar apple (Annona squamosa L.) is a semi-deciduous subtropical tree that progressively sheds its leaves in the spring. However, little information is available on the mechanism involved in flower developmental pattern. To gain a global perspective on the floral transition and flower development of sugar apple, cDNA libraries were prepared independently from inflorescent meristem and three flowering stages. Illumina sequencing generated 107,197,488 high quality reads that were assembled into 71,948 unigenes, with an average sequence length of 825.40 bp. Among the unigenes, various transcription factor families involved in floral transition and flower development were elucidated. Furthermore, a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that unigenes exhibiting differential expressions were involved in various phytohormone signal transduction events and circadian rhythms. In addition, 147 unigenes exhibiting sequence similarities to known flowering-related genes from other plants were differentially expressed during flower development. The expression patterns of 20 selected genes were validated using quantitative-PCR. The expression data presented in our study is the most comprehensive dataset available for sugar apple so far and will serve as a resource for investigating the genetics of the flowering process in sugar apple and other Annona species.
27880762	The behavioural rhythms of organisms are thought to be under strong selection, influenced by the rhythmicity of the environment. Such behavioural rhythms are well studied in isolated individuals under laboratory conditions, but free-living individuals have to temporally synchronize their activities with those of others, including potential mates, competitors, prey and predators. Individuals can temporally segregate their daily activities (for example, prey avoiding predators, subordinates avoiding dominants) or synchronize their activities (for example, group foraging, communal defence, pairs reproducing or caring for offspring). The behavioural rhythms that emerge from such social synchronization and the underlying evolutionary and ecological drivers that shape them remain poorly understood. Here we investigate these rhythms in the context of biparental care, a particularly sensitive phase of social synchronization where pair members potentially compromise their individual rhythms. Using data from 729 nests of 91 populations of 32 biparentally incubating shorebird species, where parents synchronize to achieve continuous coverage of developing eggs, we report remarkable within- and between-species diversity in incubation rhythms. Between species, the median length of one parent's incubation bout varied from 1-19 h, whereas period length-the time in which a parent's probability to incubate cycles once between its highest and lowest value-varied from 6-43 h. The length of incubation bouts was unrelated to variables reflecting energetic demands, but species relying on crypsis (the ability to avoid detection by other animals) had longer incubation bouts than those that are readily visible or who actively protect their nest against predators. Rhythms entrainable to the 24-h light-dark cycle were less prevalent at high latitudes and absent in 18 species. Our results indicate that even under similar environmental conditions and despite 24-h environmental cues, social synchronization can generate far more diverse behavioural rhythms than expected from studies of individuals in captivity. The risk of predation, not the risk of starvation, may be a key factor underlying the diversity in these rhythms.

27880079	In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia.To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control.	This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center.	GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study.	These were GE and continuous glucose monitoring (CGM).	The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study.	In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.	
27879349	Much confusion surrounds the physiological function of the cellular prion protein (PrPC). It is, however, anticipated that knowledge of its function will shed light on its contribution to neurodegenerative diseases and suggest ways to interfere with the cellular toxicity central to them. Consequently, efforts to elucidate its function have been all but exhaustive. Building on earlier work that uncovered the evolutionary descent of the prion founder gene from an ancestral ZIP zinc transporter, we recently investigated a possible role of PrPC in a morphogenetic program referred to as epithelial-to-mesenchymal transition (EMT). By capitalizing on PrPC knockout cell clones in a mammalian cell model of EMT and using a comparative proteomics discovery strategy, neural cell adhesion molecule-1 emerged as a protein whose upregulation during EMT was perturbed in PrPC knockout cells. Follow-up work led us to observe that PrPC regulates the polysialylation of the neural cell adhesion molecule NCAM1 in cells undergoing morphogenetic reprogramming. In addition to governing cellular migration, polysialylation modulates several other cellular plasticity programs PrPC has been phenotypically linked to. These include neurogenesis in the subventricular zone, controlled mossy fiber sprouting and trimming in the hippocampal formation, hematopoietic stem cell renewal, myelin repair and maintenance, integrity of the circadian rhythm, and glutamatergic signaling. This review revisits this body of literature and attempts to present it in light of this novel contextual framework. When approached in this manner, a coherent model of PrPC acting as a regulator of polysialylation during specific cell and tissue morphogenesis events comes into focus.
27878496	We studied the effect 24-h illumination on quantitative and qualitative parameters of the bone marrow cells in Wistar rats. It was shown that desynchronosis reduced the release of nucleated cells from the femoral bone, while melatonin weakened this effect. The number of bone marrow mesenchymal stromal cells was resistant to circadian rhythm disturbances, while proliferation depended on glucose concentration in the medium.
27875989	Sleep disruptions are common in epilepsy patients. Our previous study demonstrates that homeostatic factors and circadian rhythm may mediate epilepsy-induced sleep disturbances when epilepsy occurs at different zeitgeber hours. The proinflammatory cytokine, interleukin-1 (IL-1), is a somnogenic cytokine and may also be involved in epileptogenesis; however, few studies emphasize the effect of IL-1 in epilepsy-induced sleep disruption. We herein hypothesized that IL-1 receptor type 1 (IL-1R1) mediates the pathogenesis of epilepsy and epilepsy-induced sleep disturbances. We determined the role of IL-1R1 by using IL-1R1 knockout (IL-1R1 -/- KO) mice.Our results elucidated the decrease of non-rapid eye movement (NREM) sleep during the light period in IL-1R -/- mice and confirmed the somnogenic role of IL-1R1. Rapid electrical amygdala kindling was performed to induce epilepsy at the particular zeitgeber time (ZT) point, ZT13. Our results demonstrated that seizure thresholds induced by kindling stimuli, such as the after-discharge threshold and successful kindling rates, were not altered in IL-1R -/- mice when compared to those obtained from the wildtype mice (IL-1R +/+ mice). This result suggests that IL-1R1 is not involved in kindling-induced epileptogenesis. During sleep, ZT13 kindling stimulation significantly enhanced NREM sleep during the subsequent 6 h (ZT13-18) in wildtype mice, and sleep returned to the baseline the following day. However, the kindling-induced sleep alteration was absent in the IL-1R -/- KO mice.	These results indicate that the IL-1 signal mediates epilepsy-induced sleep disturbance, but dose not participate in kindling-induced epileptogenesis.	
27872501	Synchronization is central to many complex systems in engineering physics (e.g., the power-grid, Josephson junction circuits, and electro-chemical oscillators) and biology (e.g., neuronal, circadian, and cardiac rhythms). Despite these widespread applications-for which proper functionality depends sensitively on the extent of synchronization-there remains a lack of understanding for how systems can best evolve and adapt to enhance or inhibit synchronization. We study how network modifications affect the synchronization properties of network-coupled dynamical systems that have heterogeneous node dynamics (e.g., phase oscillators with non-identical frequencies), which is often the case for real-world systems. Our approach relies on a synchrony alignment function (SAF) that quantifies the interplay between heterogeneity of the network and of the oscillators and provides an objective measure for a system's ability to synchronize. We conduct a spectral perturbation analysis of the SAF for structural network modifications including the addition and removal of edges, which subsequently ranks the edges according to their importance to synchronization. Based on this analysis, we develop gradient-descent algorithms to efficiently solve optimization problems that aim to maximize phase synchronization via network modifications. We support these and other results with numerical experiments.
27871090	Organisms use endogenous clocks to anticipate regular environmental cycles, such as days and tides. Natural variants resulting in differently timed behaviour or physiology, known as chronotypes in humans, have not been well characterized at the molecular level. We sequenced the genome of Clunio marinus, a marine midge whose reproduction is timed by circadian and circalunar clocks. Midges from different locations show strain-specific genetic timing adaptations. We examined genetic variation in five C. marinus strains from different locations and mapped quantitative trait loci for circalunar and circadian chronotypes. The region most strongly associated with circadian chronotypes generates strain-specific differences in the abundance of calcium/calmodulin-dependent kinase II.1 (CaMKII.1) splice variants. As equivalent variants were shown to alter CaMKII activity in Drosophila melanogaster, and C. marinus (Cma)-CaMKII.1 increases the transcriptional activity of the dimer of the circadian proteins Cma-CLOCK and Cma-CYCLE, we suggest that modulation of alternative splicing is a mechanism for natural adaptation in circadian timing.
27871062	Biological oscillations with an ultradian time scale of 1 to several hours include cycles in behavioral arousal, episodic glucocorticoid release, and gene expression. Ultradian rhythms are thought to have an extrinsic origin because of a perceived absence of ultradian rhythmicity in vitro and a lack of known molecular ultradian oscillators. We designed a novel, non-spectral-analysis method of separating ultradian from circadian components and applied it to a published gene expression dataset with an ultradian sampling resolution. Ultradian rhythms in mouse hepatocytes in vivo have been published, and we validated our approach using this control by confirming 175 of 323 ultradian genes identified in a prior study and found 862 additional ultradian genes. For the first time, we now report ultradian expression of >900 genes in vitro Sixty genes exhibited ultradian transcriptional rhythmicity, both in vivo and in vitro, including 5 genes involved in the cell cycle. Within these 60 genes, we identified significant enrichment of specific DNA motifs in the 1000 bp proximal promotor, some of which associate with known transcriptional factors. These findings are in strong support of instrinsically driven ultradian rhythms and expose potential molecular mechanisms and functions underlying ultradian rhythms that remain unknown.-Van der Veen, D. R., Gerkema, M. P. Unmasking ultradian rhythms in gene expression.
27870848	The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.
27869716	The basic helix-loop-helix (bHLH) transcription factors in insects play essential roles in multiple developmental processes including neurogenesis, sterol metabolism, circadian rhythms, organogenesis and formation of olfactory sensory neurons. The identification and function analysis of bHLH family members of the most destructive insect pest of rice, Nilaparvata lugens, may provide novel tools for pest management. Here, a genome-wide survey for bHLH sequences identified 60 bHLH sequences (NlbHLHs) encoded in the draft genome of N. lugens. Phylogenetic analysis of the bHLH domains successfully classified these genes into 40 bHLH families in group A (25), B (14), C (10), D (1), E (8) and F (2). The number of NlbHLHs with introns is higher than many other insect species, and the average intron length is shorter than those of Acyrthosiphon pisum. High number of ortholog families of NlbHLHs was found suggesting functional conversation for these proteins. Compared to other insect species studied, N. lugens has the highest number of bHLH members. Furthermore, gene duplication events of SREBP, Kn(col), Tap, Delilah, Sim, Ato and Crp were found in N. lugens. In addition, a putative full set of NlbHLH genes is defined and compared with another insect species. Thus, our classification of these NlbHLH members provides a platform for further investigations of bHLH protein functions in the regulation of N. lugens, and of insects in general.
27869182	In mammals, the circadian rhythms of behavioral and physiological activities are regulated by an endogenous clock located in the suprachiasmatic nucleus (SCN). The SCN is composed of ~20,000 neurons, of which some are capable of self-sustained oscillations, while the others do not oscillate in a self-sustainable manner, but show arrhythmic patterns or damped oscillations. Thus far, the effects of these non-self-sustained oscillatory neurons are not fully explored. Here, we examined how the proportion of the non-self-sustained oscillators affects the free running period under constant darkness and the ability to entrain to the light-dark cycle. We find that the proportion does not affect the free running period, but plays a significant role in the range of entrainment. We also find that its effect on the entrainment range depends on the region where the non-self-sustained oscillators are located. If the non-self-sustained oscillatory neurons are situated in the light-sensitive subregion, the entrainment range narrows when the proportion increases. If they are situated in the light-insensitive subregion, however, the entrainment range broadens with the increase of the proportion. We suggest that the heterogeneity within the light-sensitive and light-insensitive subregions of the SCN has important consequences for how the clock works.
27868947	The establishment of organized sleep patterns is an important developmental process during infancy. Little is known about the role of nutrition in sleep maturation. This review focuses on exploring the link between infant sleep and nutrition with the aim to provide an overview of existing literature on the impact of diet and specific nutrients on sleep modulation in infants.An exploratory literature search was performed on the topic in Medline, Scopus and Cochrane Library databases, with a focus on publications in English.	Both the type of nutrients consumed and the timing at which they were consumed, relative to sleeping time, have been reported to influence infant sleep. Some nutrients have been shown to naturally fluctuate in maternal breast milk with circadian rhythm, and nutrients such as tryptophan, nucleotides, essential fatty acids and Omega-3 long-chain fatty acids have been suggested to impact infant sleep.	In summary, little is known about the nutritional impact on infant sleep and sleep maturation, particularly with regard to specific nutrients. While nutrients like tryptophan and nucleotides seem to impact sleep at the level of brain activity, some fatty acids may affect sleep as a result of their role in supporting the maturity of the central nervous system. In our view, the existing literature indicates that the link between nutrition and infant sleep may be a promising concept to support this crucial phase of early development.	
27868193	To investigate headache-related serum melatonin levels and melatonin excretion rhythmicity in patients with hypnic headache (HH).Strict sleep dependency of headache attacks is a pathognomonic feature of HH. Changes in melatonin levels, a marker for circadian rhythm, are assumed to play a pivotal role in the pathophysiology of HH.	Serum melatonin levels were acquired in nine patients with HH and nine age- and gender-matched healthy controls over a 20-hour time period (12 pm, 4 pm, 7 pm, 10 pm, time of headache, and 8 am).	No significant changes of melatonin levels could be detected comparing HH patients and healthy controls. Melatonin excretion rhythmicity was not significantly altered in patients with HH (Mean melatonin level in ng/mL ± SD, patients vs controls at 12 pm: 21.5 ± 9.5 vs 13.6 ± 6.3 [P = .077], 4 pm: 18.4 ± 8.4 vs 14.0 ± 4.7 [P = .222], 7 pm: 19.4 ± 5.1 vs 15.1 ± 4.5 [P = .094], 10 pm: 59.5 ± 45.0 vs 29.4 ± 12.7 [P =.136], headache time: 96.9 ± 68.3 vs 49.1 ± 22.8 [P = .94], and 8 am: 31.6 ± 18.3 vs 26.7 ± 15.6 [P = .489]).	This study is not able to confirm a significant role of melatonin concentration changes in the pathophysiology of HH and vetoes that melatonin deficiency plays a major role in the pathophysiology of the disorder.	
27867253	Insects inhabiting the temperate zones measure seasonal changes in day or night length to enter the overwintering diapause. Diapause induction occurs after the duration of the night exceeds a critical night length (CNL). Our understanding of the time measurement mechanisms is continuously evolving subsequent to Bünning's proposal that circadian systems play the clock role in photoperiodic time measurement (Bünning, 1936). Initially, the photoperiodic clocks were considered to be either based on circadian oscillators or on simple hour-glasses, depending on 'positive' or 'negative' responses in Nanda-Hamner and Bünsow experiments (Nanda & Hammer, 1958; Bünsow, 1960). However, there are also species whose responses can be regarded as neither 'positive', nor as 'negative', such as the Northern Drosophila species Drosophila ezoana, which is investigated in the present study. In addition, modelling efforts show that the 'positive' and 'negative' Nanda-Hamner responses can also be provoked by circadian oscillators that are damped to different degrees: animals with highly sustained circadian clocks will respond 'positive' and those with heavily damped circadian clocks will respond 'negative'. In the present study, an experimental assay is proposed that characterizes the photoperiodic oscillators by determining the effects of non-24-h light/dark cycles (T-cycles) on critical night length. It is predicted that there is (i) a change in the critical night length as a function of T-cycle period in sustained-oscillator-based clocks and (ii) a fixed night-length measurement (i.e. no change in critical night length) in damped-oscillator-based clocks. Drosophila ezoana flies show a critical night length of approximately 7 h irrespective of T-cycle period, suggesting a damped-oscillator-based photoperiodic clock. The conclusion is strengthened by activity recordings revealing that the activity rhythm of D. ezoana flies also dampens in constant darkness.
27867189	The importance of phosphate homeostasis in chronic kidney disease (CKD) has been recognized for decades, but novel insights - which are frequently relevant to everyday clinical practice - continue to emerge. Epidemiological data consistently indicate an association between hyperphosphataemia and poor clinical outcomes. Moreover, compelling evidence suggests direct toxicity of increased phosphate concentrations. Importantly, serum phosphate concentration has a circadian rhythm that must be considered when interpreting patient phosphate levels. Detailed understanding of dietary sources of phosphate, including food additives, can enable phosphate restriction without risking protein malnutrition. Dietary counselling provides an often underestimated opportunity to target the increasing exposure to dietary phosphate of both the general population and patients with CKD. In patients with secondary hyperparathyroidism, bone can be an important source of serum phosphate, and adequate appreciation of this fact should impact treatment. Dietary and pharmotherapeutic interventions are efficacious strategies to lower phosphate intake and serum concentration. However, strong evidence that targeting serum phosphate improves patient outcomes is currently lacking. Future studies are, therefore, required to investigate the effects of modern dietary and pharmacological interventions on clinically meaningful end points.
27867006	Circadian clock-gated cell division cycles are observed from cyanobacteria to mammals via intracellular molecular connections between these two oscillators. Here we demonstrate WNT-mediated intercellular coupling between the cell cycle and circadian clock in 3D murine intestinal organoids (enteroids). The circadian clock gates a population of cells with heterogeneous cell-cycle times that emerge as 12-hr synchronized cell division cycles. Remarkably, we observe reduced-amplitude oscillations of circadian rhythms in intestinal stem cells and progenitor cells, indicating an intercellular signal arising from differentiated cells governing circadian clock-dependent synchronized cell division cycles. Stochastic simulations and experimental validations reveal Paneth cell-secreted WNT as the key intercellular coupling component linking the circadian clock and cell cycle in enteroids.
27866957	Circadian patterns are at the core of many physiological processes, and their disruption can have short- and long-term consequences. This essay focuses on one of the best known patterns, the daily oscillation of body temperature (Tb), and the possibility of its difference between genders. From human and animal studies globally considered, the tentative conclusion is reached that differences in Tb circadian pattern between genders are very small and probably limited to the timing of the Rhythm, not to its amplitude. Such similarity between genders, despite the differences in hormona rhythm (small r) l systems, presumably testifies to the importance that the Tb circadian pattern plays in the economy of the organism and its survival against environmental challenges. The second part of the article presents some previously unpublished experimental data from behaving male and female rats during hypoxia in synchronized conditions. In adult rats hypoxia (10.5% O2 for three days) caused a profound drop of the Tb daily oscillations; by day 3 they were 55% (♀) and 22% (♂) of the normoxic amplitudes, with a statistically significant gender difference. In pre-puberty rats (26-day old) hypoxia caused a major disruption of the circadian pattern qualitatively similar to the adults but not different between genders. Hence, on the basis of this preliminary set of data, it seems that sex-hormones may be a factor in how the Tb daily pattern responds to hypoxia. The implications of the effects of hypoxia on the circadian patterns, and the possibility that such effects may differ between genders, are matters that could have biological and clinical implications and deserve further investigations.
27864091	Circadian rhythms underlie many immune responses and allergic diseases. Subcutaneous immunotherapy (SCIT) can result in adverse reactions; however, it is unclear whether such reactions have a diurnal pattern.To assess whether the timing of SCIT affects the rate of adverse reactions.	This study was a retrospective medical record review of adult patients (n = 289) who received SCIT at the Northwestern Medical Faculty Foundation, Chicago, Illinois, during a 10-year period (2004-2014). Injections were given in the outpatient setting. There were a total of 17,457 injections with 574 reactions. Covariates included age, sex, median income, asthma status, vial contents, number of injections, and previous immunotherapy reactions. Logistical regression was used to calculate the odds of having a reaction with time of SCIT administration as the primary determinate.	Immunotherapy reactions occurred more frequently after afternoon or evening (pm) injections (328/8721 = 3.8%) vs morning (am) injections (246/8736 = 2.8%), (χ2 = 12.26, P < .01). Systemic reactions, defined as World Allergy Organization grade 1 or higher, did not have diurnal variation (59/8721 = 0.67% for pm vs am 56/8736 = 0.64% for morning; χ2 = 0.08; P = .77). pm injections resulted in higher odds of reaction compared with am injection in a fully adjusted logistic regression model (odds ratio = 1.43; 95% confidence interval, 1.20-1.70; P < .01). When considering time as 4 categories, the highest odds of reaction were noted for the period from 15:01 to 17:30 (odds ratio, 1.55; 95% confidence interval, 1.21-2.00; P < .01).	pm injections of SCIT are associated with increased cutaneous reaction rates when compared with am injections. In patients experiencing bothersome local reactions, it may be beneficial to administer SCIT in the morning.	
27864040	The present study aimed to evaluate the circadian rhythmicity of some physiological variables, including rectal temperature (RT), respiration rate (RR), heart rate (HR) and skin temperature (ST) in sheep during the summer and winter in semi-arid tropical environment. Eight Malpura rams of 3-4year of age with an average body weight of 37.1±1.99kg were selected for the study. All the animals were fed individually for a maintenance requirement on a body weight basis. The RT, RR, HR and ST values were measured in each animal at 3hour intervals for 24 consecutive hours. Ambient temperature (DBT) and relative humidity (RH) was also recorded inside the shed at the time of physiological parameter study. The cosinor analysis showed a daily circadian rhythm (P<0.01) in RR, HR and ST values during the summer and winter in sheep under semi-arid environment. The RR, HR and ST differ significantly (P<0.05) between summer and winter. The amplitude of RR, RT and ST differ significantly (P<0.05) between the seasons. The results indicate that the circadian rhythmicity of RR, HR, RT and ST during summer and winter changed as expected in compliance to the seasonal requirements of animal's adaptability.
27863901	Sleep disorders are among the most common non-motor manifestations in Parkinson's disease (PD) and have a significant negative impact on quality of life. While sleep disorders in PD share most characteristics with those that occur in the general population, there are several considerations specific to this patient population regarding diagnosis, management, and implications. The available research on these disorders is expanding rapidly, but many questions remain unanswered. We thus conducted a systematic review of the literature published from 2005 to 2015 on the following disorders of sleep and wakefulness in PD: REM sleep behavior disorder, insomnia, nocturia, restless legs syndrome and periodic limb movements, sleep disordered breathing, excessive daytime sleepiness, and circadian rhythm disorders. We discuss the epidemiology, etiology, clinical implications, associated features, evaluation measures, and management of these disorders. The influence on sleep of medications used in the treatment of motor and non-motor symptoms of PD is detailed. Additionally, we suggest areas in need of further research.
27863207	This study investigated the effects of 24 weeks of morning versus evening same-session combined strength (S) and endurance (E) training on physical performance, muscle hypertrophy, and resting serum testosterone and cortisol diurnal concentrations. Forty-two young men were matched and assigned to a morning (m) or evening (e) E + S or S + E group (mE + S, n = 9; mS + E, n = 9; eE + S, n = 12; and eS + E, n = 12). Participants were tested for dynamic leg press 1-repetition maximum (1RM) and time to exhaustion (Texh) during an incremental cycle ergometer test both in the morning and evening, cross-sectional area (CSA) of vastus lateralis and diurnal serum testosterone and cortisol concentrations (0730 h; 0930 h; 1630 h; 1830 h). All groups similarly increased 1RM in the morning (14%-19%; p < 0.001) and evening (18%-24%; p < 0.001). CSA increased in all groups by week 24 (12%-20%, p < 0.01); however, during the training weeks 13-24 the evening groups gained more muscle mass (time-of-day main effect; p < 0.05). Texh increased in all groups in the morning (16%-28%; p < 0.01) and evening (18%-27%; p < 0.001), however, a main effect for the exercise order, in favor of E + S, was observed on both testing times (p < 0.051). Diurnal rhythms in testosterone and cortisol remained statistically unaltered by the training order or time. The present results indicate that combined strength and endurance training in the evening may lead to larger gains in muscle mass, while the E + S training order might be more beneficial for endurance performance development. However, training order and time seem to influence the magnitude of adaptations only when the training period exceeded 12 weeks.
27862517	Migratory behaviour is controlled by endogenous circannual rhythms that are synchronized by external cues, such as photoperiod. Investigations on the genetic basis of circannual rhythmicity in vertebrates have highlighted that variation at candidate 'circadian clock' genes may play a major role in regulating photoperiodic responses and timing of life cycle events, such as reproduction and migration. In this comparative study of 23 trans-Saharan migratory bird species, we investigated the relationships between species-level genetic variation at two candidate genes, Clock and Adcyap1, and species' traits related to migration and geographic distribution, including timing of spring migration across the Mediterranean Sea, migration distance and breeding latitude. Consistently with previous evidence showing latitudinal clines in 'circadian clock' genotype frequencies, Clock allele size increased with breeding latitude across species. However, early- and late-migrating species had similar Clock allele size. Species migrating over longer distances, showing delayed spring migration and smaller phenotypic variance in spring migration timing, had significantly reduced Clock (but not Adcyap1) gene diversity. Phylogenetic confirmatory path analysis suggested that migration date and distance were the most important variables directly affecting Clock gene diversity. Hence, our study supports the hypothesis that Clock allele size increases poleward as a consequence of adaptation to the photoperiodic regime of the breeding areas. Moreover, we show that long-distance migration is associated with lower Clock diversity, coherently with strong stabilizing selection acting on timing of life cycle events in long-distance migratory species, likely resulting from the time constraints imposed by late spring migration.
27862514	Irregular 24 h light/dark cycles with night-time light exposure and a low amplitude are disruptive for sleep, mood and circadian rhythms. Nevertheless such lighting conditions are quite common in medical care facilities. A controlled clinical trial among 196 cardiology ward patients (mean age 66.5 ± 13.1 years SD) investigated how a patient room lighting intervention affects sleep, appraisal and mood across hospitalization. Patients were either assigned to a standardly-lit room or to a room with an interventional lighting system offering a dynamic 24 h light/dark cycle with low nocturnal light exposure and 2 h of bright light (1750 lux) during daytime. Measures included wrist actigraphy and questionnaires assessing alertness, sleep quality, anxiety, depression and lighting appraisal. The median length of hospitalization was 5 days in both study arms. Subjective scores on sleep, alertness, anxiety and depression did not differ between arms. Lighting appraisal in intervention rooms was better as compared to standardly-lit rooms, both in patients (P < 0.001) and staff (P < 0.005). Actigraphic sleep duration of patients improved by 5.9 min (95% CI: 0.6-11.2; P = 0.03 intervention × time effect) per hospitalization day with interventional lighting instead of standard lighting. After 5 days of hospitalization, sleep duration in the lighting intervention rooms increased by 29 min, or a relative 7.3%, as compared to standardly-lit rooms. A 24 h lighting system with enhanced daytime brightness and restricted nocturnal light exposure can improve some aspects of appraisal and objective sleep in hospital patients. More clinical research is needed to establish the best lighting strategy to promote healing and wellbeing within healthcare settings.
27859638	Alterations of circadian rhythms are among the most debilitating non-motor symptoms in Parkinson's Disease (PD). Although a growing awareness towards these symptoms has occurred during the last decade, their underlying neuropathophysiology remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these problems. Recent studies have investigated multiple circadian rhythms at different stages of PD. The advances made have allowed an accurate evaluation of the affected underlying pathways and mechanisms. Here I dissect, over disease progression, the relative causal contribution to health impairments in PD patients of dysfunctions in the different components of the neural network governing circadian rhythms. A deeper understanding of these mechanisms will provide not only a greater understanding of disease neuropathology, but also hold the promise for effective therapies. © 2016 International Parkinson and Movement Disorder Society.
27859082	Theory suggests that high activity levels in animals increase growth at the cost of increased mortality. This growth-mortality tradeoff has recently been incorporated into the wider framework of the pace-of-life syndrome (POLS) hypothesis. However, activity is often quantified only in the laboratory and on a diurnal basis, leaving open the possibility that animals manage predation risk and feeding efficiency in the wild by modulating their circadian activity rhythms. Here we investigate how laboratory activity in wild brown trout parr (Salmo trutta L.) associates with circadian activity, growth, and mortality in their natal stream. We found that individuals with high activity in the laboratory displayed high dispersal and cathemeral activity in their natal stream. In contrast, trout with low laboratory activity showed variation of activity in the wild, which was negatively related to the light intensity. Our results do not support the growth-mortality trade-off of the POLS hypothesis as highly active, fast-growing individuals showed higher survival than inactive conspecifics. These novel results show for the first time that active and inactive individuals, as scored in the lab, can show different circadian patterns of behavior in the wild driven by light intensity. This implies that studies conducted under a narrow range of light conditions can bias our understanding of individual behavioral variation and its fitness consequences in the wild.
27858974	The American Geriatrics Society, with support from the National Institute on Aging and other funders, held its eighth Bedside-to-Bench research conference, entitled "Sleep, Circadian Rhythms, and Aging: New Avenues for Improving Brain Health, Physical Health and Functioning," October 4 to 6, 2015, in Bethesda, Maryland. Part of a conference series addressing three common geriatric syndromes-delirium, sleep and circadian rhythm (SCR) disturbance, and voiding dysfunction-the series highlighted relationships and pertinent clinical and pathophysiological commonalities between these three geriatric syndromes. The conference provided a forum for discussing current sleep, circadian rhythm, and aging research; identifying gaps in knowledge; and developing a research agenda to inform future investigative efforts. The conference also promoted networking among developing researchers, leaders in the field of SCR and aging, and National Institutes of Health program personnel.
27858294	The melatonin as the pineal gland's secretory product is implicated in the pathophysiology of migraine. Melatonin has critical functions in human physiology, and research underscores the importance of melatonin in circadian rhythm, sleep, and mood regulation. Clinical observations have indicated that migraine attacks have a seasonal, menstrual, and circadian timing, suggesting that chronobiological mechanisms and their alterations may causally involve in the etiology of the disease. However, the topic has received relatively little attention in the migraine literature. Associations between melatonin, circadian preference, sleep, and mood states were investigated in the current study. Fifty-five patients (47 females and 8 males) were compared to 57 gender and age-matched control subjects (40 females and 17 males). A socio-demographical questionnaire, the Beck Depression Inventory, Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Profile of Mood States (POMS), and Morningness-Eveningness Questionnaire were administered to volunteers. Blood samples were taken from all participants at about 1:00 AM in an unlit room not to hamper melatonin secretion, and blood melatonin levels were measured using quantitative ELISA test. In comparison with controls, melatonin levels were significantly lower among migraine patients. Migraineurs reported significantly greater scores on the BAI, confusion-bewilderment subscale of the POMS, and total and sleep latency subscale of the PSQI. Migraine patients who had nausea during the migraine attacks and who reported bouts relevant to certain food consumption, such as cheese or chocolate, had significantly lower levels of melatonin. Contrarily, groups did not reveal statistically substantial difference in circadian preferences.
27857964	This study assessed sleep and circadian rhythms across the perinatal period in new mothers with and without postpartum weight retention (PPWR).Weight was measured at 2 and 16 weeks postpartum in 21 women with previous major depression or bipolar disorder (mean age 29.5±4.7 years) who self-reported pre-pregnancy weight during third trimester. Wrist actigraphy was acquired at 33 weeks gestation and postpartum weeks 2, 6, and 16. Circadian phase was measured at 33 weeks gestation and 6 weeks postpartum. The Horne-Östberg Morningness-Eveningness Questionnaire and Pittsburgh Sleep Quality Inventory were completed during third trimester. Women were classified as PPWR+ if weight at 16 weeks postpartum exceeded pre-pregnancy weight by ≥5kg.	Compared to pre-pregnancy, average weight gain (±SD) was 6.3±8.8 kg at 2 weeks postpartum and 5.2±8.5 kg at 16 weeks postpartum. ANOVA showed that PPWR+ women (n=8, 38%) had later sleep offset times and lower sleep efficiencies than PPWR- women at all time points and were more likely to report snoring during pregnancy.	Data from this small sample showed that women with PPWR had more disturbed sleep and later wake times and were more likely to report symptoms of sleep-disordered breathing. Future work in larger samples should examine whether interventions to improve sleep during pregnancy decreases PPWR.	
27857641	The purpose of this case report was to describe the examination and management of a patient with chronic fatigue.A 34-year-old woman presented to a chiropractic clinic with complaints of fatigue and inability to lose weight for 2 years. When tested, she was found to have high serum thyroglobulin antibodies, low serum vitamin D3, low saliva dehydroepiandrosterone-sulfate, and low saliva total and diurnal cortisol.	The patient was placed on an anti-inflammatory ancestral diet and given recommendations to decrease the aerobic intensity of her exercise routine. On the basis of the result of conventional and functional laboratory tests, she was prescribed a treatment plan of targeted supplementation. After 12 weeks of application of dietary, lifestyle, and supplementation recommendations, the patient reported experiencing increased energy and weight loss of 15 pounds. Her thyroglobulin antibodies returned within reference range, salivary cortisol increased and closely followed the proper circadian rhythm, and dehydroepiandrosterone-sulfate increased.	This report describes improvement in a patient with chronic fatigue with the use of nonpharmaceutical polytherapy involving dietary changes, lifestyle modification, and supplementation.	
27857215	Close ties have been made among certain nutrients, obesity, type 2 diabetes and circadian clocks. Among nutrients, taurine has been documented as being effective against obesity and type 2 diabetes. However, the impact of taurine on circadian clocks has not been elucidated. We investigated whether taurine can modulate or correct disturbances in daily rhythms caused by a high-fat diet in mice. Male C57BL/6 mice were divided in four groups: control (C), control + taurine (C+T), high-fat diet (HFD) and HFD + taurine (HFD+T). They were administered 2% taurine in their drinking water for 10 weeks. Mice were euthanized at 6:00, 12:00, 18:00, and 24:00. HFD mice increased body weight, visceral fat and food intake, as well as higher levels of glucose, insulin and leptin, throughout the 24 h. Taurine prevented increments in food intake, body weight and visceral fat, improved glucose tolerance and insulin sensitivity and reduced disturbances in the 24 h patterns of plasma insulin and leptin. HFD downregulated the expression of clock genes Rev-erbα, Bmal1, and Per1 in pancreatic islets. Taurine normalized the gene and protein expression of PER1 in beta-cells, which suggests that it could be beneficial for the correction of daily rhythms and the amelioration of obesity and diabetes.
27856696	Light and the circadian clock have a profound effect on the biology of organisms through the regulation of large sets of genes. Toward understanding how light and the circadian clock regulate gene expression, we used genome-wide approaches to identify the direct and indirect targets of the light-responsive and clock-controlled transcription factor ADV-1 in Neurospora crassa A large proportion of ADV-1 targets were found to be light- and/or clock-controlled, and enriched for genes involved in development, metabolism, cell growth, and cell fusion. We show that ADV-1 is necessary for transducing light and/or temporal information to its immediate downstream targets, including controlling rhythms in genes critical to somatic cell fusion. However, while ADV-1 targets are altered in predictable ways in Δadv-1 cells in response to light, this is not always the case for rhythmic target gene expression. These data suggest that a complex regulatory network downstream of ADV-1 functions to generate distinct temporal dynamics of target gene expression relative to the central clock mechanism.
27856655	Glucocorticoids are steroid hormones that once bound to their receptor interact with the DNA binding domain. Almost 1000-2000 genes are sensitive to their effects, including immune/inflammatory response genes. However, their role in pathophysiology and therapy is still debated. We performed a literature survey using the key words glucocorticoids, inflammation, autoimmune disease, rheumatology and adrenal glands in order to define important targets for this review on glucocorticoids. Considering endogenous/exogenous glucocorticoids in chronic inflammatory diseases brought up five major points for discussion: inadequately low production of endogenous cortisol relative to systemic inflammation (the disproportion principle); changes of the systemic and local cortisol-to-cortisone shuttle (reactivation and degradation of cortisol); inflammation-induced glucocorticoid resistance; highlights of present glucocorticoid therapy; and the role of circadian rhythms in action of cortisol. Much of this information becomes understandable in the context of neurohormonal energy regulation as recently summarized. The optimization of long-term low-dose glucocorticoid therapy in chronic inflammatory diseases arises from the understanding of the above mentioned aspects. Since glucocorticoid resistance is a consequence of inflammation, adequate anti-inflammatory therapy is mandatory.
27856350	The circadian clock is a transcriptional/translational feedback loop that drives the rhythmic expression of downstream mRNAs. Termed "clock-controlled genes," these molecular outputs of the circadian clock orchestrate cellular, metabolic, and behavioral rhythms. As part of our on-going work to characterize key upstream regulators of circadian mRNA expression, we have identified a novel clock-controlled gene in Drosophila melanogaster, Achilles (Achl), which is rhythmic at the mRNA level in the brain and which represses expression of antimicrobial peptides in the immune system. Achilles knock-down in neurons dramatically elevates expression of crucial immune response genes, including IM1 (Immune induced molecule 1), Mtk (Metchnikowin), and Drs (Drosomysin). As a result, flies with knocked-down Achilles expression are resistant to bacterial challenges. Meanwhile, no significant change in core clock gene expression and locomotor activity is observed, suggesting that Achilles influences rhythmic mRNA outputs rather than directly regulating the core timekeeping mechanism. Notably, Achilles knock-down in the absence of immune challenge significantly diminishes the fly's overall lifespan, indicating a behavioral or metabolic cost of constitutively activating this pathway. Together, our data demonstrate that (1) Achilles is a novel clock-controlled gene that (2) regulates the immune system, and (3) participates in signaling from neurons to immunological tissues.
27855744	Melatonin is an important neurohormone, which mediates circadian rhythms and the sleep cycle. As such, it is a popular and readily available supplement for the treatment and prevention of sleep-related disorders including insomnia and jet lag. This study quantified melatonin in 30 commercial supplements, comprising different brands and forms and screened supplements for the presence of serotonin.A total of 31 supplements were analyzed by ultraperformance liquid chromatography with electrochemical detection for quantification of melatonin and serotonin. Presence of serotonin was confirmed through analysis by ultraperformance liquid chromatography with mass spectrometry detection.	Melatonin content was found to range from -83% to +478% of the labelled content. Additionally, lot-to-lot variable within a particular product varied by as much as 465%. This variability did not appear to be correlated with manufacturer or product type. Furthermore, serotonin (5-hydroxytryptamine), a related indoleamine and controlled substance used in the treatment of several neurological disorders, was identified in eight of the supplements at levels of 1 to 75 μg.	Melatonin content did not meet label within a 10% margin of the label claim in more than 71% of supplements and an additional 26% were found to contain serotonin. It is important that clinicians and patients have confidence in the quality of supplements used in the treatment of sleep disorders. To address this, manufacturers require increased controls to ensure melatonin supplements meet both their label claim, and also are free from contaminants, such as serotonin.	A commentary on this article appears in this issue on page 163.	
27855737	Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related medical and psychiatric illnesses. Twin and family studies have shown that chronotype is a heritable trait, thus directing attention toward its genetic basis. Chronotype is influenced by a large number of genetic variants, making it a complex phenotype. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWASs), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes such as chronotype. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. Several genes previously unknown to influence chronotype were identified. The present review discusses findings of these three GWASs in the context of prior research. Replicated and non-replicated results across these GWASs are discussed along with explorations of methodological differences. Future directions in molecular science, model systems, and discovery of rare variants are discussed.
27855200	Opalin, a central nervous system-specific myelin protein phylogenetically unique to mammals, has been suggested to play a role in mammalian-specific myelin. To elucidate the role of Opalin in mammalian myelin, we disrupted the Opalin gene in mice and analyzed the impacts on myelination and behavior. Opalin-knockout (Opalin-/-) mice were born at a Mendelian ratio and had a normal body shape and weight. Interestingly, Opalin-/- mice had no obvious abnormalities in major myelin protein compositions, expression of oligodendrocyte lineage markers, or domain organization of myelinated axons compared with WT mice (Opalin+/+) mice. Electron microscopic observation of the optic nerves did not reveal obvious differences between Opalin+/+ and Opalin-/- mice in terms of fine structures of paranodal loops, transverse bands, and multi-lamellae of myelinated axons. Moreover, sensory reflex, circadian rhythm, and locomotor activity in the home cage, as well as depression-like behavior, in the Opalin-/- mice were indistinguishable from the Opalin+/+ mice. Nevertheless, a subtle but significant impact on exploratory activity became apparent in Opalin-/- mice exposed to a novel environment. These results suggest that Opalin is not critical for central nervous system myelination or basic sensory and motor activities under conventional breeding conditions, although it might be required for fine-tuning of exploratory behavior.
27853566	As zebrafish emerge as a species of choice for the investigation of biological processes, a number of experimental protocols are being developed to study their social behaviour. While live stimuli may elicit varying response in focal subjects owing to idiosyncrasies, tiredness and circadian rhythms, video stimuli suffer from the absence of physical input and rely only on two-dimensional projections. Robotics has been recently proposed as an alternative approach to generate physical, customizable, effective and consistent stimuli for behavioural phenotyping. Here, we contribute to this field of investigation through a novel four-degree-of-freedom robotics-based platform to manoeuvre a biologically inspired three-dimensionally printed replica. The platform enables three-dimensional motions as well as body oscillations to mimic zebrafish locomotion. In a series of experiments, we demonstrate the differential role of the visual stimuli associated with the biologically inspired replica and its three-dimensional motion. Three-dimensional tracking and information-theoretic tools are complemented to quantify the interaction between zebrafish and the robotic stimulus. Live subjects displayed a robust attraction towards the moving replica, and such attraction was lost when controlling for its visual appearance or motion. This effort is expected to aid zebrafish behavioural phenotyping, by offering a novel approach to generate physical stimuli moving in three dimensions.
27853240	Apterous (Ap), the best studied LIM-homeodomain transcription factor in Drosophila, cooperates with the cofactor Chip (Chi) to regulate transcription of specific target genes. Although Ap regulates various developmental processes, its function in the adult brain remains unclear. Here, we report that Ap and Chi in the neurons expressing PDF, a neuropeptide, play important roles in proper sleep/wake regulation in adult flies. PDF-expressing neurons consist of two neuronal clusters: small ventral-lateral neurons (s-LNvs) acting as the circadian pacemaker and large ventral-lateral neurons (l-LNvs) regulating light-driven arousal. We identified that Ap localizes to the nuclei of s-LNvs and l-LNvs. In light-dark (LD) cycles, RNAi knockdown or the targeted expression of dominant-negative forms of Ap or Chi in PDF-expressing neurons or l-LNvs promoted arousal. In contrast, in constant darkness, knockdown of Ap in PDF-expressing neurons did not promote arousal, indicating that a reduced Ap function in PDF-expressing neurons promotes light-driven arousal. Furthermore, Ap expression in l-LNvs showed daily rhythms (peaking at midnight), which are generated by a direct light-dependent mechanism rather than by the endogenous clock. These results raise the possibility that the daily oscillation of Ap expression in l-LNvs may contribute to the buffering of light-driven arousal in wild-type flies.
27852781	Body temperature exhibits rhythmic fluctuations over a 24 h period (Refinetti and Menaker, 1992) and decreases during the night, which is associated with sleep initiation (Gilbert et al., 2004; Kräuchi, 2007a,b). However, the underlying mechanism of this temperature decrease is largely unknown. We have previously shown that Drosophila exhibit a daily temperature preference rhythm (TPR), in which their preferred temperatures increase during the daytime and then decrease at the transition from day to night (night-onset) (Kaneko et al., 2012). Because Drosophila are small ectotherms, their body temperature is very close to that of the ambient temperature (Stevenson, 1985), suggesting that their TPR generates their body temperature rhythm. Here, we demonstrate that the neuropeptide diuretic hormone 31 (DH31) and pigment-dispersing factor receptor (PDFR) contribute to regulate the preferred temperature decrease at night-onset. We show that PDFR and tethered-DH31 expression in dorsal neurons 2 (DN2s) restore the preferred temperature decrease at night-onset, suggesting that DH31 acts on PDFR in DN2s. Notably, we previously showed that the molecular clock in DN2s is important for TPR. Although PDF (another ligand of PDFR) is a critical factor for locomotor activity rhythms, Pdf mutants exhibit normal preferred temperature decreases at night-onset. This suggests that DH31-PDFR signaling specifically regulates a preferred temperature decrease at night-onset. Thus, we propose that night-onset TPR and locomotor activity rhythms are differentially controlled not only by clock neurons but also by neuropeptide signaling in the brain.Body temperature rhythm (BTR) is fundamental for the maintenance of functions essential for homeostasis, such as generating metabolic energy and sleep. One major unsolved question is how body temperature decreases dramatically during the night. Previously, we demonstrated that a BTR-like mechanism, referred to as temperature preference rhythm (TPR), exists in Drosophila Here, we demonstrate that the diuretic hormone 31 (DH31) neuropeptide and pigment-dispersing factor receptor (PDFR) regulate preferred temperature decreases at night-onset via dorsal neurons 2. This is the first in vivo evidence that DH31 could function as a ligand of PDFR. Although both DH31 and PDF are ligands of PDFR, we show that DH31 regulates night-onset TPR, but PDF does not, suggesting that night-onset TPR and locomotor activity rhythms are controlled by different neuropeptides via different clock cells.	
27849618	Circadian rhythms are based on endogenous clocks that allow organisms to adjust their physiology and behavior by entrainment to the solar day and, in turn, to select the optimal times for most biological variables. Diverse model systems-including mice, flies, fungi, plants, and bacteria-have provided important insights into the mechanisms of circadian rhythmicity. However, the general principles that govern the circadian clock of Caenorhabditis elegans have remained largely elusive. Here we report robust molecular circadian rhythms in C elegans recorded with a bioluminescence assay in vivo and demonstrate the main features of the circadian system of the nematode. By constructing a luciferase-based reporter coupled to the promoter of the suppressor of activated let-60 Ras (sur-5) gene, we show in both population and single-nematode assays that C elegans expresses ∼24-h rhythms that can be entrained by light/dark and temperature cycles. We provide evidence that these rhythms are temperature-compensated and can be re-entrained after phase changes of the synchronizing agents. In addition, we demonstrate that light and temperature sensing requires the photoreceptors LITE and GUR-3, and the cyclic nucleotide-gated channel subunit TAX-2. Our results shed light on C elegans circadian biology and demonstrate evolutionarily conserved features in the circadian system of the nematode.
27849563	The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mm Hg; 95% confidence interval, 14.1-17.8 mm Hg), nighttime systolic BP (mean difference=9.6 mm Hg; 95% confidence interval, 7.7-11.5 mm Hg), daytime systolic BP (mean difference=12.3 mm Hg; 95% confidence interval, 10.6-13.9 mm Hg), and 24-hour systolic BP (mean difference=11.2 mm Hg; 95% confidence interval, 9.7-12.8 mm Hg). The night/day systolic BP ratio was similar between the intensive (0.92±0.09) and standard-treatment groups (0.91±0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland-Altman plots. In conclusion, targeting a systolic BP of <120 mm Hg, when compared with <140 mm Hg, resulted in lower nighttime, daytime, and 24-hour systolic BP, but did not change the night/day systolic BP ratio. Ambulatory BP monitoring may be required to assess the effect of targeted hypertension therapy on out of office BP. Further studies are needed to assess whether targeting hypertension therapy based on ambulatory BP improves clinical outcomes.
27846817	MicroRNAs (miRNAs) are critical regulators responding to acute environmental stresses in both plants and animals. By modulating gene expression, miRNAs either restore or reconstitute a new expression program to enhance cell tolerance to stresses. Cold shock is one of the stresses that can induce acute physiological responses and transcriptional changes in aquatic creatures. Previous genomic studies have revealed many cold-affected genes in fish larvae and adults, however, the role of miRNAs in acute cold response is still ambiguous. To elucidate the regulatory roles of miRNAs in the cold-inducible responses, we performed small RNA-seq and RNA-seq analyses and found potential cold regulatory miRNAs and genes. We further investigated their interactions and involvements in cold tolerance.Small RNA-seq and RNA-seq identified 29 up-/26 down-regulated miRNAs and 908 up-/468 down-regulated genes, respectively, in responding to cold shock for 4 h at 18 °C. miRNA and transcriptomic analyses showed these miRNAs and mRNAs are involved in similar biological processes and pathways. Gene ontology enrichment analyses revealed the cold-induced genes were enriched in pathways, including melanogenesis, GnRH pathway, circadian rhythm, etc. We were particularly interested in the changes in circadian clock genes that affect daily metabolism. The enrichment of circadian clock genes was also observed in previous fish cold acclimation studies, but have not been characterized. To characterize the functional roles of circadian clock genes in cold tolerance, we individually overexpressed selected clock genes in zebrafish larvae and found one of the core clock genes per2 resulted in better recovery from cold shock. In addition, we validated the interaction of per2 with its associate miRNA, dre-mir-29b, which is also cold-inducible. It suggests the transcription of per2 can be modulated by miRNA upon cold shock.	Collectively, our observations suggest that miRNAs are fine turners for regulating genomic plasticity against cold shock. We further showed that the fine tuning of core clock gene per2 via its associated miRNA, dre-mir-29b, can enhance the cold tolerance of zebrafish larvae.	
27846625	A combined neuroendocrine, metabolic, and chronobiological view can help to better understand the multiple and complex mechanisms involved in obesity development and maintenance, as well as to provide new effective approaches for its control and treatment. Indeed, we have currently updated data on the whole adipogenic process involved in white adipose tissue (WAT) mass expansion, namely due to a mechanism whereby WAT cells become hypertrophic, thus inducing a serious local (WAT) inflammatory condition that in turn, will impair not only the cross-talk between the hypothalamus and the WAT, but also favoring the development of deep and widespread neuroendocrine-metabolic dysfunction. Moreover, we also have revisited the circadian clock genes involved in dysfunctional WAT mass expansion and the mechanisms that may lead to obesity development, including early metabolic dysfunctions, enhanced oxidative stress and distorted energy homeostasis. The epigenetic changes of clock genes driving metabolic disease and obesity development have also been included in this review. Finally, we have also underlined the relevance of metabolic homeostasis regulation by central and peripheral organ clocks, sleep disturbances, nutrients, and feeding time, as key factors in obesity development as well as both, classical and chronotherapeutic approaches for its prevention and treatment.
27846049	Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia.Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis.	Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms.	Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.	

27845249	The light-dark cycle and feeding can be the most important factors acting as synchronizers of biological rhythms. In this research we aimed to evaluate synchronization to feeding schedule of daily rhythms of locomotor activity and digestive enzymes of tilapia. For that purpose, 120 tilapias (65.0±0.6g) were distributed in 12 tanks (10 fish per tank) and divided into two groups. One group was fed once a day at 11:00h (zeitgeber time, ZT6) (ML group) and the other group was fed at 23:00h (ZT18) (MD group). The fish were anesthetized to collect samples of blood, stomach and midgut at 4-hour intervals over a period of 24h. Fish fed at ML showed a diurnal locomotor activity (74% of the total daily activity occurring during the light phase) and synchronization to the feeding schedule, as this group showed anticipation to the feeding time. Fish fed at MD showed a disruption in the pattern of locomotor activity and became less diurnal (59%). Alkaline protease activity in the midgut showed daily rhythm with the achrophase at the beginning of the dark phase in both ML and MD groups. Acid protease and amylase did not show significant daily rhythms. Plasma glucose showed a daily rhythm with the achrophase shifted by 12h in the ML and MD groups. These results revealed that the feeding time and light cycle synchronize differently the daily rhythms of behavior, digestive physiology and plasma metabolites in the Nile tilapia, which indicate the plasticity of the circadian system and its synchronizers.
27845062	Animal models have shown that myopic defocus is a potent inhibitor of ocular growth: brief (1-2 h) daily periods of defocus are sufficient to counter the effects of much longer periods of hyperopic defocus, or emmetropic vision. While the variables of duration and frequency have been well-documented with regard to effect, we ask whether the efficacy of the exposures might also depend on the time of day that they are given. We also ask whether there are differential effects on the rhythms in axial length or choroidal thickness. 2-week-old chickens were divided into 2 groups: (1) "2-hr lens-wear". Chicks wore monocular +10D lenses for 2 h per day for 5 days at one of 3 times of day: 5:30 a.m. (n = 11), 12 p.m. (n = 8) or 7:30 p.m. (n = 11). (2) "2-hr minus lens-removal". Chicks wore monocular -10D lenses continually for 7 days, except for a 2-hr period when lenses were removed; the removal occurred at one of 2 times: 5:30 a.m. (n = 8) or 7:30 p.m. (n = 8). Both paradigms exposed eyes to brief myopic defocus that differed in its magnitude, and in the visual experience for the rest of the day. High frequency A-scan ultrasonography was done at the start of the experiment; on the last day, it was done at 6-hr intervals, starting at noon, over 24-hr, to assess rhythm parameters. Refractive errors were measured using a Hartinger's refractometer at the end. In both paradigms, myopic defocus in the evening was significantly more effective at inhibiting eye growth than in the morning ("2-hr lens-wear": X-C: -149 vs -83 μm/5d; "2-hr lens-removal": X-C: 91 vs 245 μm/7d; post-hoc Bonferroni test, p < 0.01 for both). Data for "noon" was similar to that of "evening". In general, the refractive errors were consistent with the eye growth. In both paradigms, a 2-way ANOVA showed that "time of day" accounted for the differences between the morning versus evening groups ("2-hr lens-wear": p = 0.0161; "2-hr lens-removal": p = 0.038). In the "plus-lens" morning exposure, the rhythm in axial length could not be fit to a sinusoid. In both paradigms, the rhythm in axial length for the evening group was phase-advanced relative to noon or morning ("2-hr lens-wear": evening vs noon; 1:24 p.m. vs 6:42 p.m.; "2-hr lens-removal": evening vs morning: 12:15 p.m. vs 6:18 p.m.; p < 0.05 for both). Finally, the amplitude of the rhythm as assessed by the "day vs night" maximum and minimum respectively, was larger in the "evening" than in the "morning" group ("2-hr lens-wear": 88 vs 38 μm; "2-hr lens-removal": 104 vs 48 μm; p < 0.05 for both). For the choroidal rhythm, there was no effect on phase, however, the amplitude was larger in most, but not all, experimental groups. These findings have potential translational applications to myopia prevention in schoolchildren, who are exposed to extended periods of hyperopic defocus during reading sessions, due to the nearness of the page. We propose that bouts of such near-work might best be scheduled later in the day, along with frequent breaks for distance vision.
27844033	The sodium leak channel, a Na+-permeable, nonselective cation channel, is widely expressed in the nervous system, contributing a basal Na+-leak conductance and regulating neuronal excitability. A 3-year-old girl, heterozygous for a de novo missense mutation in NALCN (c.956C>T; p.Ala319Val) predicted to be deleterious, presented from birth with: stimulus-induced, episodic contractures of the limbs and face with associated respiratory distress; distal arthrogryposis; severe axial hypotonia; and severe global developmental delay (CLIFAHDD syndrome). In infancy, she manifested a reversed sleep-wake rhythm, nocturnal life-threatening respiratory rhythm disturbances with central apnea. Sevoflurane sensitivity caused respiratory depression and cardiac arrest.
27842272	Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are widely prescribed for the treatment of depression and anxiety disorders. Consequently, these compounds are frequently identified in global waterways where they may pose a hazard to aquatic biota. Evidence demonstrates these compounds to be capable of influencing the behaviour of fish, but the relevance of many reported behavioural endpoints is unclear and the value of some findings has been questioned. Since these compounds act on neuroendocrine-mediated pathways in vertebrates, the present study explored how exposure to two representative SSRIs (fluoxetine and sertraline) and an SNRI (venlafaxine) affect circadian rhythms in fish. Male mosquitofish (Gambusia holbrooki) were exposed to 1, 10 and 100μg/L concentrations of these compounds individually and when present as a full mixture, for a period of one week. Neither fluoxetine nor sertraline had an impact on diurnal activity patterns when fish were exposed to these compounds alone at any concentration, whereas venlafaxine significantly disrupted normal circadian rhythmicity but only at 100μg/L. When fish were exposed to the full mixture, significantly altered diurnal activity patterns were rapidly observed at nominal concentrations of 1 and 100μg/L, but there was no effect at 10μg/L. This sort of non-monotonic dose relationship is not altogether unusual for fish exposed to antidepressants, but it poses a problem when attempting to evaluate potential risks to the aquatic environment. To evaluate the possibility for misinterpretation when collecting behavioural data over short temporal scales, the data for each day of the experiment was analysed separately. The outcomes demonstrate the importance of longer periods of data collection, which may be necessary to capture the full range of natural behavioural variability that exists both amongst and within individual fish. More importantly, these findings may help reveal why discrepancies are commonly being reported in the literature with regards behavioural effects in fish exposed to antidepressants. It is thus suggested that research be aimed at documenting behavioural variability in fish species used in toxicity testing, to establish guidelines for quality control and where possible inform the development of standardised methodologies so that behavioural analysis can be more appropriately applied to the broad field of aquatic toxicology.
27841351	How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (INaP). INaP exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of INaP affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks.
27840924	The functions of basic helix-loop-helix (bHLH) transcription factor-differentiated embryonic chondrocyte (DEC)1 (BHLHE40) and 2 (BHLHE41) are involved in various fields such as circadian rhythms, immune responses, cell proliferation, hypoxia reaction as well as malignant tumors. Previous findings showed that DEC served as apoptosis regulators of various cancer cell lines. However, little is known regarding the expression of DEC1 and DEC2 in prostate cancer cells. The present study aimed to examine the roles of DEC1 and DEC2 in human prostate cancer DU145 and PC-3 cells that were treated with paclitaxel. The expression of DEC1 and DEC2 was decreased in DU145 cells but was increased in PC-3 cells when treated with paclitaxel. DU145 cells were more sensitive to paclitaxel than PC-3 cells since the amount of cleaved poly(ADP-ribose) polymerase (PARP) reached its peak at 50 µM of paclitaxel in DU145 cells but at 100 µM in PC-3 cells. In addition, the amount of cleaved PARP was decreased by DEC1 siRNA, while it was increased by DEC2 siRNA in the presence of paclitaxel. Although DEC2 overexpression slightly inhibited cleaved PARP in the two cell lines, the effects of DEC1 overexpression on apoptosis remain to be determined. In conclusion, DEC1, at least partly, exerted a pro-apoptotic effect, whereas DEC2 exerted an anti-apoptotic effect in paclitaxel-induced apoptosis of human prostate cancer cells.
27840026	For many years, a connection between circadian clocks and cancer has been postulated. Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, although the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation. Their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.
27838505	The variation in density of the symbiotic dinoflagellate Symbiodinum in coral is a basic indicator of coral bleaching, i.e. loss of the symbiotic algae or their photosynthetic pigments. However, in the field corals constantly release their symbiotic algae to surrounding water. To explore the underlying mechanism, the rate of expulsion of zooxanthellae from the coral Pocillopora damicornis was studied over a three-day period under ultraviolet radiation (UVR, 280-400nm) stress. The results showed that the algal expulsion rate appeared 10-20% higher under exposure to UV-A (320-395nm) or UV-B (295-320nm), though the differences were not statistically significant. When corals were exposed to UV-A and UV-B radiation, the maximum expulsion of zooxanthellae occurred at noon (10:00-13:00), and this timing was 1h earlier than in the control without UVR. UVR stress led to obvious decreases in the concentrations of chl a and carotenoids in the coral nubbins after a three-day exposure. Therefore, our results suggested that although the UVR effect on algal expulsion rate was a chronic stress and was not significant within a time frame of only three days, the reduction in chl a and carotenoids may potentially enhance the possibility of coral bleaching over a longer period.
27837979	A daily pattern of feed intake, milk synthesis, and plasma metabolites and hormones occurs in dairy cows fed a total mixed ration once or twice a day. The objective of this study was to determine if feeding multiple rations within a day, complementing these rhythms, would improve milk production. Twelve Holstein cows were used in a replicated 3×3 Latin square design with 21-d periods. Cows were housed in tie stalls with feed tubs, and feed weight was recorded every 10 s for observation of feeding behavior. Rations were a low fiber and high fermentable starch ration [LFHS; 27.4% neutral detergent fiber (NDF) and 31.7% starch based on 55.7% corn silage and 14.1% steam-flaked corn], a high fiber and low fermentable starch ration (HFLS; 31.7% NDF and 22.3% starch based on 44% corn silage, 26.3% alfalfa haylage, and no steam-flaked corn), and a total mixed ration that was a 1:3 ratio of LFHS and HFLS (30.7% NDF, 24.5% starch). The control treatment (CON) cows were fed the total mixed ration at 0700h, the high/low treatment (HL) fed HFLS ration at 0700h and LFHS ration at 2200h, and the low/high (LH) treatment fed LFHS ration at 0700h and HFLS ration at 1100h (LFHS and HFLS rations fed at a 1:3 ratio). No effect was found of treatment on daily milk, but LH decreased milk fat concentration and yield compared with HL (0.2 percentage units and 0.24kg, respectively). Daily dry matter and NDF intake and total-tract digestibility did not differ between treatments. The HL treatment reduced intake at the morning-conditioned meal after feeding and reduced intake before the evening feeding. A treatment by time of day interaction was found for fecal NDF and indigestible NDF concentration, blood urea nitrogen (BUN), plasma insulin, and fatty acid concentration, and body temperature. The CON and LH treatments increased the daily amplitude of fecal NDF by 1.0 and 1.1 percentage units compared with HL. Plasma insulin was higher in HL than CON at 0100 and 0400h, but lower at 1300 and 1900h. Plasma fatty acids were higher for CON than HL at 0700h and HL was lower than LH at 0400 and 1900h. Plasma BUN was higher for HL than control at 0100h, but lower at 1000h. Body temperature in CON and HL treatments followed a similar diurnal pattern, whereas body temperature for LH was lower than that of HL treatment at 1300 and 2300h. No daily rhythm was found of fecal indigestible NDF concentration, plasma glucose, or fatty acids detected in the HL treatment, and the amplitude of plasma insulin and BUN was lower for HL compared with CON (70 and 60% decrease, respectively). In conclusion, feeding 2 rations that differ in fiber and fermentable starch modifies diurnal rhythms in dairy cows. Furthermore, feeding a high fiber and low fermentable starch ration during the high intake period of the day may stabilize nutrient absorption across the day.
27837007	Light and temperature are two key environmental signals that profoundly affect plant growth and development, but underlying molecular mechanisms of how light and temperature signals affect the circadian clock are largely unknown. Here, we report that COR27 and COR28 are regulated not only by low temperatures but also by light signals. COR27 and COR28 are negative regulators of freezing tolerance but positive regulators of flowering, possibly representing a trade-off between freezing tolerance and flowering. Furthermore, loss-of-function mutations in COR27 and COR28 result in period lengthening of various circadian output rhythms and affect central clock gene expression. Also, the cor27 cor28 double mutation affects the pace of the circadian clock. Additionally, COR27 and COR28 are direct targets of CCA1, which represses their transcription via chromatin binding. Finally, we report that COR27 and COR28 bind to the chromatin of TOC1 and PRR5 to repress their transcription, suggesting that their effects on rhythms are in part due to their regulation of TOC1 and PRR5 These data demonstrate that blue light and low temperature-regulated COR27 and COR28 regulate the circadian clock as well as freezing tolerance and flowering time.
27836939	This article is part of a Journal of Biological Rhythms series exploring analysis and statistical topics relevant to researchers in biological rhythms and sleep research. The goal is to provide an overview of the most common issues that arise in the analysis and interpretation of data in these fields. In this article, we address issues related to the collection of multiple data points from the same organism or system at different times, since such longitudinal data collection is fundamental to the assessment of biological rhythms. Rhythmic longitudinal data require additional specific statistical considerations, ranging from curve fitting to threshold definitions to accounting for correlation structure. We discuss statistical analyses of longitudinal data including issues of correlational structure and stationarity, markers of biological rhythms, demasking of biological rhythms, and determining phase, waveform, and amplitude of biological rhythms.
27836938	The Journal of Biological Rhythms will be publishing articles exploring analysis and statistical topics relevant to researchers in biological rhythms and sleep research. The goal is to provide an overview of the most common issues that arise in the analysis and interpretation of data in these fields. By using case examples and highlighting the pearls and pitfalls of statistical inference, the authors will identify and explain ways in which experimental scientists can avoid common analytical and statistical mistakes and use appropriate analytical and statistical methods in their research. In this first article, we address the first steps in analysis of data: understanding the underlying statistical distribution of the data and establishing associative versus causal relationships. These ideas are then applied to sample size, power calculations, correlation testing, differences between description and prediction, and the narrative fallacy.
27836462	Attention deficit/hyperactivity disorder (ADHD) is frequently associated with comorbid aggression and sleep disturbances. The sleep/wake cycle is under the control of the circadian system which is moderated by clock genes. Clock genes can regulate the transcription of monoamine oxidase A, which is involved in the degradation of monoamines. Disturbances in monoamine interaction with clock genes in those with monoamine gene polymorphisms may regulate susceptibility of ADHD and comorbid aggression/sleep disturbances. While monoamines influence circadian rhythm and clock gene expression, circadian rhythm components modulate aggressive behavior, and altered clock genes expression have been associated with ADHD. We propose a mechanism by which circadian rhythm and clock gene expression may influence ADHD and comorbid aggression through the modulation of neurotransmitters. The role of clock genes in ADHD patients with comorbid aggression awaits further research; therefore we also indicate directions for future studies to help increase understanding of the underlying mechanisms in ADHD with comorbid aggression and sleep disturbances.
27836181	To assess circadian preference among a community sample of people with bipolar disorder, major depression and without any mood disorders. Secondly, we investigated the association of circadian preference with cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and, tumor necrosis factor alpha (TNF-α) and oxidative stress assessed by thiobarbituric acid reactive substances (TBARS), uric acid and Protein Carbonyl Content (PCC).A cross-sectional study nested in a population-based sample. Caseness was confirmed with the Structured Clinical Interview for DSM-IV. A sample of 215 participants, in whom we measured circadian preferences, IL-6, IL-10, TNF-α, TBARS, uric acid, PCC. Biological rhythms were evaluated using the Biological Interview of Assessment in Neuropsychiatry.	Bipolar group presented a higher alteration in biological rhythms (40.40±9.78) when compared with the major depression group (36.35±9.18) and control group (27.61±6.89) p<0.001. Subjects with bipolar disorder who were active at night and had a day/night cycle reverse showed decreased levels of IL-6 (t, 44=2.096; p=0.042), (t, 44=2.213; p=0.032), respectively. In the bipolar disorder group subjects who presented day/night cycle reverse had lower TBARS levels (t, 41=2.612; p=0.013). TNF-α were decreased in subjects more active at night with bipolar disorder.	Lower serum levels of IL-6, TNF-α and TBARS were associated with evening preference in bipolar disorder group. These findings suggest that chronotype may alter the levels of interleukins and oxidative stress levels in bipolar and healthy subjects. A better understanding of the role of circadian preferences in levels of interleukins and oxidative stress are needed.	
27835725	Bright light therapy has demonstrated efficacy and is an accepted treatment for seasonal depression. It has been suggested that bright light therapy may have efficacy in nonseasonal depressions. Also, there is evidence that bright light therapy may improve responsiveness to antidepressant pharmacotherapy.We searched PubMed/MEDLINE, PsycINFO, PsycARTICLES, CINAHL, EMBASE, Scopus, and Academic OneFile for English-language literature published between January 1998 and April 2016, using the keywords bright light therapy AND major depression, bright light therapy AND depress*, bright light therapy AND bipolar depression, bright light therapy AND affective disorders, circadian rhythm AND major depression, circadian rhythm AND depress*, and circadian rhythm AND affective disorder.	Studies that reported randomized trials comparing antidepressant pharmacotherapy with bright light therapy ≥ 5,000 lux for ≥ 30 minutes to antidepressant pharmacotherapy without bright light therapy for the treatment of nonseasonal depression were included. Studies of seasonal depression were excluded. Following review of the initial 112 returns, 2 of the authors independently judged each trial, applying the inclusionary and exclusionary criteria. Ten studies were selected as meeting these criteria. Subjects in these studies were pooled using standard techniques of meta-analysis.	Ten studies involving 458 patients showed improvement using bright light therapy augmentation versus antidepressant pharmacotherapy alone. The effect size was similar to that of other accepted augmentation strategies, roughly 0.5.	Analysis of pooled data from randomized trials provides evidence for the efficacy of use of bright light therapy ≥ 5,000 lux for periods ≥ 30 minutes when used as augmentation to standard antidepressant pharmacotherapy in the treatment of major depressive disorder and bipolar depression without a seasonal pattern.	
27834804	Night-shift work is linked to a shift in food intake toward the normal sleeping period, and to metabolic disturbance. We applied a rat model of night-shift work to assess the immediate effects of such a shift in food intake on metabolism. Male Wistar rats were subjected to 8 h of forced activity during their rest (ZT2-10) or active (ZT14-22) phase. Food intake, body weight, and body temperature were monitored across four work days and eight recovery days. Food intake gradually shifted toward rest-work hours, stabilizing on work day three. A subgroup of animals was euthanized after the third work session for analysis of metabolic gene expression in the liver by real-time polymerase chain reaction (PCR). Results show that work in the rest phase shifted food intake to rest-work hours. Moreover, liver genes related to energy storage and insulin metabolism were upregulated, and genes related to energy breakdown were downregulated compared to non-working time-matched controls. Both working groups lost weight during the protocol and regained weight during recovery, but animals that worked in the rest phase did not fully recover, even after eight days of recovery. In conclusion, three to four days of work in the rest phase is sufficient to induce disruption of several metabolic parameters, which requires more than eight days for full recovery.
27834218	The circadian clock and cell cycle networks are interlocked on the molecular level, with the core clock loop exerting a multilevel regulatory role over cell cycle components. This is particularly relevant to the circadian factor Period 2 (Per2), which modulates the stability of the tumor suppressor p53 in unstressed cells and transcriptional activity in response to genotoxic stress. Per2 binding prevents Mdm2-mediated ubiquitination of p53 and, therefore, its degradation, and oscillations in the peaks of Per2 and p53 were expected to correspond. However, our findings showed that Per2 and p53 rhythms were significantly out-of-phase relative to each other in cell lysates and in purified cytoplasmic fractions. These seemingly conflicting experimental data motivated the use of a combined theoretical and experimental approach focusing on the role played by Per2 in dictating the phase of p53 oscillations. Systematic modeling of all possible regulatory scenarios predicted that the observed phase relationship between Per2 and p53 could be simulated if (i) p53 was more stable in the nucleus than in the cytoplasm, (ii) Per2 associates to various ubiquitinated forms of p53, and (iii) Per2 mediated p53 nuclear import. These predictions were supported by a sevenfold increase in p53's half-life in the nucleus and by in vitro binding of Per2 to the various ubiquitinated forms of p53. Last, p53's nuclear shuttling was significantly favored by ectopic expression of Per2 and reduced because of Per2 down-regulation. Our combined theoretical/mathematical approach reveals how clock regulatory nodes can be inferred from oscillating time course data.
27833750	Most songbird migrants travel between their breeding areas and wintering grounds by a series of nocturnal flights. The exact nocturnal departure time for these flights varies considerably between individuals even of the same species. Although the basic circannual and circadian rhythms of songbirds, their adaptation to migration, and the factors influencing the birds' day-to-day departure decision are reasonably well studied, we do not understand how birds time their departures within the night. These decisions are crucial, because the nocturnal departure time defines the potential flight duration of the migratory night. The distances covered during the nocturnal migratory flights in the course of migration in turn directly affect the overall speed of migration. To understand the factors influencing the arrival of the birds in the breeding/wintering areas, we need to investigate the mechanisms that control nocturnal departure time. Here, we provide the first conceptual framework for explaining the variation commonly observed in this migratory trait. The basic schedule of nocturnal departure is likely regulated by both the circannual and circadian rhythms of the innate migration program. We postulate that the endogenously controlled schedule of nocturnal departures is modified by intrinsic and extrinsic factors. So far there is only correlative evidence that birds with a high fuel load or a considerable increase in fuel load and significant wind (flow) assistance towards their migratory goal depart early within the night. In contrast, birds migrating with little fuel and under unfavorable wind conditions show high variation in their nocturnal departure time. The latter may contain an unknown proportion of nocturnal movements not directly related to migratory flights. Excluding such movements is crucial to clearly identify the main drivers of the variation in nocturnal departure time. In general we assume that the observed variation in the nocturnal departure time is explained by individually different reactions norms of the innate migration program to both intrinsic and extrinsic factors.
27833615	Tropical evergreen perennials undergo recurrent flush growth, and their terminal buds alternate between growth and dormancy. In sharp contrast to the intensive studies on bud development in temperate deciduous trees, there is little information about bud development regulation in tropical trees. In this study, litchi (Litchi chinensis Sonn.) was used as a model tropical perennial for morphological characterization and transcriptomic analysis of bud development. Litchi buds are naked with apical meristem embraced by rudimentary leaves, which are brown at dormant stage (Stage I). They swell and turn greenish as buds break (Stage II), and as growth accelerates, the rudimentary leaves elongate and open exposing the inner leaf primodia. With the outgrowth of the needle-like leaflets, bud growth reaches a maximum (Stage III). When leaflets expand, bud growth cease with the abortion of the rudimentary leaves at upper positions (Stage IV). Then buds turn brown and reenter dormant status. Budbreak occurs again when new leaves become hard green. Buds at four stages (Stage I to IV) were collected for respiration measurements and in-depth RNA sequencing. Respiration rate was the lowest at Stage I and highest at Stage II, decreasing toward growth cessation. RNA sequencing obtained over 5 Gb data from each of the bud samples and de novo assembly generated a total of 59,999 unigenes, 40,119 of which were annotated. Pair-wise comparison of gene expression between stages, gene profiling across stages, GO/KEGG enrichment analysis, and the expression patterns of 17 major genes highlighted by principal component (PC) analysis displayed significant changes in stress resistance, hormone signal pathways, circadian rhythm, photosynthesis, cell division, carbohydrate metabolism, programmed cell death during bud development, which might be under epigenetic control involving chromatin methylation. The qPCR results of 8 selected unigenes with high PC scores agreed with the RPKM values obtained from RNA-seq. Three Short Vegetative Phase (SVP) genes, namely LcSVP1, LcSVP2, and LcSVP3 displayed different expression patterns, suggesting their differential roles in bud development regulation. The study brought an understanding about biological processes associated with the phase transitions, molecular regulation of bud development, as well as cyclic bud growth as a strategy to survive tropical conditions.
27830946	This fact-finding expedition explores the perspectives and knowledge of the origin and functional relevance of the 7 d domain of the biological time structure, with special reference to human beings. These biological rhythms are displayed at various levels of organization in diverse species - from the unicellular sea algae of Acetabularia and Goniaulax to plants, insects, fish, birds and mammals, including man - under natural as well as artificial, i.e. constant, environmental conditions. Nonetheless, very little is known about their derivation, functional advantage, adaptive value, synchronization and potential clinical relevance. About 7 d cosmic cycles are seemingly too weak, and the 6 d work/1 d rest week commanded from G-d through the Laws of Mosses to the Hebrews is too recent an event to be the origin in humans. Moreover, human and insect studies conducted under controlled constant conditions devoid of environmental, social and other time cues report the persistence of 7 d rhythms, but with a slightly different (free-running) period (τ), indicating their source is endogenous. Yet, a series of human and laboratory rodent studies reveal certain mainly non-cyclic exogenous events can trigger 7 d rhythm-like phenomena. However, it is unknown whether such triggers unmask, amplify and/or synchronize previous non-overtly expressed oscillations. Circadian (~24 h), circa-monthly (~30 d) and circannual (~1 y) rhythms are viewed as genetically based features of life forms that during evolution conferred significant functional advantage to individual organisms and survival value to species. No such advantages are apparent for endogenous 7 d rhythms, raising several questions: What is the significance of the 7 d activity/rest cycle, i.e. week, storied in the Book of Genesis and adopted by the Hebrews and thereafter the residents of nearby Mediterranean countries and ultimately the world? Why do humans require 1 d off per 7 d span? Do 7 d rhythms bestow functional advantage to organisms? Is the magic ascribed to the number 7 of relevance? We hypothesize the 7 d time structure of human beings is endogenous in origin - a hypothesis that is affirmed by a wide array of evidence - and synchronized by sociocultural factors linked to the Saturday (Hebrews) or Sunday (Christian) holy day of rest. We also hypothesize they are representative, at least in part, of the biological requirement for rest and repair 1 d each 7 d, just as the circadian time structure is representative, in part, of the biological need for rest and repair each 24 h.
27830059	Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G ( e.g., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone-regardless of whether they present with syphilitic ALS or non-syphilitic ALS-may be effective at treating this rapidly progressive, highly devastating disease.
27825849	Retinoid-related orphan receptor α (RORα), a member of the metabolic nuclear receptor superfamily, plays a vital regulatory role in circadian rhythm and metabolism. Here, we investigated the role of RORα in high-fat diet (HFD)-induced cardiac impairments and the underlying mechanisms involved. RORα-deficient stagger mice (sg/sg) and wild type (WT) littermates were fed with either standard diet or HFD. At 20weeks after HFD treatment, RORα deficiency resulted in significantly decreased body weight gain, improved dyslipidemia and ameliorated insulin resistance (evaluated by blood biochemical and glucose/insulin tolerance tests) compared with WT control. However, compared with HFD-treated WT mice, HFD-treated sg/sg mice exhibited significantly augmented myocardial hypertrophy, cardiac fibrosis (wheat germ agglutinin, masson trichrome and sirius red staining) and cardiac dysfunction (echocardiography and hemodynamics). Mechanistically, RORα deficiency impaired mitochondrial biogenesis and function. Additionally, RORα deficiency resulted in inhibition of the AMPK-PGC1α signaling pathway. In contrast, cardiomyocyte-specific RORα overexpression ameliorated myocardial hypertrophy, fibrosis and dysfunction by restoring AMPK-PGC1α signaling, and subsequently normalizing mitochondrial biogenesis. These findings demonstrated for the first time that nuclear receptor RORα deficiency aggravated HFD-induced myocardial dysfunction at least in part by impairing mitochondrial biogenesis in association with disrupting AMPK-PGC1α signaling. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren and Megan Yingmei Zhang.
27825406	Objective To investigate the relationships of blood pressure circadian rhythm and brain natriuretic peptide (BNP) with left ventricular hypertrophy (LVH) in patients with primary hypertension. Methods Totally 349 patients (74 with LVH and 275 without LVH) with primary hypertension were enrolled in this study.Echocardiography was performed to determine left ventricular mass index (LVMI) using the Devereux formula. The nocturnal blood pressure decline rate,24-hour blood pressure (24 h PP; especially 24 h mean systolic blood pressure,24 h SBP) and blood pressure index (PPI) were determined by 24 h-ambulatory blood pressure monitoring. These 349 hypertensive patients were divided into four groups including supper-dipper group (defined as≥;20%, n=7),dipper group (defined as 10%- 20%, n=77),non-dipper group (defined as 0- 10%, n=173),and anti-dipper group (defined as<0, n=92). The baseline demographic characteristics of patients were collected. Fasting blood sugar,blood lipids,blood urea nitrogen,serum cretinine,cystatin C,uric acid,and plasma BNP level were measured. Results The patients with LVH (n=74) had significantly higher percentage of grade 3 hypertension (85.1% vs. 46.9%;χ2=34.428,P<0.001),24 h SBP (134 mmHg vs. 129 mmHg; t=3.175,P=0.002)(1 mmHg=0.133 kPa),daytime-mean SBP (134 mmHg vs. 130 mmHg; t=2.197,P=0.029),night-mean SBP(132 mmHg vs. 121 mmHg; t=4.763,P<0.001),and 24 h PP(57 mmHg vs. 52 mmHg; t=4.120,P<0.001) and PPI (0.43 vs. 0.41; t=3.335,P=0.001) and lower nocturnal blood pressure decline rate [(1.30±8.02)% vs. (5.68±7.25)%; t=-4.510,P<0.001] than the non-LVH patients (n=275). The LVH hypertensive group had significantly higher BNP level (87.8 pg/ml vs. 28.8 pg/ml; t=2.170,P=0.034) and LVMI (135.1 g/m2 vs. 88.7 g/m2; t=15.285,P<0.001) than the control group. No significant difference was observed in the BNP level among supper-dipper,dipper,non-dipper and anti-dipper groups (P=0.137).However,the difference was statistically significant in the LVMI (P=0.001). Additionally,patients in the anti-dipper group had significantly higher LVMI than those in the dipper patients (100.3 g/m2 vs. 86.3 g/m2; t=4.335,P<0.001) and non-dipper (100.3 g/m2 vs.93.7 g/m2; t=1.987,P=0.048). Patients in the non-dipper group had significantly higher LVMI than those in the dipper group (93.7 g/m2 vs. 86.3 g/m2; t=2.693,P=0.008). The multivariate linear correation analysis and logistic regressions analysis suggested a significant correlation of LVMI with BNP and the grade of hypertension. Conclusion With the increasing of plasma BNP level,the left ventricular hypertrophy is closely related to abnormal blood pressure circadian rhythm and the grade of hypertension in primary hypertensive patients.
27824104	Alzheimer's disease (AD) patients suffer sleep disorders and circadian rhythm disturbances (CRDs). The underlying mechanisms are incompletely understood, and treatments are lacking. In this study, we characterized the locomotor activity, clock gene expression, morphological degeneration and energy metabolism of suprachiasmatic nucleus (SCN), together with retinal light sensing, in ApoE-/- mice, a model for AD. Compared with the control C57BL/6J mice, ApoE-/- mice exhibited disordered circadian locomotor activity under dim light and constant darkness, with impaired re-entrainment to phase change schedules. Decreased retinal melanopsin expression, together with amyloidosis and tau deposition, was evident in ApoE-/- mice. Mitochondrial and synaptic deterioration, altered SIRT1-mediated energy metabolism and clock gene expression were also observed in ApoE-/- SCN. Supplementation with fat or ketone bodies but not glucose, or intraperitoneal administration of nicotinamide, restored the locomotor rhythmicity and circadian expression of SIRT1 and clock genes, as well as reducing neurodegeneration. Taken together, ApoE deficiency induced degeneration and a significant disturbance in the SCN rhythmicity. Decline of retinal light sensing and SCN structural and metabolic deteriorations represented the major pathologies accounting for the CRDs in ApoE-/- mice. Our curative experiments may help develop future therapies to treat the CRDs and sleep disorders in AD patients.
27823719	Individual and socio-demographic factors have been found to be associated with sleep disturbances in children. Few studies have examined these factors among children presenting for care at pediatric sleep clinics. This study examined individual and socio-demographic factors in association with presenting problems and diagnostic impressions for new patients at an interdisciplinary pediatric sleep clinic.Data were collected from electronic medical records of 207 consecutive patients (54% male, 59% White, Meanage = 7.73, SD = 5.62).	Older age, female gender, and White race were associated with higher likelihood of presenting with difficulty falling asleep; younger age, male gender, and Black race were associated with higher likelihood of presenting with obstructive sleep apnea (OSA)-related concerns. Older age was associated with diagnostic impressions of inadequate sleep hygiene, insufficient sleep, circadian rhythm disorder/delayed sleep phase disorder, periodic limb movement disorder/restless legs syndrome, and insomnia, while younger age was associated with provisional OSA and behavioral insomnia of childhood (BIC) diagnoses. Male gender was associated with provisional OSA. White race was associated with BIC. Age-based analyses were also conducted to further understand the findings within a developmental context.	Age- and gender-related findings converged with prevalence literature on pediatric sleep disorders. Race was only associated with presenting concern and BIC, and one association for neighborhood disadvantage was found within the age-based analysis. Results suggest a potential service delivery gap, with racial/ethnic minority youth being less likely to present for sleep services, despite prevalence data on the increased likelihood of sleep disturbances among these youth.	
27822054	SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP) lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin) on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin-angiotensin-aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose control.
27821737	We have characterized a light-input pathway regulating Drosophila clock neuron excitability. The molecular clock drives rhythmic electrical excitability of clock neurons, and we show that the recently discovered light-input factor Quasimodo (Qsm) regulates this variation, presumably via an Na+, K+, Cl- cotransporter (NKCC) and the Shaw K+ channel (dKV3.1). Because of light-dependent degradation of the clock protein Timeless (Tim), constant illumination (LL) leads to a breakdown of molecular and behavioral rhythms. Both overexpression (OX) and knockdown (RNAi) of qsm, NKCC, or Shaw led to robust LL rhythmicity. Whole-cell recordings of the large ventral lateral neurons (l-LNv) showed that altering Qsm levels reduced the daily variation in neuronal activity: qsmOX led to a constitutive less active, night-like state, and qsmRNAi led to a more active, day-like state. Qsm also affected daily changes in K+ currents and the GABA reversal potential, suggesting a role in modifying membrane currents and GABA responses in a daily fashion, potentially modulating light arousal and input to the clock. When directly challenged with blue light, wild-type l-LNvs responded with increased firing at night and no net response during the day, whereas altering Qsm, NKKC, or Shaw levels abolished these day/night differences. Finally, coexpression of ShawOX and NKCCRNAi in a qsm mutant background restored LL-induced behavioral arrhythmicity and wild-type neuronal activity patterns, suggesting that the three genes operate in the same pathway. We propose that Qsm affects both daily and acute light effects in l-LNvs probably acting on Shaw and NKCC.
27821114	Depression during pregnancy is a common and high impact disease. Generally, 5-10 % of pregnant women suffer from depression. Children who have been exposed to maternal depression during pregnancy have a higher risk of adverse birth outcomes and more often show cognitive, emotional and behavioural problems. Therefore, early detection and treatment of antepartum depression is necessary. Both psychotherapy and antidepressant medication, first choice treatments in a non-pregnant population, have limitations in treating depression during pregnancy. Therefore, it is urgent and relevant to investigate alternative treatments for antepartum depression. Bright light therapy (BLT) is a promising treatment for pregnant women with depressive disorder, for it combines direct availability, sufficient efficacy, low costs and high safety, taking the safety for the unborn child into account as well.In this study, 150 pregnant women (12-18 weeks pregnant) with a DSM-V diagnosis of depressive disorder will be randomly allocated in a 1:1 ratio to one of the two treatment arms: treatment with BLT (9.000 lux) or treatment with dim red light therapy (100 lux). Both groups will be treated for 6 weeks at home on a daily basis for 30 min, within 30 min of habitual wake-up time. Follow-up will take place after 6 weeks of therapy, 3 and 10 weeks after end of therapy, at birth and 2, 6 and 18 months postpartum. Primary outcome will be the average change in depressive symptoms between the two groups, as measured by the Structured Interview Guide for the Hamilton Depression Scale - Seasonal Affective Disorder version and the Edinburg Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time will be analysed using generalized linear mixed models. Secondary outcomes will be the changes in maternal cortisol and melatonin levels, in maternal sleep quality and gestational age, birth weight, infant behaviour, infant cortisol exposure and infant cortisol stress response.	If BLT reduces depressive symptoms in pregnant women, it will provide a safe, cheap, non-pharmacological and efficacious alternative treatment for psychotherapy and antidepressant medication in treating antepartum depression, without any expected adverse reactions for the unborn child.	Netherlands Trial Register NTR5476 . Registered 5 November 2015.	
27819313	Jet travel and night shift work produce large changes in when people sleep, work and eat; a challenge that was not encountered during most of our evolution. Successful adaptation would require the internal, master, circadian clock to make large phase shifts to reduce the circadian misalignment between circadian rhythms and the times for sleep, work and meals. We compared African-Americans and non-Hispanic European-Americans in how much their circadian clocks shifted after a 9 hour phase delay of the light/dark, sleep/wake and meal schedule, which has similarities to flying west or sleeping in the daytime after night shifts. We also measured their free-running circadian periods using a forced desynchrony protocol with a 5-h day. European-Americans had longer free-running periods and larger phase delays than African-Americans. Correlations (among all subjects, just African-Americans and just European-Americans) showed that longer circadian periods were associated with larger phase delays. Larger phase delays, facilitated by longer circadian periods, reduce jet lag after westward travel and make it easier to work night shifts and sleep during the daytime after night work. On the other hand, a shorter circadian period, which makes one more of a morning-type person, is better for most people given our early-bird dominated society.
27818261	Circadian clocks are self-sustainable endogenous oscillators, present in virtually every cell, driving daily cycles of metabolism and physiology. The molecular mechanism of the circadian clock is based on interconnected transcriptional and translational feedback loops. While many studies have addressed circadian rhythms of the transcriptome and, to a lesser extent, the proteome, none have investigated the phosphoproteome. We apply mass spectrometry-based phosphoproteomics to obtain the first global in vivo quantification of circadian phosphorylation in mammals. Of more than 20,000 phosphosites, 25% significantly oscillate in the mouse liver, including novel sites on core clock proteins. The extent and amplitude of phosphorylation cycles far exceeds those observed in RNA and protein abundance. Our data indicate a dominant regulatory role for phosphorylation-dependent circadian tuning of signaling pathways. This allows the organism to integrate different signals and rapidly and economically respond to daily changes in nutrient availability and physiological states.
27818260	Diurnal oscillations of gene expression controlled by the circadian clock and its connected feeding rhythm enable organisms to coordinate their physiologies with daily environmental cycles. While available techniques yielded crucial insights into regulation at the transcriptional level, much less is known about temporally controlled functions within the nucleus and their regulation at the protein level. Here, we quantified the temporal nuclear accumulation of proteins and phosphoproteins from mouse liver by SILAC proteomics. We identified around 5,000 nuclear proteins, over 500 of which showed a diurnal accumulation. Parallel analysis of the nuclear phosphoproteome enabled the inference of the temporal activity of kinases accounting for rhythmic phosphorylation. Many identified rhythmic proteins were parts of nuclear complexes involved in transcriptional regulation, ribosome biogenesis, DNA repair, and the cell cycle and its potentially associated diurnal rhythm of hepatocyte polyploidy. Taken together, these findings provide unprecedented insights into the diurnal regulatory landscape of the mouse liver nucleus.

27816550	Opiate withdrawal syndrome is temporally associated with the hyperactivity of locus coeruleus neurons. Previous studies have shown that this hyperactivity, at least in part, results from the activity of excitatory afferents which mainly include the orexinergic neurons of hypothalamus and glutamatergic neurons of paragigantocellularis (PGi) nucleus. The effect of intra LC orexin type 1 receptor antagonism was investigated on expression of glutamate-induced morphine withdrawal-like signs in rats. Regarding the involvement of both orexin and LC in modulation of circadian rhythm, experimental procedures were performed during the rest (day) and the active (night) phases. Male Wistar rats (250-300g) received escalating doses (6, 16, 26, 36, 46, 56, 66mg/kg, 2ml/kg) of morphine sulfate subcutaneously for 7days. Then, glutamate (100nM, 200nl) was microinjected into the LC region and the subsequent behavioral manifestations were visually monitored in both rest and active phases. SB-334867 (as a selective orexin type 1 receptor antagonist) was microinjected into the LC prior to glutamate administration. Results indicate that intra-LC microinjection of glutamate elicits morphine withdrawal-like behavioral signs in rats. It is noteworthy that this effect was significantly suppressed in rats pretreated with SB-334867 only during the active phase. It could be concluded that orexin-A plays a role in expression of glutamate-induced opiate withdrawal-like signs and differential orexinergic tone during the rest and active phases might explain the observed difference in activity of LC neurons.
27816422	The prevalence of childhood obesity has increased significantly in recent years. Obesity is associated with a range of adverse physiological, psychological and social outcomes and places a huge economical burden on healthcare systems around the world. Insufficient sleep duration is common in adolescents and exacerbated by contemporary lifestyles, but may be a contributor to obesity onset and metabolic disruption. We briefly review the current evidence surrounding the associations between sleep and obesity as well as diabetes. Sleep improvement programs have been suggested as a potential avenue to raise awareness of the importance of sleep and ultimately enhance sleep behaviors/routines. A review of the current literature supporting the efficacy of such programs is tentative. Furthermore, very few studies have investigated if sleep enhancement has downstream positive effects on metabolic function or body weight in adolescents. We highlight biological and social factors that intensify sleep loss in adolescents and recommend that these be targeted components in future interventions aimed at improving adolescent sleep.
27816011	Airline pilots' sleep and on-duty alertness are important focus areas in commercial aviation. Until now, studies pertaining to this topic have mainly focused on specific characteristics of flights and thus a comprehensive picture of the matter is not well established. In addition, research knowledge of what airline pilots actually do to maintain their alertness while being on duty is scarce. To address these gaps in research knowledge, we conducted a field study on a representative sample of the airline pilots of a medium-sized airline. The sample consisted of 90 pilots, of whom 30 flew long-haul (LH) routes, 30 short-haul (SH) routes, and 30 flew both. A total of 86 pilots completed the measurements that lasted for almost two months per pilot. The measurements resulted in a total of 965 flight duty periods (FDPs) including SH flights and 627 FDPs including LH flights. During the measurement periods, sleep was measured by a diary and actigraphs, on-duty alertness by the Karolinska Sleepiness Scale (KSS) in all flight phases, and on-duty alertness management strategies by the diary. Results showed that SH and LH FDPs covering the whole domicile night (00:00-06:00 at home base) were most consistently associated with reduced sleep-wake ratio and subjective alertness. Approximately every 3rd FDP falling into this category involved a reduced sleep-wake ratio (1:3 or lower) and every 2nd a reduced level of subjective alertness (KSS rating 8-9 in at least one flight phase). The corresponding frequencies for the SH and LH FDPs that partly covered the domicile night were every 10th and every 5th FDP and for the pure non-night FDPs every 30th and every 36th FDP, respectively. The results also showed that the pilots tended to increase the use of effective on-duty alertness management strategies (consuming alertness-promoting products and taking strategic naps) in connection with the FDPs that overlapped the domicile night. Finally, the results showed that the frequency of flights involving reduced subjective alertness depended on how alertness was assessed. If it was assessed solely in the flight phase just before starting the landing procedures (top of descent) the phenomenon was less frequent than if the preceding cruise phase was also taken into account. Our results suggest that FDPs covering the whole domicile night should be prioritised over the other FDPs in fatigue management, regardless of whether an FDP is a short-haul or a long-haul. In addition, the identification of fatigue in flight operations requires one to assess pilots' alertness across all flight phases, not only at ToD. Due to limitations in our data, these conclusions can, however, be generalise to only LH FDPs during which pilots can be expected to be well acclimatised to the local time at their home base and SH night FDPs that include at least 3h of flying in the cruise phase.
27814712	Perinatal depression (PND) has an overall estimated prevalence of roughly 12 %. Untreated PND has significant negative consequences not only on the health of the mothers, but also on the physical, emotional and cognitive development of their children. No certain risk factors are known to predict PND and no completely safe drug treatments are available during pregnancy and breastfeeding. Sleep and depression are strongly related to each other because of a solid reciprocal causal relationship. Bright light therapy (BLT) is a well-tested and safe treatment, effective in both depression and circadian/sleep disorders.In a 3-year longitudinal, observational, multicentre study, about 500 women will be recruited and followed-up from early pregnancy (10-15 gestational week) until 12 months after delivery. The primary aim of the present study is to systematically explore and characterize risk factors for PND by prospective sleep assessment (using wrist actigraphy, polysomnography and various sleep questionnaires) and bloodbased analysis of potential markers during the perinatal period (Life-ON study). Secondary aims are to explore the relationship between specific genetic polymorphisms and PND (substudy Life-ON1), to investigate the effectiveness of BLT in treating PND (substudy Life-ON2) and to test whether a short term trial of BLT during pregnancy can prevent PND (substudy Life-ON3).	The characterization of specific predictive and risk factors for PND may substantially contribute to improve preventive medical and social strategies for the affected women. The study results are expected to promote a better understanding of the relationship between sleep disorders and the development of PND and to confirm, in a large sample of women, the safety and efficacy of BLT both in prevention and treatment of PND.	
27814527	Cyanobacterial blooms threaten human health as well as the population of other living organisms in the aquatic environment, particularly due to the production of natural toxic components, the cyanotoxin. So far, the most studied cyanotoxins are microcystins (MCs). In this study, the hepatic alterations at histological, proteome and transcriptome levels were evaluated in female and male medaka fish chronically exposed to 1 and 5 μg L-1 microcystin-LR (MC-LR) and to the extract of MC-producing Microcystis aeruginosa PCC 7820 (5 μg L-1 of equivalent MC-LR) by balneation for 28 days, aiming at enhancing our understanding of the potential reproductive toxicity of cyanotoxins in aquatic vertebrate models. Indeed, both MC and Microcystis extract adversely affect reproductive parameters including fecundity and egg hatchability. The liver of toxin treated female fish present glycogen storage loss and cellular damages. The quantitative proteomics analysis revealed that the quantities of 225 hepatic proteins are dysregulated. In particular, a notable decrease in protein quantities of vitellogenin and choriogenin was observed, which could explain the decrease in reproductive output. Liver transcriptome analysis through Illumina RNA-seq reveals that over 100-400 genes are differentially expressed under 5 μg L-1 MC-LR and Microcystis extract treatments, respectively. Ingenuity pathway analysis of the omic data attests that various metabolic pathways, such as energy production, protein biosynthesis and lipid metabolism, are disturbed by both MC-LR and the Microcystis extract, which could provoke the observed reproductive impairment. The transcriptomics analysis also constitutes the first report of the impairment of circadian rhythm-related gene induced by MCs. This study contributes to a better understanding of the potential consequences of chronic exposure of fish to environmental concentrations of cyanotoxins, suggesting that Microcystis extract could impact a wider range of biological pathways, compared with pure MC-LR, and even 1 μg L-1 MC-LR potentially induces a health risk for aquatic organisms.
27814361	The Drosophila circadian oscillator controls daily rhythms in physiology, metabolism and behavior via transcriptional feedback loops. CLOCK-CYCLE (CLK-CYC) heterodimers initiate feedback loop function by binding E-box elements to activate per and tim transcription. PER-TIM heterodimers then accumulate, bind CLK-CYC to inhibit transcription, and are ultimately degraded to enable the next round of transcription. The timing of transcriptional events in this feedback loop coincide with, and are controlled by, rhythms in CLK-CYC binding to E-boxes. PER rhythmically binds CLK-CYC to initiate transcriptional repression, and subsequently promotes the removal of CLK-CYC from E-boxes. However, little is known about the mechanism by which CLK-CYC is removed from DNA. Previous studies demonstrated that the transcription repressor CLOCKWORK ORANGE (CWO) contributes to core feedback loop function by repressing per and tim transcription in cultured S2 cells and in flies. Here we show that CWO rhythmically binds E-boxes upstream of core clock genes in a reciprocal manner to CLK, thereby promoting PER-dependent removal of CLK-CYC from E-boxes, and maintaining repression until PER is degraded and CLK-CYC displaces CWO from E-boxes to initiate transcription. These results suggest a model in which CWO co-represses CLK-CYC transcriptional activity in conjunction with PER by competing for E-box binding once CLK-CYC-PER complexes have formed. Given that CWO orthologs DEC1 and DEC2 also target E-boxes bound by CLOCK-BMAL1, a similar mechanism may operate in the mammalian clock.
27813571	Marine animals exhibit a variety of biological rhythms, such as solar and lunar-related cycles; however, our current molecular understanding of biological rhythms in marine animals is quite limited. Identifying and understanding the expression patterns of clock genes from available transcriptomes will help elucidate biological rhythms in marine species. Here, we perform a comprehensive survey of phototransduction and circadian genes using the mantle transcriptome of the scallop Patinopecten yessoensis and compare the results with those from three other bivalves. The comparison reveals the presence of transcripts for most of the core members of the phototransduction and circadian networks seen in terrestrial model species in the four marine bivalves. Matches were found for all 37 queried genes, and the expressed transcripts from the deep sequencing data matched 8 key insect and mammalian circadian genes. This demonstrates the high level of conservation of the timekeeping mechanism from terrestrial species to marine bivalves. The results provide a valuable gene resource for studies of "marine rhythms" and also further our understanding of the diversification and evolution of rhythms in marine species.
27812851	Affective disorders in young people have been associated with disruptions in circadian rhythms, including abnormalities in secretion of the pineal hormone melatonin. Previous research reports relationships between pineal gland volumes, melatonin secretion, and sleep-wake cycles, but the relationship between these factors has not been explored in affective disorders. This study aimed to characterize these factors and explore associations with mood symptoms and functioning in a sample of young people with affective disorders. Pineal volume from magnetic resonance imaging and melatonin assay from evening dim-light saliva collection were evaluated in 50 individuals (15-30 years old; 72 % female) with bipolar, depressive, or anxiety disorders. Actigraphy monitoring was also conducted for approximately two weeks to derive sleep-wake measures. Pineal volume was associated with melatonin secretion across the evening, replicating previous findings in psychiatrically healthy individuals. Pineal volume was smaller in participants in which melatonin onset was not detected. Timing of melatonin secretion was related to sleep timing, but amount of melatonin and pineal volume were not related to any sleep-wake measures. A shorter phase angle between onset of melatonin secretion and sleep onset was associated with longer total sleep time. Lower melatonin levels were associated with poorer social and occupational functioning. Although pineal volume is not directly related to sleep disturbances or symptoms, melatonin may influence both sleep-wake cycles and functioning in the early stages of affective disorder. Causal links remain to be established, however, treatments that target circadian rhythms may be useful in improving functioning in young people with affective disorders.
27812555	The shift from a biphasic to a monophasic sleep schedule is a fundamental milestone in early childhood. This transition, however, may result in periods of acute sleep loss as children may nap on some but not all days. Although data indicating the behavioral consequences of nap deprivation in young children are accumulating, little is known about changes to sleep neurophysiology following daytime sleep loss. This study addresses this gap in knowledge by examining the effects of acute nap deprivation on subsequent nighttime sleep electroencephalographic (EEG) parameters in toddlers. Healthy children (n=25; 11 males; ages 30-36 months) followed a strict sleep schedule for ≥5 days before sleep EEG recordings performed on 2 non-consecutive days: one after 13 h of prior wakefulness and another at the same clock time but preceded by a daytime nap. Total slow-wave energy (SWE) was computed as cumulative slow-wave activity (SWA; EEG power in 0.75-4.5 Hz range) over time. Nap and subsequent night SWE were added and compared to SWE of the night after a missed nap. During the night following a missed nap, children fell asleep faster (11.9 ± 8.7 versus 37.3 ± 22.1 min; d=1.6, p=0.01), slept longer (10.1 ± 0.7 versus 9.6 ± 0.6 h; d=0.7, p<0.01) and exhibited greater SWA (133.3 ± 37.5 versus 93.0 ± 4.7 %; d=0.9, p<0.01) compared to a night after a daytime nap. SWE for combined nap and subsequent night sleep did not significantly differ from the night following nap deprivation (12141.1 ± 3872.9 versus 11588 ± 3270.8 µV2*h; d=0.6, p=0.12). However, compared to a night following a missed nap, children experienced greater time in bed (13.0±0.8 versus 10.9±0.5; d=3.1, p<0.01) and total sleep time (11.2±0.8 versus 10.1±0.7; d=1.4, p<0.01). Shorter sleep latency, longer sleep duration, and increased SWA in the night following a missed nap indicate that toddlers experience a physiologically meaningful homeostatic challenge after prolonged wakefulness. Whether toddlers fully recover from missing a daytime nap in the subsequent night necessitates further examination of daytime functioning.
27811855	Sleep disturbances and poor rest-activity rhythms, which can reduce the quality of life, are highly prevalent among patients with lung cancer.This trial investigated the effects of a 12-week exercise intervention including home-based walking exercise training and weekly exercise counseling on 111 lung cancer patients. Participants were randomly allocated to receive the intervention or usual-care. Outcomes included objective sleep (total sleep time, TST; sleep efficiency, SE; sleep onset latency, SOL; and wake after sleep onset, WASO), subjective sleep (Pittsburgh Sleep Quality Index, PSQI), and rest-activity rhythms (r24 and I<O). Outcomes were assessed at baseline and 3 and 6 months after intervention.	The PSQI (Wald χ2=15.16, P=0.001) and TST (Wald χ2=7.59, P=0.023) of the patients in the exercise group significantly improved 3 and 6 months after intervention. The moderating effect of I<O on TST was significant (β of group × I<O=3.70, P=0.032).	The walking program is an effective intervention for improving the subjective and objective sleep quality of lung cancer patients and can be considered an optional component of lung cancer rehabilitation.	
27811524	Light exposure has a close link with numerous aspects of human physiology including circadian rhythm, mood disorders, metabolism, and eye growth. Here, a lightweight wrist-worn device was employed to continuously measure light exposure and activity across seasons and between refractive error groups to assess objectively measured differences and compare with subjectively reported data.Subjects, aged 21-65 years (n = 55), wore an actigraph device (Actiwatch Spectrum) continuously for 14 days to quantify light exposure, activity, and sleep. Subjects were classified as emmetropic (n = 18) or myopic (n = 37), and answered an activity questionnaire. Additionally, devices were calibrated against a lux meter and UV sensor for indoor and outdoor settings, and used to measure ambient illumination in various environmental conditions.	Subjects spent 1:52 ± 0:56 hours outside per day, as measured objectively. Subjectively reported measures overestimated objective measures by 0:25 ± 1:19 hours per day (range -1:49 to +4:29 hours, P < .05). Subjects spent 1:04 hours more outdoors in summer and received an increased cumulative light dose compared to winter (P < .005). There were no significant differences in objective measurements of time outdoors between myopic and emmetropic subjects. Ambient illumination measures from the Actiwatch correlated with a lux meter for all locations tested (R = 0.99, P < .001). Ambient illumination was highest in the summer at 176,497 ± 20,310 lux and lowest for indoor artificial light at 142 ± 150 lux.	Subjects spent more time outdoors and received an increased light dose in summer, with no differences between refractive error groups in this adult population. Various environmental and seasonal measurements revealed significantly different available light in winter versus summer and indoors versus outdoors. Objective devices such as the Actiwatch can be valuable in studies where quantification of environmental factors is critical.	
27810175	Light plays an important role in the synchronization of the internal biological clock and the environmental day/night pattern. Thus, absence of vision is often associated with both increases in reported sleep disturbances and incidence of free-running circadian rhythms. In this study we discuss variability in the sleep-wake pattern between blind and normal-sighted individuals.Thirty-day actigraphy recordings were collected from 11 blind individuals without residual light perception and 11 age- and sex-matched normal-sighted controls. From these recordings, we extracted parameters of sleep and wake, including episodes of rest, day-time and night-time sleep periods, and the number of awakenings throughout sleep. A measure of sleep efficiency was derived from these measures for each night-time sleep episode. We also examined complementary measures of sleep quality, using the Pittsburgh Sleep Quality Index, and chronotype, using the Morningness-Eveningness Questionnaire.	Although no group differences were found when averaging over the entire recording period, we found a greater variability throughout the 30-days in both sleep efficiency and timing of the night-time sleep episode in blind participants as compared to sighted control participants. We also confirm previous reports of reduced sleep quality in blind individuals. Notably, the variability in sleep efficiency and in the timing of sleep correlated with the severity of sleep disturbances.	The timing and physiology of sleep are strongly dependent on the endogenous circadian phase; therefore, observed findings support the hypothesis of free-running circadian rhythms as a dominant factor for the sleep disturbances experienced in blindness.	
27809780	Photoperiodism refers to the ability of plants to measure day length to determine the season. This ability enables plants to coordinate internal biological activities with external changes to ensure normal growth. However, the influence of the photoperiod on maize flowering and stress responses under long-day (LD) conditions has not been analyzed by comparative transcriptome sequencing. The ZmCCT gene was previously identified as a homolog of the rice photoperiod response regulator Ghd7, and associated with the major quantitative trait locus (QTL) responsible for Gibberella stalk rot resistance in maize. However, its regulatory mechanism has not been characterized.We mapped the ZmCCT-associated QTL (ZmCCT-AQ), which is approximately 130 kb long and regulates photoperiod responses and resistance to Gibberella stalk rot and drought in maize. To investigate the effects of ZmCCT-AQ under LD conditions, the transcriptomes of the photoperiod-insensitive inbred line Huangzao4 (HZ4) and its near-isogenic line (HZ4-NIL) containing ZmCCT-AQ were sequenced. A set of genes identified by RNA-seq exhibited higher basal expression levels in HZ4-NIL than in HZ4. These genes were associated with responses to circadian rhythm changes and biotic and abiotic stresses. The differentially expressed genes in the introgressed regions of HZ4-NIL conferred higher drought and heat tolerance, and stronger disease resistance relative to HZ4. Co-expression analysis and the diurnal expression rhythms of genes related to stress responses suggested that ZmCCT and one of the circadian clock core genes, ZmCCA1, are important nodes linking the photoperiod to stress tolerance responses under LD conditions.	Our study revealed that the photoperiod influences flowering and stress responses under LD conditions. Additionally, ZmCCT and ZmCCA1 are important functional links between the circadian clock and stress tolerance. The establishment of this particular molecular link has uncovered a new relationship between plant photoperiodism and stress responses.	
27600138	The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from harmful compounds. P-glycoprotein (P-gp) is one of the major efflux transporters at the BBB. In the present study, we assessed whether (1) P-gp function in the brain is constant or fluctuates across the day and (2) if it is affected by sleep deprivation. Four groups of rats were PET scanned with a radiolabeled P-gp substrate [18F]MC225, each at a different moment of the 12-h light-dark cycle to study diurnal variations: early sleep phase (ZT3), late sleep phase (ZT9), early active phase (ZT15), and late active phase (ZT21). In two additional groups, controls were allowed to sleep normally while experimental animals were sleep-deprived for 10 h in a slowly rotating drum during the sleep phase. Kinetic modeling with a one-tissue compartment model fit resulted for all brain regions in 1.2-1.8-fold higher distribution volumes (V T ) at ZT15 than at other time points. V T -values at ZT3, ZT9, and ZT21 were not significantly different from each other. Regional tracer distribution volumes in controls and sleep-deprived animals were also not significantly different. Our results indicate that P-gp function in rats displays a daily rhythm with reduced function at the beginning of the active phase. This rhythm is not dependent on sleep since acute sleep deprivation had no effect. Knowing the diurnal variation of P-gp function could be important for the design of PET studies and for choosing the correct administration time for P-gp-dependent drugs.
27451293	Here, we examined diurnal changes in the ruminal microbial community and fermentation characteristics of dairy cows fed total mixed rations containing either corn silage (CS) or grass silage (GS) as forage. The rations, which consisted of 52% concentrate and 48% GS or CS, were offered for ad libitum intake over 20 days to three ruminal-fistulated lactating Jersey cows during three consecutive feeding periods. Feed intake, ruminal pH, concentrations of short chain fatty acids and ammonia in rumen liquid, as well as abundance change in the microbial populations in liquid and solid fractions, were monitored in 4-h intervals on days 18 and 20. The abundance of total bacteria and Fibrobacter succinogenes increased in solids in cows fed CS instead of GS, and that of protozoa increased in both solid and liquid fractions. Feeding GS favored numbers of F. succinogenes and Selenomonas ruminantium in the liquid fraction as well as the numbers of Ruminobacter amylophilus, Prevotella bryantii and ruminococci in both fractions. Minor effects of silage were detected on populations of methanogens. Despite quantitative changes in the composition of the microbial community, fermentation characteristics were less affected by forage source. These results suggest a functional adaptability of the ruminal microbiota to total mixed rations containing either GS or CS as the source of forage. Diurnal changes in microbial populations were primarily affected by feed intake and differed between species and fractions, with fewer temporal fluctuations evident in the solid than in the liquid fraction. Interactions between forage source and sampling time were of minor importance to most of the microbial species examined. Thus, diurnal changes of microbial populations and fermentative activity were less affected by the two silages.
27808276	The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.
27807442	Tetrapyrroles make critical contributions to a number of important processes in diverse organisms. In plants, tetrapyrroles are essential for light signaling, the detoxification of reactive oxygen species, the assimilation of nitrate and sulfate, respiration, photosynthesis, and programed cell death. The misregulation of tetrapyrrole metabolism can produce toxic reactive oxygen species. Thus, it is not surprising that tetrapyrrole metabolism is strictly regulated and that tetrapyrrole metabolism affects signaling mechanisms that regulate gene expression. In plants and algae, tetrapyrroles are synthesized in plastids and were some of the first plastid signals demonstrated to regulate nuclear gene expression. In plants, the mechanism of tetrapyrrole-dependent plastid-to-nucleus signaling remains poorly understood. Additionally, some of experiments that tested ideas for possible signaling mechanisms appeared to produce conflicting data. In some instances, these conflicts are potentially explained by different experimental conditions. Although the biological function of tetrapyrrole signaling is poorly understood, there is compelling evidence that this signaling is significant. Specifically, this signaling appears to affect the accumulation of starch and may promote abiotic stress tolerance. Tetrapyrrole-dependent plastid-to-nucleus signaling interacts with a distinct plastid-to-nucleus signaling mechanism that depends on GENOMES UNCUOPLED1 (GUN1). GUN1 contributes to a variety of processes, such as chloroplast biogenesis, the circadian rhythm, abiotic stress tolerance, and development. Thus, the contribution of tetrapyrrole signaling to plant function is potentially broader than we currently appreciate. In this review, I discuss these aspects of tetrapyrrole signaling.
27806809	To determine the mean morning surge (MS) in blood pressure, the frequency of increased morning surge in normotensive subjects, and to compare those with morning surge with those without MS.Across-sectional, comparative study.	The Department of Medicine, The Aga Khan University Hospital, Karachi, from April 2011 to March 2012.	Adult normotensive healthy volunteers aged 35 to 65 years were inducted. Their ambulatory blood pressure (ABP) was measured over a 24-hour period, using digital ambulatory blood pressure monitors. Morning surge was calculated as the average of four readings after waking minus the lowest three nocturnal readings. Increased morning surge was defined as > 11 mm Hg in systolic (SBP) or > 12 mm Hg in diastolic (DBP). Dipping was defined as > 10% dipping in blood pressure.	Eighty-two healthy volunteers were recruited. Their mean age was 36.9 ±1.2 years; 74.4 (61%) were men, and 58.5 (48%) woke up for morning prayers. Mean overall SBPwas 113 ±1.6 mm Hg, overall DBPwas 73.9 ±0.7 mm Hg, and overall heart rate was 75 (10) beats/minute. Mean morning surge was 17.6 ±1.0 mm Hg in SBPand 16.0 ±0.8 mm Hg in DBP. The frequency of increased morning surge was 66 (80.5%) in SBP, and 57 (69%) in DBP. On comparison of participants with normal morning surge and increased morning surge in SBP, there was a significant difference in nondipping status (13.4% in normal vs. 18.3% in increased morning surge, p= 0.001).	Mean morning surge in SBPand DBPare relatively higher in this subset population in a tertiary care center in Pakistan. These values are higher than those reported in the literature.	
27806623	Whole brain radiotherapy (WBRT) is commonly used to treat brain metastases. Previous studies have explored how radiotherapy treatment time can affect response. The present study evaluated the influence of treatment time on overall survival (OS) for cancer patients receiving WBRT.Patients who received WBRT from 2004 to 2016 were included. Demographic information including age, performance status, primary site, dose, fraction, treatment time, and date of death were collected. Based on different percentages of treatment times falling into one time frame (i.e., 100%, ≥80%, ≥70%, or ≥60%), patients were allocated to three cohorts (8:00-11:00 AM, 11:01 AM-2:00 PM, 2:01-5:00 PM). Demographics were compared among cohorts using the Kruskal-Wallis nonparametric test and Fisher exact test. To control the multiple comparisons on select demographic variables a Bonferroni adjusted P value was considered statistically significant. Kaplan-Meier curves were created for OS. Univariate and multivariate Cox proportional hazard (PH) model were used to find predictive factors of OS in all patients, females and males.	A total of 755 patients were included with a median age of 66 years. The actuarial median OS was 2.37 months. Treatment time was not associated with OS for all patients or males only. In elderly female patients (>65 years), a significant difference in OS was found among treatment cohorts (P=0.02). Treatment time (when ≥80% or ≥70% of treatment times were in one time frame), age, and Karnofsky performance status (KPS) were significant predictive factors of OS in univariate analysis for females. Only age and KPS remained significant in multivariate analysis.	Time of WBRT delivery for brain metastases was significantly related to OS upon univariate analyses in females only. Future investigations should be conducted prospectively with homogenous patient groups to elucidate the effect of chronotherapy in palliative brain metastases patients as time of WBRT administration may affect OS in specific subsets of patients.	
27551752	The aim of this study was to examine the association of breast cancer incidence with cosmic radiation dose and circadian rhythm disruption in a cohort of 6093 US female flight attendants.The association of breast cancer risk with cumulative cosmic radiation dose, time spent working during the standard sleep interval, and time zones crossed (all lagged by ten years), adjusted for non-occupational breast cancer risk factors, was evaluated using Cox regression. Individual exposure estimates were derived from work history data and domicile- and era-specific exposure estimates. Breast cancers were identified from telephone interviews and state cancer registries, and covariate data were obtained from telephone interviews.	Breast cancer incidence in the overall cohort was not associated with exposure. Positive associations in breast cancer incidence were observed with all three exposures only among the 884 women with parity of ≥3. Adjusted excess relative risks for women with parity of ≥3 were 1.6 [95% confidence interval (95% CI) 0.14-6.6], 0.99 (95% CI -0.04-4.3), and 1.5 (95% CI 0.14-6.2) per 10 mGy, per 2000 hours spent working in the standard sleep interval, and per 4600 time zones crossed (the approximate means of the fourth exposure quintiles among breast cancer cases), respectively.	Positive exposure-response relations, although observed only in a small subset of the cohort, were robust. Future studies of breast cancer incidence among other workers with circadian rhythm disruption should assess interaction with parity to see if our findings are confirmed.	
27806419	The circadian rhythms coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Because multiple-oscillator circadian mechanisms are likely to play a role in regulating human health, and may contribute to the aging process, we give an overview of the relationship between the central clock in the hypothalamus and peripheral clocks for psychological health and aging.
27805978	Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia.Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis.	Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms.	Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.	
27805047	In optogenetics, researchers use light and genetically encoded photoreceptors to control biological processes with unmatched precision. However, outside of neuroscience, the impact of optogenetics has been limited by a lack of user-friendly, flexible, accessible hardware. Here, we engineer the Light Plate Apparatus (LPA), a device that can deliver two independent 310 to 1550 nm light signals to each well of a 24-well plate with intensity control over three orders of magnitude and millisecond resolution. Signals are programmed using an intuitive web tool named Iris. All components can be purchased for under $400 and the device can be assembled and calibrated by a non-expert in one day. We use the LPA to precisely control gene expression from blue, green, and red light responsive optogenetic tools in bacteria, yeast, and mammalian cells and simplify the entrainment of cyanobacterial circadian rhythm. The LPA dramatically reduces the entry barrier to optogenetics and photobiology experiments.
27803975	Solute Carrier 15 (SLC15) family, alias H+-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their role in the cellular uptake of di- and tripeptides (di/tripeptides) and peptide-like molecules. Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from dietary protein digestion, while SLC15A2 (PEPT2) mainly allows renal tubular reabsorption of di/tripeptides from ultrafiltration, SLC15A3 (PHT2) and SLC15A4 (PHT1) possibly interact with di/tripeptides and histidine in certain immune cells, and SLC15A5 has unknown function. Our understanding of this family in vertebrates has steadily increased, also due to the surge of genomic-to-functional information from 'non-conventional' animal models, livestock, poultry, and aquaculture fish species. Here, we review the literature on the SLC15 transporters in teleost fish with emphasis on SLC15A1 (PEPT1), one of the solute carriers better studied amongst teleost fish because of its relevance in animal nutrition. We report on the operativity of the transporter, the molecular diversity, and multiplicity of structural-functional solutions of the teleost fish orthologs with respect to higher vertebrates, its relevance at the intersection of the alimentary and osmoregulative functions of the gut, its response under various physiological states and dietary solicitations, and its possible involvement in examples of total body plasticity, such as growth and compensatory growth. By a comparative approach, we also review the few studies in teleost fish on SLC15A2 (PEPT2), SLC15A4 (PHT1), and SLC15A3 (PHT2). By representing the contribution of teleost fish to the knowledge of the physiology of di/tripeptide transport and transporters, we aim to fill the gap between higher and lower vertebrates.
27803791	Type 2 diabetes mellitus (T2DM) is associated with circadian disruption. Our previous experimental results have showed that dietary Lycium barbarum. polysaccharide (LBP-4a) exhibited hypoglycemic and improving insulin resistance (IR) activities. This study was to explore the mechanisms of LBP-4a for improving hyperglycemia and IR by regulating biological rhythms in T2DM rats.The rats of T2DM were prepared by the high-sucrose-fat diets and injection of streptozotocin (STZ). The levels of insulin, leptin and melatonin were measured by enzyme linked immunosorbent assay (ELISA). The effect of LBP-4a on mRNA expression of melatonin receptors (MT2) in epididymal adipose tissue was evaluated by RT-PCR. The expression of CLOCK and BMAL1 in pancreatic islet cells was detected by Western blotting.	Our data indicated that the 24-hr rhythm of blood glucose appeared to have consistent with normal rats after gavaged administration of LBP-4a for each day of the 4 weeks, and the effects of hypoglycemia and improving hyperinsulinemia in T2DM rats treated at high dose were much better than that at low dose. The mechanisms were related to increasing MT2 level in epididymal adipose tissue and affecting circadian clocks gene expression of CLOCK and BMAL1 in pancreatic islet cells.	LBP-4a administration could treat T2DM rats. These observations provided the background for the further development of LBP-4a as a potential dietary therapeutic agent in the treatment of T2DM.	
27803010	This review summarises the literature on shift work and its relation to insufficient sleep, chronic diseases, and accidents. It is based on 38 meta-analyses and 24 systematic reviews, with additional narrative reviews and articles used for outlining possible mechanisms by which shift work may cause accidents and adverse health. Evidence shows that the effect of shift work on sleep mainly concerns acute sleep loss in connection with night shifts and early morning shifts. A link also exists between shift work and accidents, type 2 diabetes (relative risk range 1.09-1.40), weight gain, coronary heart disease (relative risk 1.23), stroke (relative risk 1.05), and cancer (relative risk range 1.01-1.32), although the original studies showed mixed results. The relations of shift work to cardiometabolic diseases and accidents mimic those with insufficient sleep. Laboratory studies indicate that cardiometabolic stress and cognitive impairments are increased by shift work, as well as by sleep loss. Given that the health and safety consequences of shift work and insufficient sleep are very similar, they are likely to share common mechanisms. However, additional research is needed to determine whether insufficient sleep is a causal pathway for the adverse health effects associated with shift work.
27758845	Bromocriptine is a glucose-lowering drug, which was shown to be effective in obese subjects with insulin resistance. It is usually administered in the morning. The exact working mechanism of bromocriptine still has to be elucidated. Therefore, in this open-label randomized prospective cross-over mechanistic study, we assessed whether the timing of bromocriptine administration (morning vs evening) results in different effects and whether these effects differ between lean and obese subjects. We studied the effect of bromocriptine on insulin sensitivity in 8 lean and 8 overweight subjects using an oral glucose tolerance test. The subjects used bromocriptine in randomized cross-over order for 2 weeks in the morning and 2 weeks in the evening. We found that in lean subjects, bromocriptine administration in the evening resulted in a significantly higher post-prandial insulin sensitivity as compared with the pre-exposure visit (glucose area under the curve (AUC) 742 mmol/L * 120 min (695-818) vs 641 (504-750), P = 0.036, AUC for insulin did not change, P = 0.575). In obese subjects, both morning and evening administration of bromocriptine resulted in a significantly higher insulin sensitivity: morning administration in obese: insulin AUC (55,900 mmol/L * 120 min (43,236-96,831) vs 36,448 (25,213-57,711), P = 0.012) and glucose AUC P = 0.069; evening administration in obese: glucose AUC (735 mmol/L * 120 min (614-988) vs 644 (568-829), P = 0.017) and insulin AUC, P = 0.208. In conclusion, bromocriptine increases insulin sensitivity in both lean and obese subjects. In lean subjects, this effect only occurred when bromocriptine was administrated in the evening, whereas in the obese, insulin sensitivity increased independent of the timing of bromocriptine administration.
27629575	Very preterm infants often receive donor milk from mothers who deliver at term, but its composition differs from that of their own mother's milk. Because breast-milk glucocorticoids can support developing neonates, we explored concentration variability within and between mothers.We hypothesized that breast-milk glucocorticoid concentrations would be higher after very preterm delivery [gestational age (GA) <32 wk; study 1] and would follow the diurnal rhythm of maternal adrenocortical activity (study 2).	Study 1 assessed differences in milk cortisol, cortisone, and the cortisone-to-(cortisol+cortisone) ratio of mothers who delivered at (median) GA: 28.6 wk or at term weekly during the first month postpartum. Study 2 assessed variations in milk cortisol, cortisone, and the cortisone-to-(cortisol+cortisone) ratio over 24 h, and tested Pearson correlations between milk and salivary concentrations in mothers who delivered at term (median GA: 38.9 wk) during week 4 postpartum. In these studies, foremilk glucocorticoids were measured by liquid chromatography-tandem mass spectrometry. Associations of milk cortisol, milk cortisone, and the milk cortisone-to-(cortisol+cortisone) ratio with prematurity (study 1) or collection time (study 2) were studied with longitudinal data analyses.	In study 1, giving birth to a very preterm infant was associated with reductions in milk cortisol and cortisone concentrations of 50% (β: 0.50; 95% CI: 0.26, 0.99; P = 0.05) and 53% (β: 0.53; 95% CI: 0.30, 0.93; P = 0.03), respectively, when adjusted for collection time. In study 2, concentrations of milk cortisol and cortisone were associated with collection time (both P < 0.01), peaking at ∼0700. Milk and salivary concentrations of cortisol (r = 0.92, P < 0.01) and cortisone (r = 0.93, P < 0.01) as well as the cortisone-to-(cortisol+cortisone) ratio (r = 0.64, P < 0.01) were correlated with one another.	Breast-milk glucocorticoid concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis activity and are lower in mothers who deliver very preterm.	
27604751	Sleep, like eating and breathing, is an essential part of the daily life cycle. Although the science is still emerging, sleep plays an important role in immune, cardiovascular, and neurocognitive function. Despite its great importance, nearly 40% of U.S. adults experience problems with sleep ranging from insufficient total sleep time, trouble initiating or maintaining sleep (Insomnia), circadian rhythm disorders, sleep-related movement disorders, and sleep-related breathing disorders such as obstructive sleep apnea (OSA). Herein, we discuss new evidence that suggests that sleep may also affect carcinogenesis. Specifically, we review recent epidemiologic data suggesting links between cancer and OSA. As OSA is a common, underdiagnosed, and undertreated condition, this has public health implications. Intriguing animal model data support a link between cancer and sleep/OSA, although mechanisms are not yet clear. Leaders in the fields of sleep medicine, pulmonology, and oncology recently met to review and discuss these data, as well as to outline future directions of study. We propose a multidisciplinary, three-pronged approach to studying the associations between cancer and sleep, utilizing mutually interactive epidemiologic studies, preclinical models, and early-phase clinical trials. Cancer Prev Res; 9(11); 821-7. ©2016 AACR.
27440795	The circadian clock is thought to adjust retinal sensitivity to ambient light levels, yet the involvement of specific clock genes is poorly understood. We explored the potential role of the nuclear receptor subfamily 1, group D, member 1 (REV-ERBα; or NR1D1) in this respect. In light-evoked behavioral tests, compared with wild-type littermates, Rev-Erbα-/- mice showed enhanced negative masking at low light levels (0.1 lx). Rev-Erbα-/- mouse retinas displayed significantly higher numbers of intrinsically photosensitive retinal ganglion cells (ipRGCs; 62% more compared with wild-type) and more intense melanopsin immunostaining of individual ipRGCs. In agreement with a pivotal role for melanopsin, negative masking at low light intensities was abolished in Rev-Erbα-/- Opn4-/- (melanopsin gene) double-null mice. Rev-Erbα-/- mice showed shortened latencies of both a and b electroretinogram waves, modified scotopic and photopic b-wave and scotopic threshold responses, and increased pupillary constriction, all of which suggested increased light sensitivity. However, wild-type and Rev-Erbα-/- mice displayed no detectable differences by in vivo fundus imaging, retinal histology, or expression of cell type-specific markers for major retinal cell populations. We conclude that REV-ERBα plays a major role in retinal information processing, and we speculate that REV-ERBα and melanopsin set sensitivity levels of the rod-mediated ipRGC pathway to coordinate activity with ambient light.-Ait-Hmyed Hakkari, O., Acar, N., Savier, E., Spinnhirny, P., Bennis, M., Felder-Schmittbuhl, M.-P., Mendoza, J., Hicks, D. Rev-Erbα modulates retinal visual processing and behavioral responses to light.
27430197	Effects of a bacterial probiotic (BP) on ruminal fermentation and plasma metabolites were evaluated in four Holstein cattle (body weight, 645 ± 62 kg; mean ± SD) with induced subacute ruminal acidosis (SARA). SARA was induced by feeding a SARA-inducing diet, and thereafter, 20, 50 or 100 g per head of a commercial BP was administered for 7 consecutive days during the morning feeding. Cattle without BP served as the control. The 24-hr mean ruminal pH in the control was lower, whereas those in the BP groups administered 20 or 50 g were significantly higher compared to the control from days 2 to 7. Circadian patterns of the 1-hr mean ruminal pH were identical (6.4-6.8) among all cattle receiving BP. Although the mean minimum pH in the control on day -7 and day 0 was <5.8, the pH in the treatment groups on day 7 was >5.8 and significantly higher than that of the control group ( >5.2). Ruminal volatile fatty acid (VFA) concentrations were not affected by BP treatment; however, the BP groups had lower lactic acid levels compared with the control group at 20:00 on day 7. Additionally, non-esterified fatty acid levels decreased from 8:00 to 20:00 in all BP groups on day 7. These results suggest that administration of 20 to 50 g of a multi-strain BP for 7 days might improve the low pH and high lactic acid level of the ruminal fluid in SARA cattle.

26492570	There is a dynamic interplay between metabolic processes and gene regulation via the remodeling of chromatin. Most chromatin-modifying enzymes use cofactors, which are products of metabolic processes. This article explores the biosynthetic pathways of the cofactors nicotinamide adenine dinucleotide (NAD), acetyl coenzyme A (acetyl-CoA), S-adenosyl methionine (SAM), α-ketoglutarate, and flavin adenine dinucleotide (FAD), and their role in metabolically regulating chromatin processes. A more detailed look at the interaction between chromatin and the metabolic processes of circadian rhythms and aging is described as a paradigm for this emerging interdisciplinary field.
27802074	Chronic exposure to light at night, as in shift work, alters biological clocks (chronodisruption), negatively impacting pregnancy outcome in humans. Actually the interaction of maternal and fetal circadian systems could be a key factor determining a fitting health in adults. We propose that chronic photoperiod shift (CPS) during pregnancy alter maternal circadian rhythms and impair circadian physiology in the adult offspring, increasing health risks. Pregnant rats were exposed to normal photoperiod (12 h light, 12 h dark) or to CPS until 85% of gestation. The effects of gestational CPS were evaluated on the mother and adult offspring. In the mother we measured rhythms of heart rate, body temperature, and activity through gestation and daily rhythms of plasma variables (melatonin, corticosterone, aldosterone, and markers of renal function) at 18 days of gestation. In adult offspring, we measured rhythms of the clock gene expression in the suprachiasmatic nucleus (SCN), locomotor activity, body temperature, heart rate, blood pressure, plasma variables, glucose tolerance, and corticosterone response to ACTH. CPS altered all maternal circadian rhythms, lengthened gestation, and increased newborn weight. The adult CPS offspring presented normal rhythms of clock gene expression in the SCN, locomotor activity, and body temperature. However, the daily rhythm of plasma melatonin was absent, and corticosterone, aldosterone, renal markers, blood pressure, and heart rate rhythms were altered. Moreover, CPS offspring presented decreased glucose tolerance and an abnormal corticosterone response to ACTH. Altogether these data show that gestational CPS induced long-term effects on the offspring circadian system, wherein a normal SCN coexists with altered endocrine, cardiovascular, and metabolic function.
27799619	Various aspects of the immune system display circadian rhythms. Although lymphocyte trafficking has been suggested to show diurnal variations, the mechanisms and influences on immune responses are unclear. Here, we show in mice that inputs from adrenergic nerves contribute to the diurnal variation of lymphocyte recirculation through lymph nodes (LNs), which is reflected in the magnitude of the adaptive immune response. Neural inputs to β2-adrenergic receptors (β2ARs) expressed on lymphocytes reduced the frequency of lymphocyte egress from LNs at night, which was accompanied by an increase of lymphocyte numbers in LNs. Immunization during the period of lymphocyte accumulation in LNs enhanced antibody responses. The diurnal variation of the humoral immune response was dependent on β2AR-mediated neural signals and was diminished when lymphocyte recirculation through LNs was stopped. This study reveals the physiological role of adrenergic control of lymphocyte trafficking in adaptive immunity and establishes a novel mechanism that generates diurnal rhythmicity in the immune system.
27747949	The annual migration of a bird can involve thousands of kilometres of nonstop flight, requiring accurately timed seasonal changes in physiology and behaviour. Understanding the molecular mechanisms controlling this endogenous programme can provide functional and evolutionary insights into the circannual biological clock and the potential of migratory species to adapt to changing environments. Under naturally timed photoperiod conditions, we maintained captive Swainson's thrushes (Catharus ustulatus) and performed RNA sequencing (RNA-Seq) of the ventral hypothalamus and optic chiasma to evaluate transcriptome-wide gene expression changes of individuals in migratory condition. We found that 188 genes were differentially expressed in relation to migratory state, 86% of which have not been previously linked to avian migration. Focal hub genes were identified that are candidate variables responsible for the occurrence of migration (e.g. CRABP1). Numerous genes involved in cell adhesion, proliferation and motility were differentially expressed (including RHOJ, PAK1 and TLN1), suggesting that migration-related changes are regulated by seasonal neural plasticity.
27690690	The circadian rhythm of glucocorticoids affects diverse physiological systems, including stress responses and the coordination of rhythmic functions in peripheral and central tissues. Circadian clocks are considered to be important coordinators of glucocorticoid release and loss of the core clock component Brain and muscle Arnt-like protein-1 leads to ablation of behavioral and physiological rhythms, hypocortisolism, impaired ACTH, and behavioral stress responses. Transplantation and conditional clock gene knock-down studies in mice suggest an important role of local adrenocortical clock function in this context. Here, we present a Cre-loxP-mediated conditional knockout of Bmal1 in the steroidogenic cells of the adrenal cortex in mice. Mutant animals show a loss of molecular clock gene activity rhythms in this tissue with subsequent disruption of rhythmic steroidogenic gene expression. However, despite this loss of normal clock rhythmicity in the adrenal cortex, behavioral and physiological rhythms and acute stress responses persist in mutant mice. These findings reveal a dissociation of transcriptional and endocrine rhythm regulation in the adrenal cortex, arguing for a less pivotal function of the local clock machinery in the regulation of circadian and acute glucocorticoid outputs.
21413413	For the greater part of 150 years it was assumed that the mammalian retina contained only two classes of photoreceptors, rods and cones. However, a flurry of studies in the late 1990s and early 2000s demonstrated the existence of a third class of mammalian photoreceptors that differs greatly from rods and cones. It utilizes a different photopigment, is much less sensitive to light, responds to light far more slowly, and has far lower spatial resolution, characteristics that fit with its primary function of signaling ambient light levels (irradiance) to the brain. Most surprisingly, these photoreceptors are retinal ganglion cells (RGCs), and thus, have the unique ability to communicate directly with higher visual centers of the brain. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are a rare subpopulation of ganglion cells (<5%) whose primary role is to signal light for largely subconscious, non-image-forming visual reflexes, such as pupillary constriction, neuroendocrine regulation, and synchronizing daily (“circadian”) physiological rhythms to the light/dark cycle (“circadian photoentrainment”). Recent research has revealed additional roles for ipRGCs in conscious visual perception, including brightness discrimination and contrast detection. Many visual behaviors under ipRGC control are remarkably tonic, and require prolonged integration of ambient light levels. The unique properties of ipRGCs make them well suited for regulating such behaviors.
27798346	Synchronizing eating schedules to daily circadian rhythms may improve metabolic health, but its association with gestational glycemia is unknown.This study examined the association of maternal night-fasting intervals and eating episodes with blood glucose concentrations during pregnancy.	This was a cross-sectional study within a prospective cohort in Singapore. Maternal 24-h dietary recalls, fasting glucose, and 2-h glucose concentrations were ascertained at 26-28 wk gestation for 1061 women (aged 30.7 ± 5.1 y). Night-fasting intervals were based on the longest fasting duration during the night (1900-0659). Eating episodes were defined as events that provided >50 kcal, with a time interval between eating episodes of ≥15 min. Multiple linear regressions with adjustment for confounders were conducted.	Mean ± SD night-fasting intervals and eating episodes per day were 9.9 ± 1.6 h and 4.2 ± 1.3 times/d, respectively; fasting and 2-h glucose concentrations were 4.4 ± 0.5 and 6.6 ± 1.5 mmol/L, respectively. In adjusted models, each hourly increase in night-fasting intervals was associated with a 0.03 mmol/L decrease in fasting glucose (95% CI: -0.06, -0.01 mmol/L), whereas each additional daily eating episode was associated with a 0.15 mmol/L increase in 2-h glucose (95% CI: 0.03, 0.28 mmol/L). Conversely, night-fasting intervals and daily eating episodes were not associated with 2-h and fasting glucose, respectively.	
27798273	Circadian clock components oscillate in cells of the cardiovascular system. Disruption of these oscillations has been observed in cardiovascular diseases. We hypothesized that obstructive sleep apnea, which is associated with cerebrovascular diseases, disrupts the cerebrovascular circadian clock and rhythms in vascular function. Apneas were produced in rats during sleep. Following two weeks of sham or obstructive sleep apnea, cerebral arteries were isolated over 24 h for mRNA and functional analysis. mRNA expression of clock genes exhibited 24-h rhythms in cerebral arteries of sham rats (p < 0.05). Interestingly, peak expression of clock genes was significantly lower following obstructive sleep apnea (p < 0.05). Obstructive sleep apnea did not alter clock genes in the heart, or rhythms in locomotor activity. Isolated posterior cerebral arteries from sham rats exhibited a diurnal rhythm in sensitivity to luminally applied ATP, being most responsive at the beginning of the active phase (p < 0.05). This rhythm was absent in arteries from obstructive sleep apnea rats (p < 0.05). Rhythms in ATP sensitivity in sham vessels were absent, and not different from obstructive sleep apnea, following treatment with L-NAME and indomethacin. We conclude that cerebral arteries possess a functional circadian clock and exhibit a diurnal rhythm in vasoreactivity to ATP. Obstructive sleep apnea attenuates these rhythms in cerebral arteries, potentially contributing to obstructive sleep apnea-associated cerebrovascular disease.
27797990	Cardiovascular disease (CVD) is a major challenge to global health. The same epidemiological transition scenario is replayed as countries develop, but with variations based on environment, culture and ethnic mixture. The Baependi Heart Study was set up in 2005 to develop a longitudinal family-based cohort study that reflects on some of the genetic and lifestyle-related peculiarities of the Brazilian populations, in order to evaluate genetic and environmental influences on CVD risk factor traits.Probands were recruited in Baependi, a small rural town in the state of Minas Gerais, Brazil, following by first-degree and then increasingly more distant relatives. The first follow-up wave took place in 2010, and the second in 2016. At baseline, the study evaluated 1691 individuals across 95 families. Cross-sectional data have been collected for 2239 participants.	Environmental and lifestyle factors and measures relevant to cardiovascular health have been reported. Having expanded beyond cardiovascular health outcomes, the phenotype datasets now include genetics, biochemistry, anthropometry, mental health, sleep and circadian rhythms. Many of these have yielded heritability estimates, and a shared genetic background of anxiety and depression has recently been published. In spite of universal access to electricity, the population has been found to be strongly shifted towards morningness compared with metropolitan areas.	A new follow-up, marking 10 years of the study, is ongoing in 2016, in which data are collected as in 2010 (with the exception of the neuropsychiatric protocol). In addition to this, a novel questionnaire package collecting information about intelligence, personality and spirituality is being planned. The data set on circadian rhythms and sleep will be amended through additional questionnaires, actimetry, home sleep EEG recording and dim light melatonin onset (DLMO) analysis. Finally, the anthropometric measures will be expanded by adding three-dimensional facial photography, voice recording and anatomical brain MRI.	
27796320	Alzheimer's disease (AD) is a circadian clock-related disease. However, it is not very clear whether pre-symptomatic AD leads to circadian disruption or whether malfunction of circadian rhythms exerts influence on development of AD. Here, we report a functional clock that exists in the hippocampus. This oscillator both receives input signals and maintains the cycling of the hippocampal Per2 gene. One of the potential inputs to the oscillator is orexin signaling, which can shorten the hippocampal clock period and thereby regulate the expression of clock-controlled-genes (CCGs). A 24-h time course qPCR analysis followed by a JTK_CYCLE algorithm analysis indicated that a number of AD-risk genes are potential CCGs in the hippocampus. Specifically, we found that Bace1 and Bace2, which are related to the production of the amyloid-beta peptide, are CCGs. BACE1 is inhibited by E4BP4, a repressor of D-box genes, while BACE2 is activated by CLOCK:BMAL1. Finally, we observed alterations in the rhythmic expression patterns of Bace2 and ApoE in the hippocampus of aged APP/PS1dE9 mice. Our results therefore indicate that there is a circadian oscillator in the hippocampus whose oscillation could be regulated by orexins. Hence, orexin signaling regulates both the hippocampal clock and the circadian oscillation of AD-risk genes.
27795550	Disruption of circadian rhythms is one of the proposed mechanisms linking late sleep timing to obesity risk but few studies have evaluated biological markers outside of the laboratory. The goal of this study was to determine the relationship between the timing and alignment of melatonin and sleep onset (phase angle) with body mass index (BMI), body fat and obesity-related behaviors. We hypothesized that circadian alignment (relationship of melatonin to sleep timing) rather than circadian (melatonin) timing would be associated with higher BMI, body fat, dietary intake and lower physical activity.Adults with sleep duration ⩾6.5 h completed 7 days of wrist actigraphy, food diaries and SenseWear arm band monitoring. Circadian timing, measured by dim light melatonin onset was measured in the clinical research unit. Circadian alignment was calculated as the duration between dim light melatonin onset and average sleep onset time in the prior week (phase angle). Body fat was evaluated using dual-energy X-ray absorptiometry. Data were analyzed using bivariate correlations and multivariable regression analyses controlling for age, sex, sleep duration and evening light exposure.	Participants included 97 adults (61 F, age 26.8±7.3 years) with average sleep duration 443.7 (s.d.=50.4) minutes. Average phase angle was 2.2 h (s.d.=1.5). Circadian alignment was associated with circadian timing (P<0.001) and sleep duration (P=0.005). In multivariable analyses, later circadian timing was associated with lower BMI (P=0.04). Among males only, circadian alignment was associated with percent body fat (P=0.02) and higher android/gynoid fat ratio (P=0.04). Circadian alignment was associated with caloric intake (P=0.049) carbohydrate intake (P=0.04) and meal frequency (P=0.03) among both males and females.	Circadian timing and alignment were not associated with increased BMI or body fat, among healthy adults with ⩾6.5 h of sleep, but circadian alignment was associated with dietary intake. There may be sex differences in the relationship between circadian alignment and body fat.	
27789784	Photoperiod disruption, which occurs during shift work, is associated with changes in metabolism or physiology (e.g. hypertension and hyperglycaemia) that have the potential to adversely affect stroke outcome. We sought to investigate if photoperiod disruption affects vulnerability to stroke by determining the impact of photoperiod disruption on infarct size following permanent middle cerebral artery occlusion. Adult male Wistar rats (210-290 g) were housed singly under two different light/dark cycle conditions ( n = 12 each). Controls were maintained on a standard 12:12 light/dark cycle for nine weeks. For rats exposed to photoperiod disruption, every three days for nine weeks, the lights were switched on 6 h earlier than in the previous photoperiod. T2-weighted magnetic resonance imaging was performed at 48 h after middle cerebral artery occlusion. Disruption of photoperiod in young healthy rats for nine weeks did not alter key physiological variables that can impact on ischaemic damage, e.g. blood pressure and blood glucose immediately prior to middle cerebral artery occlusion. There was no effect of photoperiod disruption on infarct size after middle cerebral artery occlusion. We conclude that any potentially adverse effect of photoperiod disruption on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities.
27664156	Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs). These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b). After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.
27465471	Underlying mechanisms of the elevated risks of hypertension and cardiovascular disease (CVD) in Cushing's syndrome (CS) are unclear. We treated an adult woman with CS because of a cortisol-secreting adrenal tumor. After tumor resection, the 24-h blood pressure (BP) level improved from 156/91 to 131/84 mmHg; the morning BP surprisingly improved from 174/98 to 127/93 mmHg, although we reduced her antihypertensive medication. Her sleep quality (by the Pittsburgh Sleep Quality Index) improved from 7 to 2 points. Disturbed circadian BP rhythm is often observed in CS, but was reported only as altered nocturnal BP fall. This is the first report showing the disappearance of the morning BP surge evaluated by ambulatory BP monitoring with postsurgery sleep quality improvement. Poor-quality sleep, followed by exaggerated morning BP surge may thus be a cause of CS-related cardiovascular events. Sleep quality and BP circadian rhythm evaluations may clarify hypertension and high CVD risk in CS.
27391362	The lancet fluke, Dicrocoelium dendriticum, is perhaps the best-known example of parasite manipulation of host behavior, which is manifested by a radically changed behavior that leaves infected ants attached to vegetation at times when transmission to an herbivore host is optimal. Despite the publicity surrounding this parasite, curiously little is known about factors inducing and maintaining behavioral changes in its ant intermediate host. This study examined the importance of 3 environmental factors on the clinging behavior of red wood ants, Formica polyctena , infected with D. dendriticum . This behavior, hypothesized to involve cramping of the mandibular muscles in a state of tetany, was observed in naturally infected F. polyctena under controlled temperature, light, and humidity conditions. We found that low temperature significantly stimulated and maintained tetany in infected ants while light, humidity, ant size, and infection intensity had no influence on this behavior. Under none of the experimental conditions did uninfected ants attach to vegetation, demonstrating that tetany was induced by D. dendriticum . Temperature likely has a direct impact on the initiation of clinging behavior, but it may also serve as a simple but reliable indicator of the encounter rate between infected ants and ruminant definitive hosts. In addition, temperature-sensitive behavior manipulation may protect infected ants from exposure to temperatures in the upper thermal range of the host.
27793219	Sleep is profoundly altered during the course of infectious diseases. The typical response to infection includes an initial increase in nonrapid eye movement sleep (NREMS) followed by an inhibition in NREMS. REMS is inhibited during infections. Bacterial cell wall components, such as peptidoglycan and lipopolysaccharide, macrophage digests of these components, such as muramyl peptides, and viral products, such as viral double-stranded RNA, trigger sleep responses. They do so via pathogen-associated molecular pattern recognition receptors that, in turn, enhance cytokine production. Altered sleep and associated sleep-facilitated fever responses are likely adaptive responses to infection. Normal sleep in physiological conditions may also be influenced by gut microbes because the microbiota is affected by circadian rhythms, stressors, diet, and exercise. Furthermore, sleep loss enhances translocation of viable bacteria from the intestine, which provides another means by which sleep-microbe interactions impact neurobiology.
27793218	Circadian rhythms are 24-h patterns regulating behavior, organs, and cells in living organisms. These rhythms align biological functions with regular and predictable environmental patterns to optimize function and health. Disruption of these rhythms can be detrimental resulting in metabolic syndrome, cancer, or cardiovascular disease, just to name a few. It is now becoming clear that the intestinal microbiome is also regulated by circadian rhythms via intrinsic circadian clocks as well as via the host organism. Microbiota rhythms are regulated by diet and time of feeding which can alter both microbial community structure and metabolic activity which can significantly impact host immune and metabolic function. In this review, we will cover how host circadian rhythms are generated and maintained, how host circadian rhythms can be disrupted, as well as the consequences of circadian rhythm disruption. We will further highlight the newly emerging literature indicating the importance of circadian rhythms of the intestinal microbiota.
27793063	This study examined the effects of electrostimulation (ES) strength training at the same time-of-day on the diurnal fluctuations of maximal voluntary isometric contractions (MVIC) and surface electromyography (EMG). 20 male performed 3 MVICs of knee extension coupled with surface EMG before and after 5 weeks of 3 ES training sessions per week. Each ES training session consisted in 45 isometric contractions. The participants were randomly assigned to either a morning (MTG, 07:00-08:00 h) or an evening (ETG, 17:00-18:00 h) training group. Both groups performed the evaluation tests at 07:00 and 17:00 h. Before ES training, MVIC was significantly higher in the evening compared to the morning for all groups, but there was no significant difference between groups for all EMG parameters. After the ES training, the diurnal variations in MVIC were blunted in the MTG and persisted in the ETG. Significant time-of-day effect was noticed for all EMG parameters but there was no group effect. The elimination of the diurnal fluctuations of MVIC and the appearance of EMG variations by training in the morning hours suggest that neural adaptations are the main source of temporal specificity of neuromuscular performance after ES strength training.
27792172	Modern lifestyles, such as shift work, nocturnal social activities, and jet lag, disturb the circadian rhythm. The interaction between mammals and the co-evolved intestinal microbiota modulates host physiopathological processes. Radiotherapy is a cornerstone of modern management of malignancies; however, it was previously unknown whether circadian rhythm disorder impairs prognosis after radiotherapy. To investigate the effect of circadian rhythm on radiotherapy, C57BL/6 mice were housed in different dark/light cycles, and their intestinal bacterial compositions were compared using high throughput sequencing. The survival rate, body weight, and food intake of mice in diverse cohorts were measured following irradiation exposure. Finally, the enteric bacterial composition of irradiated mice that experienced different dark/light cycles was assessed using 16S RNA sequencing. Intriguingly, mice housed in aberrant light cycles harbored a reduction of observed intestinal bacterial species and shifts of gut bacterial composition compared with those of the mice kept under 12 h dark/12 h light cycles, resulting in a decrease of host radioresistance. Moreover, the alteration of enteric bacterial composition of mice in different groups was dissimilar. Our findings provide novel insights into the effects of biological clocks on the gut bacterial composition, and underpin that the circadian rhythm influences the prognosis of patients after radiotherapy in a preclinical setting.
27791401	Circadian regulation of behavior worsens with age, however, the mechanism behind this phenomenon is still poorly understood. Specifically, it is not clear to what extend the ability of the circadian clock in the suprachiasmatic nuclei (SCN) to generate the rhythm is affected by aging. This study aimed to ascertain the effect of aging on the functioning of the SCN of mPer2Luciferase mice under unnatural lighting conditions, such as constant light (LL). Under LL, which worsened the age-induced effect on behavioral rhythms, a marginal age-dependent effect on in vitro rhythmicity in explants containing the middle, but not the rostral/caudal, regions of the SCN was apparent; the proportion of mice in which middle-region SCN explants were completely arrhythmic or had an extremely long period (>30 h) was 47% in aged mice and 27% in adults. The results suggest that in some of the aged animals, LL may weaken the coupling among oscillators in specific sub-regions of the SCN, leaving other sub-regions better synchronized. In the standard light/dark cycle and in constant darkness, the SCN ability to produce bioluminescence rhythms in vitro was not compromised in aged mice although aging significantly affected their SCN-driven locomotor activity rhythms. Therefore, our results demonstrate that although age worsened the SCN output rhythm, the SCN molecular core clock mechanism itself was relatively resilient to aging in these same animals. The results suggest the involvement of pathways downstream of the core clock mechanism which are responsible for this phenomenon.
27791397	Decision-making is affected by psychological factors like emotional state or cognitive control, which may also vary with circadian rhythmicity. Here, we tested the influence of chronotype (32 morning-type versus 32 evening-type) and time of day (9 a.m. versus 5 p.m.) on interpersonal decision-making as measured by the Ultimatum Game. Participants had to accept or reject different economic offers proposed by a virtual participant. Acceptance involved distribution of gains as proposed, whereas rejection resulted in no gain for either player. The results of the game showed a deviation from rational performance, as participants usually rejected the unfair offers. This behaviour was similar for both chronotype groups, and in both times of day. This result may reflect the robustness of decision-making strategies across standard circadian phases under ecological conditions. Furthermore, morning-types invested more time than evening-types to respond to high-uncertainty offers. This more cautious decision-making style of morning-types fits with our finding of higher proactive control as compared to evening-types when performing the AX-Continuous Performance Task. In line with the literature on personality traits, our results suggest that morning-types behave with more conscientiousness and less risk-taking than evening-type individuals.
27791392	In Drosophila melanogaster, Ataxin-2 is a crucial activator of Period and is involved in the control of circadian rhythms. However, in mammals the function of Ataxin-2 is unknown despite its involvement in the inherited neurogenerative disease Spinocerebellar Ataxia type 2 in humans. Therefore, we analyzed locomotor behavior of Atxn2-deficient mice and their WT littermates under entrained- and free-running conditions as well as after experimental jet lag. Furthermore, we compared the PER1 and PER2 immunoreaction (IR) in the SCN. Atxn2-/- mice showed an unstable rhythmicity of locomotor activity, but the level of PER1 and PER2 IR in the SCN did not differ between genotypes.
27790629	Most of the computations and tasks performed by the brain require the ability to tell time, and process and generate temporal patterns. Thus, there is a diverse set of neural mechanisms in place to allow the brain to tell time across a wide range of scales: from interaural delays on the order of microseconds to circadian rhythms and beyond. Temporal processing is most sophisticated on the scale of tens of milliseconds to a few seconds, because it is within this range that the brain must recognize and produce complex temporal patterns-such as those that characterize speech and music. Most models of timing, however, have focused primarily on simple intervals and durations, thus it is not clear whether they will generalize to complex pattern-based temporal tasks. Here, we review neurobiologically based models of timing in the subsecond range, focusing on whether they generalize to tasks that require placing consecutive intervals in the context of an overall pattern, that is, pattern timing.
27790157	In the present study, we investigated whether the daily fluctuations of internal body temperature (Tb) and spontaneous locomotor activity (SLA) interact with the thermal and neuronal adjustments induced by high-intensity aerobic exercise until fatigue. The body temperature and SLA of adult Wistar rats (n = 23) were continuously recorded by telemetry for 48 h. Then, the rats were subjected to a protocol of graded exercise until fatigue or rest on the treadmill during light and dark-phases. Tb, tail skin temperature and ambient temperature during each experimental session were recorded. At the end of the last experimental session, the animals were anaesthetized; the brains were perfused and removed for immunohistochemical analysis of c-fos neuronal activation. The daily rhythms of SLA and Tb were strongly correlated (r = 0.88 and p < 0.001), and this was followed by a daily oscillation in both the ratio and the correlation index between these variables (p < 0.001). Exercise capacity was associated with a lower resting Tb (p < 0.01) and was higher in the light-phase (p < 0.001), resulting in an increased capacity to accumulate heat during exercise (p < 0.01). Independent of time-of-day, high intensity exercise strongly activated the hypothalamic paraventricular nucleus (PVN), the supra-optic nucleus (SON) and the locus coeruleus (LC) (p < 0.001) but not the suprachiasmatic nucleus (SCN). Taken together, our results points toward a role of the circadian system in a basal activity control of the thermoregulatory system as an important component for the onset of physical activities. In fact, rather than directly limiting the adjustments induced by exercise the present study brings new evidence that the effect of time-of-day on exercise performance occurs at the threshold level for each thermoregulatory system effector activity. This assumption is based on the observed resilience of the central clock to high-intensity exercise and the similarities in exercise-induced neuronal activation in the PVN, SON, and LC.
27789727	In the vertebrate retina, three types of photoreceptors-visual photoreceptor cones and rods and the intrinsically photosensitive retinal ganglion cells (ipRGCs)-converged through evolution to detect light and regulate image- and nonimage-forming activities such as photic entrainment of circadian rhythms, pupillary light reflexes, etc. ipRGCs express the nonvisual photopigment melanopsin (OPN4), encoded by two genes: the Xenopus (Opn4x) and mammalian (Opn4m) orthologs. In the chicken retina, both OPN4 proteins are found in ipRGCs, and Opn4x is also present in retinal horizontal cells (HCs), which connect with visual photoreceptors. Here we investigate the intrinsic photosensitivity and functioning of HCs from primary cultures of embryonic retinas at day 15 by using calcium fluorescent fluo4 imaging, pharmacological inhibitory treatments, and Opn4x knockdown. Results show that HCs are avian photoreceptors with a retinal-based OPN4X photopigment conferring intrinsic photosensitivity. Light responses in HCs appear to be driven through an ancient type of phototransduction cascade similar to that in rhabdomeric photoreceptors involving a G-protein q, the activation of phospholipase C, calcium mobilization, and the release of the inhibitory neurotransmitter GABA. Based on their intrinsic photosensitivity, HCs may have a key dual function in the retina of vertebrates, potentially regulating nonvisual tasks together with their sister cells, ipRGCs, and with visual photoreceptors, modulating lateral interactions and retinal processing.
27789706	We report a database of circadian genes in eukaryotes (CGDB, http://cgdb.biocuckoo.org), containing ∼73 000 circadian-related genes in 68 animals, 39 plants and 41 fungi. Circadian rhythm is ∼24 h rhythm in behavioral and physiological processes that exists in almost all organisms on the earth. Defects in the circadian system are highly associated with a number of diseases such as cancers. Although several databases have been established for rhythmically expressed genes, a comprehensive database of cycling genes across phyla is still lacking. From the literature, we collected 1382 genes of which transcript level oscillations were validated using methods such as RT-PCR, northern blot and in situ hybridization. Given that many genes exhibit different oscillatory patterns in different tissues/cells within an organism, we have included information regarding the phase and amplitude of the oscillation, as well as the tissue/cells in which the oscillation was identified. Using these well characterized cycling genes, we have then conducted an orthologous search and identified ∼45 000 potential cycling genes from 148 eukaryotes. Given that significant effort has been devoted to identifying cycling genes by transcriptome profiling, we have also incorporated these results, a total of over 26 000 genes, into our database.
27688202	Photic stimulation of rods, cones and intrinsically photosensitive melanopsin-containing retinal ganglion cells (ipRGCs) mediates non-visual light responses, including entrainment of circadian rhythms and pupillary light reflex. Unlike visual responses to photic stimulation, the cerebral correlates of non-visual light responses in humans remains elusive. In this study, we used functional magnetic resonance imaging (fMRI) in 14 healthy young participants, to localize cerebral regions which are differentially activated by metameric light that gave rise to different levels of melanopic excitation. Mean blood oxygen-level dependent (BOLD) responses disclosed bilateral activation of the frontal eye fields during exposure to light geared towards melanopsin. Furthermore, multivariate pattern analyses showed distinct bilateral pattern activity in the inferior temporal gyri and the caudate nuclei. Taken together, our findings suggest that melanopsin-based photoreception activates a cerebral network including frontal regions, classically involved in attention and ocular motor responses.
27639775	Endogenous circadian clocks with ~24-h periodicity are found in most organisms from cyanobacteria to humans. Daylight synchronizes these clocks to solar time. In humans, shift-work and jet lag perturb clock synchronization, and such perturbations, when repeated or chronic, are strongly suspected to be detrimental to healthspan. Here we investigated locomotor aging and longevity in Drosophila melanogaster with genetically or environmentally disrupted clocks. We compared two mutations in period (per, a gene essential for circadian rhythmicity in Drosophila), after introducing them in a common reference genetic background: the arrhythmic per01, and perT which displays robust short 16-h rhythms. Compared to the wild type, both per mutants showed reduced longevity and decreased startle-induced locomotion in aging flies, while spontaneous locomotor activity was not impaired. The per01 phenotypes were generally less severe than those of perT, suggesting that chronic jet lag is more detrimental to aging than arrhythmicity in Drosophila. Interestingly, the adjustment of environmental light-dark cycles to the endogenous rhythms of the perT mutant fully suppressed the acceleration in the age-related decline of startle-induced locomotion, while it accelerated this decline in wild-type flies. Overall, our results show that chronic jet lag accelerates a specific form of locomotor aging in Drosophila, and that this effect can be alleviated by environmental changes that ameliorate circadian rhythm synchronization.
27637496	Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways.
27634039	Liver regeneration offers a distinctive opportunity to study cell proliferation in vivo Mammalian silent information regulator 1 (SIRT1), a NAD+-dependent histone deacetylase, is an important regulator of various cellular processes, including proliferation, metabolism, and circadian rhythms. In the liver, SIRT1 coordinates the circadian oscillation of clock-controlled genes, including genes that encode enzymes involved in metabolic pathways. We performed partial hepatectomy in WT and liver-specific Sirt1-deficient mice and analyzed the expression of cell cycle regulators in liver samples taken at different times during the regenerative process, by real time PCR, Western blotting analysis, and immunohistochemistry. Lipidomic analysis was performed in the same samples by MS/HPLC. We showed that G1/S progression was significantly affected by absence of SIRT1 in the liver, as well as circadian gene expression. This was associated to lipid accumulation due to defective fatty acid beta-oxidation. Our study revealed for the first time the importance of SIRT1 in the regulation of hepatocellular proliferation, circadian rhythms, and lipid metabolism during liver regeneration in mice. These results represent an additional step toward the characterization of SIRT1 function in the liver.
27338118	To evaluate the relationship between retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery, and short posterior ciliary artery and 24-hour blood pressure (BP) measurements in dipper and nondipper patients with primary open-angle glaucoma (POAG).A prospective, cross-sectional, and observational study was conducted on consecutive patients, referred or recruited, attending the outpatient service of our ophthalmology department. Ambulatory BP monitoring, Doppler imaging, and ocular pulse amplitude measurements were performed on the same day. Patients with nocturnal BP decrease up to 10% of the diurnal BP were defined as dippers and those with BP decrease less than 10% were defined as nondippers.	A total of 114 patients (36 nondippers and 78 dippers) were included in the study. The end-diastolic velocity was significantly lower and the resistivity index (RI) was significantly higher in the dippers than in the nondippers (p&lt;0.0001 and p&lt;0.0001, respectively). The RI in the OA was significantly correlated with daytime and nighttime systolic BP and with the daytime mean arterial pressure in the dippers.	The RI in the OA significantly correlates with BP in patients with POAG with nocturnal BP dips. Additionally, retrobulbar blood flow parameters are reduced in dippers as compared with nondippers with POAG.	
26947135	Among police officers in Denmark, we studied (i) how many consecutive night shifts participants preferred at baseline; (ii) preferences regarding three intervention conditions (two, four, and seven consecutive night shifts followed by the same number of days off/day shifts: '2 + 2', '4 + 4', '7 + 7') at follow-up; (iii) characteristics of participants preferring each of these intervention conditions. Questionnaire data from a crossover intervention study were used (baseline: n = 73; follow-up: n = 68). At baseline, 49% preferred four consecutive night shifts. At follow-up, 57% preferred '4 + 4', 26% preferred '2 + 2' and 26% preferred '7 + 7'. Participants, who preferred longer spells of night work experienced that night work was less demanding, found it easier to sleep at different times of the day, and were more frequently evening types compared with participants who preferred shorter spells of night work. The participants' preferences are likely to be influenced by their previous shift work experience. Practitioner Summary: We investigated police officers' preferences regarding the number of consecutive night shifts. The majority preferred four consecutive night shifts. Those who preferred the longer spells of night work found night work less demanding, found it easier to sleep at different times of the day, and were more frequently evening types.
27788402	Human behavior and physiology exhibit diurnal fluctuations. These rhythms are entrained by light and social cues, with vast individual differences in the phase of entrainment - referred as an individual's chronotype - ranging in a continuum between early larks and late owls. Understanding whether decision-making in real-life situations depends on the relation between time of the day and an individual's diurnal preferences has both practical and theoretical implications. However, answering this question has remained elusive because of the difficulty of measuring precisely the quality of a decision in real-life scenarios. Here we investigate diurnal variations in decision-making as a function of an individual's chronotype capitalizing on a vast repository of human decisions: online chess servers. In a chess game, every player has to make around 40 decisions using a finite time budget and both the time and quality of each decision can be accurately determined. We found reliable diurnal rhythms in activity and decision-making policy. During the morning, players adopt a prevention focus policy (slower and more accurate decisions) which is later modified to a promotion focus (faster but less accurate decisions), without daily changes in performance.
27786517	The study examined diurnal regulation of salivary alpha-amylase (sAA) in association with daily stressors, adult day services (ADS) use, and other caregiving characteristics.A sample of 165 family caregivers of individuals with dementia (IWD) completed an 8-day diary study. Caregivers provided 5 saliva samples across the 8 days. On some days, caregivers provided all or most of the care. On other days, their relative attended ADS for part of the day. A 3-level unconditional linear spline model was fit to describe the typical sAA diurnal rhythms. Predictors were then added to the unconditional model to test the hypotheses on ADS use and daily stressors.	Daily ADS use did not have an effect on diurnal sAA regulation. However, controlling for daily ADS use, greater ADS use over the 8 days was associated with a more prominent rise between 30 min after wake-up and before lunch, and a more prominent decline between before lunch and late afternoon. Fewer ADS days were associated with a more flattened sAA diurnal rhythm. Additionally, greater daily care-related stressor exposures had a within-person association with lower sAA levels in the late afternoon. Care-related stressor exposures had significant within- and between-person associations with sAA diurnal slopes. Furthermore, daily positive experiences had a significant between-person association with sAA diurnal slopes.	Caring for a disabled family member may heighten the vulnerability to potential physiological conditions. Respite from care stressors from ADS use may have some biobehavioral benefits on sAA regulations. (PsycINFO Database Record	
27786253	The synchronization of stochastic coupled oscillators is a central problem in physics and an emerging problem in biology, particularly in the context of circadian rhythms. Most measurements on the biological clock are made at the macroscopic level of millions of cells. Here measurements are made on the oscillators in single cells of the model fungal system, Neurospora crassa, with droplet microfluidics and the use of a fluorescent recorder hooked up to a promoter on a clock controlled gene-2 (ccg-2). The oscillators of individual cells are stochastic with a period near 21 hours (h), and using a stochastic clock network ensemble fitted by Markov Chain Monte Carlo implemented on general-purpose graphical processing units (or GPGPUs) we estimated that >94% of the variation in ccg-2 expression was stochastic (as opposed to experimental error). To overcome this stochasticity at the macroscopic level, cells must synchronize their oscillators. Using a classic measure of similarity in cell trajectories within droplets, the intraclass correlation (ICC), the synchronization surface ICC is measured on >25,000 cells as a function of the number of neighboring cells within a droplet and of time. The synchronization surface provides evidence that cells communicate, and synchronization varies with genotype.
27784754	Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC) complexes activate transcription of period (per) and timeless (tim) genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi) knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls) or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans.
27784643	This study was aimed to explore the mechanisms underlying cadmium-induced circadian rhythms disruption. Two groups of zebrafish larvae treated with or without 5 ppm CdCl2 were incubated in a photoperiod of 14-h light/10-h dark conditions. The mRNA levels of clock1a, bmal1b, per2 and per1b in two groups were determined. Microarray data were generated in two group of samples. Differential expression of genes were identified and the changes in expression level for some genes were validated by RT-PCR. Finally, Gene Ontology functional and KEGG pathway enrichment analysis of differentially expressed genes (DEGs) were performed. In comparison with normal group, the mRNA levels of clock1a, bmal1b, and per2 were significantly changed and varied over the circadian cycle in CdCl2-treated group. DEGs were obtained from the light (84 h, ZT12) and dark (88 h, ZT16) phase. In addition, G-protein coupled receptor protein signaling pathway and immune response were both enriched by DEGs in both groups. While, proteolysis and amino acid metabolism were found associated with DEGs in light phase, and Neuroactive ligand-receptor interaction and oxidation-reduction process were significantly enriched by DEGs in dark phase. Besides, the expression pattern of genes including hsp70l and or115-11 obtained by RT-PCR were consistent with those obtained by microarray analysis. As a consequence, cadmium could make significant effects on circadian rhythms through immune response and G protein-coupled receptor signaling pathway. Besides, between the dark and the light phase, the mechanism by which cadmium inducing disruption of circadian rhythms were different to some extent.
27699644	Circadian rhythms are a collection of endogenously driven biochemical, physiological, and behavioral processes that oscillate in a 24-h cycle and can be entrained by external cues. Circadian clock molecules are responsible for the expression of regulatory components that modulate, among others, the cell's metabolism and energy consumption. In clinical practice, the regulation of clock mechanisms is relevant to biotransformation of therapeutics. Accordingly, xenobiotic metabolism and detoxification, the two processes that directly influence drug effectiveness and toxicity, are direct manifestations of the daily oscillations of the cellular and biochemical processes taking place within the gastrointestinal, hepatic/biliary, and renal/urologic systems. Consequently, the impact of circadian timing should be factored in when developing therapeutic regimens aimed at achieving maximum efficacy, minimum toxicity, and decreased adverse effects in a patient. However, and despite a strong mechanistic foundation, only 0.16 % of ongoing clinical trials worldwide exploit the concept of 'time-of-day' administration to develop safer and more effective therapies. In this article, we (1) emphasize points of control at which circadian biology intersects critical processes governing treatment interventions; (2) explore the extent to which chronotherapeutics are incorporated into clinical trials; (3) recognize roadblocks; and (4) recommend approaches to precipitate the integration of chronobiological concepts into clinical practice.
27693853	As light plays an important role in the synchronisation of the internal biological clock to the environmental day/night schedule, we compared the 24-h profiles of biological circadian markers in blind and normal sighted individuals. Salivary melatonin and cortisol concentrations were collected every two hours in eleven blind subjects, reporting no conscious light perception, and eleven age- and sex-matched normal sighted controls. Timing of melatonin onset and associated cortisol quiescence period confirm an increased incidence of abnormal circadian patterns in blindness. Additionally, blind subjects showed a greater overall melatonin concentration throughout the 24-h period. Cortisol profiles, including concentration and morning cortisol peaks, on the other hand, did not differ between blind and sighted individuals. These findings support previous reports of an increase in abnormal circadian rhythms and the absence of the entrainment properties of light in blindness.
27642096	Organisms that live on the Earth are subjected to environmental variables that display cyclic variations, such as light, temperature and tides. Since these cyclic changes in the environment are constant and predictable, they have affected biological evolution through selecting the occurrence of biological rhythms in the physiology of all living organisms, from prokaryotes to mammals. Biological clocks confer organisms an adaptive advantage as they can synchronize their behavioral and physiological processes to occur at a given moment of time when effectiveness and success would be greater and/or the cost and risk for organisms would be lower. Among environmental synchronizers, light has been mostly widely studied to date. However, other environmental signals play an important role in biological rhythms, especially in aquatic animals like fish. This review focuses on current knowledge about the role of nonphotic synchronizers (temperature, food and tidal cycles) on biological rhythms in fish, and on the entrainment of the fish circadian system to these synchronizers.
27593450	The biogenic amine octopamine (OA) modulates invertebrate behavior by changing neuronal responses from sensory inputs to motor outputs. However, the OA modulation of visual sensitivity and its possible coupling to diurnal cycles remains unexplored. Here we studied the diurnal variations in the OA levels in the hemolymph of the crayfish Procambarus clarkii, its release from the structures in the eyestalk and its modulation of the retinal light sensitivity. The hemolymph concentration of OA and its amino acid precursor tyrosine was measured by high-resolution liquid chromatography; OA varied along the 24-hcycle. The peak value appeared about 2h before the light offset which preceded the peak locomotor activity. OA was found in every structure of the eyestalk but displayed higher levels in the retina-lamina ganglionaris. Moreover, OA was released from isolated eyestalks at a rate of 92nmol/eyestalk/min and a calcium-dependent release was evoked by incubation in a high potassium solution. OA injected into dark-adapted crayfish or applied to the isolated retina at concentrations of 1, 10 and 100μM produced a proportionally increasing reduction in the amplitude of the photoreceptor light responses. These OA concentrations did not affect the position of the visual accessory pigments. Our results suggest that OA release in the crayfish eyestalk is coupled to the 24-hcycle to regulate the diurnal reduction of the photoreceptor sensitivity and to favor the expression of exploratory locomotion during the dark phase of the circadian cycle.
27783925	In this work, we studied the characteristics of recovery from desensitization of the light-elicited current of crayfish. Applying a two-flash protocol, we found that the first flash triggers a current that activates with a noticeable latency, reaches a peak value, and thereafter decays along a single exponential time course. In comparison with the first-elicited current, the current elicited by the second flash not only presents an expected smaller peak current, depending on the time between flashes, but it also displays a different latency and decay time constant. Recovery of the first flash values of these current parameters depends on the circadian time at which the experiments are conducted, and on the presence of pigment-dispersing hormone. Our data also suggest the existence of distinctive desensitized states, whose induction depends on circadian time and the presence of pigment-dispersing hormone.
27781473	Cells in the brain's Suprachiasmatic Nucleus (SCN) are known to regulate circadian rhythms in mammals. We model synchronization of SCN cells using the forced Kuramoto model, which consists of a large population of coupled phase oscillators (modeling individual SCN cells) with heterogeneous intrinsic frequencies and external periodic forcing. Here, the periodic forcing models diurnally varying external inputs such as sunrise, sunset, and alarm clocks. We reduce the dimensionality of the system using the ansatz of Ott and Antonsen and then study the effect of a sudden change of clock phase to simulate cross-time-zone travel. We estimate model parameters from previous biological experiments. By examining the phase space dynamics of the model, we study the mechanism leading to the difference typically experienced in the severity of jet-lag resulting from eastward and westward travel.
27781260	Video cameras recorded the diurnal visitation rates of transient (large home range) piscivorous fishes to coral patch reefs in The Bahamas and identified 11 species. Visits by bar jack Caranx ruber, mutton snapper Lutjanus analis, yellowtail snapper Ocyurus chrysurus, barracuda Sphyraena barracuda and cero Scomberomorus regalis were sufficiently frequent to correlate with a range of biophysical factors. Patch-reef visitation rates and fish abundances varied with distance from shore and all species except S. regalis were seen more frequently inshore. This pattern is likely to be caused by factors including close proximity to additional foraging areas in mangroves and on fore-reefs and higher abundances close to inshore nursery habitats. Visitation rates and abundances of C. ruber, L. analis, O. chrysurus and S. regalis also varied seasonally (spring v. winter), possibly as fishes responded to temperature changes or undertook spawning migrations. The abundance of each transient predator species on the patch reefs generally exhibited limited diurnal variability, but L. analis was seen more frequently towards dusk. This study demonstrates that the distribution of transient predators is correlated spatially and temporally with a range of factors, even within a single lagoon, and these drivers are species specific. Transient predators are considered an important source of mortality shaping reef-fish assemblages and their abundance, in combination with the biomass of resident predators, was negatively correlated with the density of prey fishes. Furthermore, transient predators are often targeted by fishers and understanding how they utilize seascapes is critical for protecting them within reserves.
27744087	In a natural environment, social abilities of an animal are important for its survival. Particularly, it must recognize its own social rank and the social rank of a conspecific and have a good social memory. While the role of the circadian system for object and spatial recognition and memory is well known, the impact of the social rank and circadian disruptions on social recognition and memory were not investigated so far. In the present study, individual recognition of social rank and social memory performance of Djungarian hamsters revealing different circadian phenotypes were investigated. Wild type (WT) animals show a clear and well-synchronized daily activity rhythm, whereas in arrhythmic (AR) hamsters, the suprachiasmatic nuclei (SCN) do not generate a circadian signal. The aim of the study was to investigate putative consequences of these deteriorations in the circadian system for animalś cognitive abilities. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14l/10 D lighting regimen. Experimental animals were assigned to different groups (WT and AR) according to their activity pattern obtained by means of infrared motion sensors. Before the experiments, the animals were given to develop a dominant-subordinate relationship in a dyadic encounter. Experiment 1 dealt with individual recognition of social rank. Subordinate and dominant hamsters were tested in an open arena for their behavioral responses towards a familiar (known from the agonistic encounters) or an unfamiliar hamster (from another agonistic encounter) which had the same or an opposite social rank. The investigation time depended on the social rank of the WT subject hamster and its familiarity with the stimulus animal. Both subordinate and dominant WT hamsters preferred an unfamiliar subordinate stimulus animal. In contrast, neither subordinate nor dominant AR hamsters preferred any of the stimulus animals. Thus, disruptions in circadian system result in an impaired individual recognition of social rank. A social recognition/discrimination task was used in Experiment 2 to quantify social memory performance. In a training session, the hamsters were confronted with two unfamiliar stimulus animals. In the test session, one of the two animals was replaced. The training-test interval was 2min or 24h. The times animals did explore the novel and the familiar stimulus animal were recorded, and the discrimination index as a measure of cognitive performance was calculated. Behavioral tests revealed that after 2min both subordinate and dominant WT hamsters were able to discriminate between familiar and novel stimulus animals but after 24h only the subordinate animals. On contrary in AR hamsters, only subordinates were able to perform the social recognition/discrimination task and only after a training-test interval of 2min. The results show that the social rank and the circadian system have an impact on the cognitive abilities of Djungarian hamsters. Disruptions of circadian rhythms impair individual recognition and social memory performance.
27233157	(1) To assess real-time patterns of fatigue; (2) to assess the association between a real-time fatigue score and 3 commonly used questionnaires (Checklist Individual Strength [CIS] fatigue subscale, Modified Fatigue Impact Scale (MFIS), and Fatigue Severity Scale [FSS]); and (3) to establish factors that confound the association between the real-time fatigue score and the conventional fatigue questionnaires in patients with multiple sclerosis (MS).Cross-sectional study.	MS-specialized outpatient facility.	Ambulant patients with MS (N=165) experiencing severe self-reported fatigue.	Not applicable.	A real-time fatigue score was assessed by sending participants 4 text messages on a particular day (How fatigued do you feel at this moment?; score range, 0-10). Latent class growth mixed modeling was used to determine diurnal patterns of fatigue. Regression analyses were used to assess the association between the mean real-time fatigue score and the CIS fatigue subscale, MFIS, and FSS. Significant associations were tested for candidate confounders (eg, disease severity, work status, sleepiness).	Four significantly different fatigue profiles were identified by the real-time fatigue score, namely a stable high (n=79), increasing (n=57), stable low (n=16), and decreasing (n=13). The conventional questionnaires correlated poorly (r<.300) with the real-time fatigue score. The Epworth Sleepiness Scale significantly reduced the regression coefficient between the real-time fatigue score and conventional questionnaires, ranging from 15.4% to 35%.	Perceived fatigue showed 4 different diurnal patterns in patients with MS. Severity of sleepiness is an important confounder to take into account in the assessment of fatigue.	
27780145	This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time.A total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12h light and 12h dark were used. A single INH (100mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19h after light onset, HALO). At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48h following drug injection. The pharmacokinetics parameters (AUC0-∞, Ke, Cmax, T 1/2, ClT and Vd) were calculated for each circadian-time.	There were relevant differences in Cmax between the four circadian groups (p<0.005), maximum and minimum Cmax were obtained when INH was injected at 1 HALO (490mgL-1) and at 7 HALO (270mgL-1) respectively. AUC0-∞ also varied significantly according to the circadian-time of injection (2093mgL-1h-1 at 1 HALO vs 759mgL-1h-1 at 7 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22Lh-1kg-1) and 1 HALO (0.13Lh-1kg-1) respectively (p<0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0-∞ have a significant circadian rhythm with an acrophase located at 2.64 HALO±0.21h (the beginning of the rest span) (p<0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.4 HALO and at 8.66 HALO (the second half of the rest span) (p<0.001).	Plasma INH chronopharmacokinetics might be involved in the mechanism of circadian variation of toxicity since the time of optimal tolerance to INH corresponds to that of the lowest Cmax and AUC0-∞ and the highest ClT occured when this drug injected in the second half of light-rest phase (7 HALO).	
27780005	Environmental enrichment (EE) gives laboratory animals opportunities to engage in species-specific behaviors. However, the effects of EE devices on normal physiology and scientific outcomes must be evaluated. We hypothesized that the spectral transmittance (color) of light to which rats are exposed when inside colored enrichment devices (CED) affects the circadian rhythms of various plasma markers. Pair-housed male Crl:SD rats were maintained in ventilated racks under a 12:12-h light:dark environment (265.0 lx; lights on, 0600); room lighting intensity and schedule remained constant throughout the study. Treatment groups of 6 subjects were exposed for 25 d to a colored enrichment tunnel: amber, red, clear, or opaque. We measured the proportion of time rats spent inside their CED. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and analyzed for plasma melatonin, total fatty acids, and corticosterone. Rats spent more time in amber, red, and opaque CED than in clear tunnels. All tubes were used significantly less after blood draws had started, except for the clear tunnel, which showed no change in use from before blood sampling began. Normal peak nighttime melatonin concentrations showed significant disruption in the opaque CED group. Food and water intakes and body weight change in rats with red-tinted CED and total fatty acid concentrations in the opaque CED group differed from those in other groups. These results demonstrate that the color of CED altered normal circadian rhythms of plasma measures of metabolism and physiology in rats and therefore might influence the outcomes of scientific investigations.
27780004	Regular cycles of exposure to light and dark control pineal melatonin production and temporally coordinate circadian rhythms of metabolism and physiology in mammals. Previously we demonstrated that the peak circadian amplitude of nocturnal blood melatonin levels of rats were more than 6-fold higher after exposure to cool white fluorescent (CWF) light through blue-tinted (compared with clear) rodent cages. Here, we evaluated the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit light rich in the blue-appearing portion of the visible spectrum (465-485 nm), compared with standard broadspectrum CWF light, on melatonin levels during the subsequent dark phase and on plasma measures of metabolism and physiology. Compared with those in male rats under a 12:12-h light:dark cycle in CWF light, peak plasma melatonin levels at the middark phase (time, 2400) in rats under daytime LED light were over 7-fold higher, whereas midlight phase levels (1200) were low in both groups. Food and water intakes, body growth rate, and total fatty acid content of major metabolic tissues were markedly lower, whereas protein content was higher, in the LED group compared with CWF group. Circadian rhythms of arterial plasma levels of total fatty acids, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were generally lower in LED-exposed rats. Therefore, daytime exposure of rats to LED light with high blue emissions has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing and thus may influence scientific outcomes.
27779473	Our recent research on the pineal gland of young chickens confirmed that three genes encoding enzymes involved in pineal melatonin biosynthesis, tryptophan hydroxylase 1 (Tph1), arylalkylamine-N-acetyltransferase (Aanat) and acetylserotonin O-methyltransferase (Asmt), are transcribed rhythmically under light:dark (L:D) 12:12 conditions in vivo. Additionally, in the pineal gland of maturing chickens, the dopa decarboxylase (Ddc) gene is transcribed rhythmically at a specific stage of the developmental process. Therefore, the aim of the present study was to verify whether all of these genes are transcribed rhythmically in vivo under constant darkness (D:D) and in pinealocyte cultures under both L:D and D:D. Experiments were performed on chickens maintained under L:D 12:12 conditions. Chickens at 15 days of age were divided into two groups; chickens from the first group remained under the same conditions, whereas those from the second group were kept in darkness. Subsequently, 16-day-old animals were sacrificed every 2 hours over a 24-h period. For the in vitro experiments, 16-day-old chickens were sacrificed at ZT 6, and their pineal glands were isolated. Pineal cultures were maintained for up to two days in L:D conditions. Then, the pinealocyte cultures were divided into two groups: the first remained under L:D conditions, whereas the second was transferred to D:D conditions. Pinealocytes were subsequently collected every 2 hours over a 24-h period. Transcription was evaluated using the RT-qPCR method, and the rhythm percentage was calculated through Cosinor analysis. The mRNA levels of all genes examined were rhythmic under all conditions. Moreover, in silico analysis of the promoters of all of the genes examined revealed the presence of enhancer box sequences in all of the promoters as well as DBP/E4BP4 binding elements in the promoters of Tph1 and Asmt. This suggests that these genes may all be regulated transcriptionally by the molecular clock mechanism and may be considered clock as controlled genes.
27743421	Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time.At intake, caregivers of 50 children and nine adults with SMS were surveyed about the sleep pattern and potential melatonin administration. Sampling of salivary melatonin levels was performed.	At intake, exogenous melatonin was used by 16 children (27.1% of sample; 56.3% male) with mean age 6.8 ± 2.8 years, whereas 34 children (57.6%; 7.5 ± 4.8 years old; 64.7% male) and nine adults (15.3%; 36.8 ± 15.3 years old; 44.4% male) were not taking melatonin at intake. Participants were reported to have problems with night waking and early awakenings regardless of melatonin administration. Overall, moderate to high levels of salivary melatonin at noon were found in individuals with SMS. In particular, children with SMS showed a disrupted melatonin pattern. Furthermore, the endogenous melatonin level, age, and gender may potentially interact, yielding the severity range of sleep disturbances reported in SMS.	Treatment of sleep problems in SMS is complex, and our findings may support person-centered sleep and medication management. Future clinical trials including larger groups may shed light on such approaches.	
27643985	The avian pineal gland is a master clock that can receive external photic cues and translate them into output rhythms. To clarify whether a shift in light wavelength can influence the circadian expression in chick pineal gland, a total of 240 Arbor Acre male broilers were exposed to white light (WL), red light (RL), green light (GL) or blue light (BL). After 2weeks light illumination, circadian expressions of seven core clock genes in pineal gland and the level of melatonin in plasma were examined. The results showed after illumination with monochromatic light, 24h profiles of all clock gene mRNAs retained circadian oscillation, except that RL tended to disrupt the rhythm of cCry2. Compared to WL, BL advanced the acrophases of the negative elements (cCry1, cCry2, cPer2 and cPer3) by 0.1-1.5h and delayed those of positive elements (cClock, cBmal1 and cBmal2) by 0.2-0.8h. And, RL advanced all clock genes except cClock and cPer2 by 0.3-2.1h, while GL delayed all clock genes by 0.5-1.5h except cBmal2. Meanwhile, GL increased the amplitude and mesor of positive and reduced both parameters of negative clock genes, but RL showed the opposite pattern. Although the acrophase of plasma melatonin was advanced by both GL and RL, the melatonin level was significantly increased in GL and decreased in RL. This tendency was consistent with the variations in the positive clock gene mRNA levels under monochromatic light and contrasted with those of negative clock genes. Therefore, we speculate that GL may enhance positive clock genes expression, leading to melatonin synthesis, whereas RL may enhance negative genes expression, suppressing melatonin synthesis.
27601067	Melatonin, a molecule involved in the regulation of circadian rhythms, has protective effects against myocardial injuries. However, its capability to regulate the maturation of cardiac progenitor cells is unclear. Recently, several studies have shown that melatonin inhibits the stabilization of hypoxia-inducible factors (HIFs), important signaling molecules with cardioprotective effects. In this study, by employing differentiating mouse embryonic stem cells, we report that melatonin significantly upregulated the expression of cardiac cell-specific markers (myosin heavy chains six and seven) as well as the percentage of myosin heavy chain-positive cells. Importantly, melatonin decreased HIF-1α stabilization and transcriptional activity and, in contrast, induced HIF-2α stabilization. Interestingly, the deletion of HIF-1α completely inhibited the pro-cardiomyogenic effect of melatonin as well as the melatonin-mediated HIF-2α stabilization. Moreover, melatonin increased Sirt-1 levels in a HIF-1α-dependent manner. Taken together, we provide new evidence of a time-specific inhibition of HIF-1α stabilization as an essential feature of melatonin-induced cardiomyogenesis and unexpected different roles of HIF-1α stabilization during various stages of cardiac development. These results uncover new mechanisms underlying the maturation of cardiac progenitor cells and can help in the development of novel strategies for using melatonin in cardiac regeneration therapy.
27062511	Recent research has shown that the microbiota affects the biology of associated host epithelial tissues, including their circadian rhythms, although few data are available on how such influences shape the microarchitecture of the brush border. The squid-vibrio system exhibits two modifications of the brush border that supports the symbionts: effacement and repolarization. Together these occur on a daily rhythm in adult animals, at the dawn expulsion of symbionts into the environment, and symbiont colonization of the juvenile host induces an increase in microvillar density. Here we sought to define how these processes are related and the roles of both symbiont colonization and environmental cues. Ultrastructural analyses showed that the juvenile-organ brush borders also efface concomitantly with daily dawn-cued expulsion of symbionts. Manipulation of the environmental light cue and juvenile symbiotic state demonstrated that this behaviour requires the light cue, but not colonization. In contrast, symbionts were required for the observed increase in microvillar density that accompanies post dawn brush-border repolarization; this increase was induced solely by host exposure to phosphorylated lipid A of symbiont cells. These data demonstrate that a partnering of environmental and symbiont cues shapes the brush border and that microbe-associated molecular patterns play a role in the regulation of brush-border microarchitecture.
27776182	To investigate whether diurnal fluctuation in intraocular pressure (IOP) can influence the result of the correlations between IOP-related factors and progression of normal tension glaucoma (NTG).Glaucoma progression was defined as visual field (VF) progression and changes in the optic disc and/or retinal nerve fiber layer (RNFL). Two different methods were used to evaluate the impact of the diurnal fluctuation in IOP. 'Conventional method' used in previous studies included all IOP measurements during the follow up time. 'Time adjusted method' was used to adjust diurnal fluctuation in IOP with the preferred time. Mean IOP, long term IOP fluctuation and the difference between the lowest and highest IOP were calculated using both methods. Cox regression analyses were performed to evaluate the association between IOP-related factors and NTG progression.	One hundred and forty eyes of 140 patients with NTG were included in this study. 41% (58 of 140 eyes) of eyes underwent NTG progression. Long term IOP variation calculated by conventional method was not a significant risk factor for NTG progression (hazard ratio[HR], 0.311; 95% confidence interval[CI], 0.056-1.717; P = 0.180). Long term IOP variation calculated by time adjusted method, however, was related to progression, with an HR of 5.260 (95% CI,1.191-23.232; P = 0.029).	Although having the same IOP-related factors, if diurnal fluctuation is included, different results may be found on the relationship between IOP-related factors and NTG progression. Based on our results, diurnal fluctuation in IOP should be considered when IOP-related factors are studied in the future.	
27775953	Daylight savings time transitions affect approximately 1.6 billion people worldwide. Prior studies have documented associations between daylight savings time transitions and adverse health outcomes, but it remains unknown whether they also cause an increase in the incidence rate of depressive episodes. This seems likely because daylight savings time transitions affect circadian rhythms, which are implicated in the etiology of depressive disorder. Therefore, we investigated the effects of daylight savings time transitions on the incidence rate of unipolar depressive episodes.Using time series intervention analysis of nationwide data from the Danish Psychiatric Central Research Register from 1995 to 2012, we compared the observed trend in the incidence rate of hospital contacts for unipolar depressive episodes after the transitions to and from summer time to the predicted trend in the incidence rate.	The analyses were based on 185,419 hospital contacts for unipolar depression and showed that the transition from summer time to standard time were associated with an 11% increase (95% CI = 7%, 15%) in the incidence rate of unipolar depressive episodes that dissipated over approximately 10 weeks. The transition from standard time to summer time was not associated with a parallel change in the incidence rate of unipolar depressive episodes.	This study shows that the transition from summer time to standard time was associated with an increase in the incidence rate of unipolar depressive episodes. Distress associated with the sudden advancement of sunset, marking the coming of a long period of short days, may explain this finding. See video abstract at, http://links.lww.com/EDE/B179.	
27774604	Relaxin-3 is a member of a superfamily of structurally-related peptides that includes relaxin and insulin-like peptide hormones. Soon after the discovery of the relaxin-3 gene, relaxin-3 was identified as an abundant neuropeptide in brain with a distinctive topographical distribution within a small number of GABAergic neuron populations that is well conserved across species. Relaxin-3 is thought to exert its biological actions through a single class-A GPCR - relaxin-family peptide receptor 3 (RXFP3). Class-A comprises GPCRs for relaxin-3 and insulin-like peptide-5 and other peptides such as orexin and the monoamine transmitters. The RXFP3 receptor is selectively activated by relaxin-3, whereas insulin-like peptide-5 is the cognate ligand for the related RXFP4 receptor. Anatomical and pharmacological evidence obtained over the last decade supports a function of relaxin-3/RXFP3 systems in modulating responses to stress, anxiety-related and motivated behaviours, circadian rhythms, and learning and memory. Electrophysiological studies have identified the ability of RXFP3 agonists to directly hyperpolarise thalamic neurons in vitro, but there are no reports of direct cell signalling effects in vivo. This article provides an overview of earlier studies and highlights more recent research that implicates relaxin-3/RXFP3 neural network signalling in the integration of arousal, motivation, emotion and related cognition, and that has begun to identify the associated neural substrates and mechanisms. Future research directions to better elucidate the connectivity and function of different relaxin-3 neuron populations and their RXFP3-positive target neurons in major experimental species and humans are also identified.This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.	
27773697	Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner. ChIP-seq analyses of hypoxia-inducible factor HIF1A and the core clock component BMAL1 revealed crosstalk between hypoxia and the clock at the genome level. Further, severe consequences caused by acute hypoxia, such as those that occur with heart attacks, were correlated with defects in circadian rhythms. We propose that the clock plays functions in fine-tuning hypoxic responses under pathophysiological conditions. We argue that the clock can, and likely should, be exploited therapeutically to reduce the severity of fatal hypoxia-related diseases.
27773695	The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag.
27771773	Colorectal cancer (CRC) is one of the most common and preventable forms of cancer but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70-90 % of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation.Patients recruited from a local endoscopy clinic provided informed consent and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios (ORs) and 95 % confidence intervals (95% CIs) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders.	Complete data were available for 107 participants; 36 % had adenomas (men 40 %, women 31 %). Hypomethylation of the MINT1 locus (OR 5.3, 95% CI 1.0-28.2) and the PER1 (OR 2.9, 95% CI 1.1-7.7) and PER3 (OR 11.6, 95% CI 1.6-78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71-97 %), sensitivity was relatively low (18-45 %).	Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance.	
27771728	Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life.
27771283	Aging brain undergoes several changes leading to a decline in cognitive functions. Memory and learning-related genes such as Creb, Bdnf and its receptor TrkB, are expressed in different brain regions including prefrontal cortex. Those genes' proteins regulate a wide range of functions such as synaptic plasticity and long-term potentiation. In this work, our objectives were: 1) to investigate whether Creb1, Bdnf and TrkB genes display endogenous circadian expression rhythms, in the prefrontal cortex of rats maintained under constant darkness conditions; 2) to study the synchronization of those temporal patterns to the local cellular clock and 3) to evaluate the aging consequences on both cognition-related genes and activating clock transcription factor, BMAL1, rhythms. A bioinformatics analysis revealed clock-responsive (E-box) sites in regulatory regions of Creb1, Bdnf and TrkB genes. Additionally, cAMP response elements (CRE) were found in Bdnf and TrkB promoters. We observed those key cognition-related factors expression oscillates in the rat prefrontal cortex. Creb1 and TrkB mRNAs display a circadian rhythm with their highest levels occurring at the second half of the 24h period. Interestingly, the cosinor analysis revealed a 12-h rhythm of Bdnf transcript levels, with peaks occurring at the second half of the subjective day and night, respectively. As expected, the BMAL1 rhythm's acrophase precedes Creb1 and first Bdnf expression peaks. Noteworthy, Creb1, Bdnf and TrkB expression rhythms are lost in the prefrontal cortex of aged rats, probably, as consequence of the loss of BMAL1 protein circadian rhythm and altered function of the local cellular clock.
27725099	Peripheral clocks are set by different nervous, hormonal and metabolic stimuli, and regulate the circadian expression of several genes. We investigated whether a peripheral clock could be induced in the human adrenocortical cell line H295R and whether glucocorticoid receptor isoforms (GRα and GRß) are involved in this clock system. After synchronization of cells with serum shock, the rhythmic oscillation of clock genes PER1, PER2, REV-ERBα, and ARNTL was confirmed. In addition, H295R cells even without serum shock showed rhythmic expression of PER1, PER2, CRY1 and ARNTL. Glucocorticoid treatment induced a rapid response of PER1, PER2 and CRY1 in a GRα-dependent manner. Continuous glucocorticoid stimulation after 6h caused suppression of REV-ERBα. Administration of a GR antagonist, RU486, disrupted the circadian oscillation of clock genes and prevented the acute changes in PER1, PER2 and CRY1 levels. Overexpression of the GRß isoform alone did not alter the expression of the examined clock genes, but did prevent the GRα-related suppression of REV-ERBα. These alterations occurred independently from ACTH and CRH. Our data demonstrate that a peripheral clock system is present in a human adrenocortical cell line and that periodic oscillations of clock genes are influenced by glucocorticoids, mainly through GRα.
27594095	Sleep-wake behavior exhibits diurnal rhythmicity, rebound responses to acute total sleep deprivation (TSD), and attenuated rebounds following chronic sleep restriction (CSR). We investigated how these long-term patterns of behavior emerge from stochastic short-term dynamics of state transition. Male Sprague-Dawley rats were subjected to TSD (1day×24h, N=9), or CSR (10days×18h TSD, N=7) using a rodent walking-wheel apparatus. One baseline day and one recovery day following TSD and CSR were analyzed. The implications of the zero sum principle were evaluated using a Markov model of sleep-wake state transition. Wake bout duration (a combined function of the probability of wake maintenance and proportional representations of brief and long wake) was a key variable mediating the baseline diurnal rhythms and post-TSD responses of all three states, and the attenuation of the post-CSR rebounds. Post-NREM state transition trajectory was an important factor in REM rebounds. The zero sum constraint ensures that a change in any transition probability always affects bout frequency and cumulative time of at least two, and usually all three, of wakefulness, NREM and REM. Neural mechanisms controlling wake maintenance may play a pivotal role in regulation and dysregulation of all three states.
27586251	Time-restricted feeding ameliorates the deleterious effects of a high-fat diet on body weight and metabolism in young adult mice. Because obesity is highly prevalent in the middle-aged population, this study tested the hypothesis that time-restricted feeding alleviates the adverse effects of a high-fat diet in male middle-aged (12months) mice. C57BL6/J mice were fed one of three diets for 21-25weeks: 1) high-fat diet (60% total calories from fat) ad-libitum (HFD-AL), 2) HFD, time-restricted feeding (HFD-TRF), and 3) low-fat diet (10% total calories from fat) ad-libitum (LFD-AL) (n=15 each). HFD-TRF mice only had food access for 8h/day during their active period. HFD-TRF mice gained significantly less weight than HFD-AL mice (~20% vs 55% of initial weight, respectively). Caloric intake differed between these groups only during the first 8weeks and accounted for most but not all of their body weight difference during this time. TRF of a HFD lowered glucose tolerance in terms of incremental area under the curve (iAUC) (p<0.02) to that of LFD-AL mice. TRF of a HFD lowered liver weight (p<0.0001), but not retroperitoneal or epididymal fat pad weight, to that of LFD-AL mice. Neither HFD-AL nor HFD-TRF had any effect on performance in the novel object recognition or object location memory tests. Circulating corticosterone levels either before or after restraint stress were not affected by diet. In conclusion, TRF without caloric restriction is an effective strategy in middle-aged mice for alleviating the negative effects of a HFD on body weight, liver weight, and glucose tolerance.
27568094	Aged animals exhibit diminished circadian rhythms, and both aging and circadian disruption sensitize neuroinflammatory responses. Microglia-the innate immune cell of the central nervous system-possess endogenous timekeeping mechanisms that regulate immune responses. Here, we explored whether aging is associated with disrupted diurnal rhythms in microglia and neuroinflammatory processes. First, hippocampal microglia isolated from young rats (4 months F344XBN) rhythmically expressed circadian clock genes, whereas microglia isolated from the hippocampus of aged rats (25 months) had aberrant Per1 and Per2 rhythms. Unstimulated microglia from young rats exhibited robust rhythms of TNFα and IL-1β mRNA expression, whereas those from aged rats had flattened and tonically elevated cytokine expression. Similarly, microglial activation markers were diurnally regulated in the hippocampus of young but not aged rats and diurnal differences in responsiveness to both ex vivo and in vivo inflammatory challenges were abolished in aged rats. Corticosterone is an entraining signal for extra-suprachiasmatic nucleus circadian rhythms. Here, corticosterone stimulation elicited similar Per1 induction in aged and young microglia. Overall, these results indicate that aging dysregulates circadian regulation of neuroinflammatory functions.
27354230	Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1. We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.
27769202	A disturbed circadian rhythm seems to be a causal factor in the occurrence of depressive disorders in patients with Parkinson's disease (PD). The circadian rhythm can be restored with light. Therefore, Bright Light Therapy (BLT) might be a new treatment option for depression in PD patients.In this double-blind controlled trial, 84 subjects with idiopathic PD are randomized to either BLT or a control light condition. The BLT condition emits white light with an intensity of 10,000 Lux, while the control device emits dim white light of 200 Lux, which is presumed to be too low to influence the circadian rhythm. Subjects receive 30 min of home treatment twice daily for three months. Timing of treatment is based on the individual chronotype. After finishing treatment, subjects enter a follow-up period of six months. The primary outcome of the study is the severity of depressive symptoms, as measured with the Hamilton Depression Rating Scale. Secondary outcomes are alternative depression measures, objective and subjective sleep measures, and salivary melatonin and cortisol concentrations. For exploratory purposes, we also assess the effects on motor symptoms, global cognitive function, comorbid psychiatric disorders, quality of life and caregiver burden. Data will be analyzed using a linear mixed models analysis.	Performing a placebo-controlled trial on the effects of BLT in PD patients is challenging, as the appearance of the light may provide clues on the treatment condition. Moreover, fixed treatment times lead to an improved sleep-wake rhythm, which also influences the circadian system. With our study design, we do not compare BLT to placebo treatment, i.e. an ineffective control treatment. Rather, we compare structuring of the sleep-wake cycle in both conditions with additional BLT in the experimental condition, and additional dim light in the control condition. Participants are not informed about the exact details of the two light devices and the expected therapeutic effect, and expectancies are rated prior to the start of treatment. Ideally, the design of a future study on BLT should include two extra treatment arms where BLT and control light are administered at random times.	
27646506	Huntington's disease (HD) is a progressive genetic neurodegenerative disorder characterised by motor and cognitive deficits, as well as sleep and circadian abnormalities. In the R6/2 mouse, a fragment model of HD, rest-activity rhythms controlled by the suprachiasmatic nucleus disintegrate completely by 4months of age. Rhythms driven by a second circadian oscillator, the methamphetamine-sensitive circadian oscillator (MASCO), are disrupted even earlier, and cannot be induced after 2months of age. Here, we studied the effect of the HD mutation on the expression of MASCO-driven rhythms in a more slowly developing, genetically relevant mouse model of HD, the Q175 'knock-in' mouse. We induced expression of MASCO output by administering low dose methamphetamine (0.005%) chronically via the drinking water. We measured locomotor activity in constant darkness in wild-type and Q175 mice at 2 (presymptomatic), 6 (early symptomatic), and 12 (symptomatic) months of age. At 2months, all mice expressed MASCO-driven rhythms, regardless of genotype. At older ages, however, there was a progressive gene dose-dependent deficit in MASCO output in Q175 mice. At 6months of age, these rhythms could be observed in only 45% of heterozygous and 15% of homozygous mice. By 1year of age, 90% of homozygous mice had an impaired MASCO output. There was also an age-dependent disruption of MASCO output seen in wild-type mice. The fact that the progressive deficit in MASCO-driven rhythms in Q175 mice is HD gene dose-dependent suggests that, whatever its role in humans, abnormalities in MASCO output may contribute to the HD circadian phenotype.
27506697	We evaluated nocturnal urine production and circadian rhythms of renal function (glomerular filtration, and water and solute diuresis) in adults with spinal cord injury compared to controls.This prospective observational study was done at Ghent University Hospital, Belgium. Participants were asked to perform a 24-hour urine collection. A blood sample was taken to calculate the diuresis rate and the renal clearance of creatinine, free water, solutes, sodium and urea.	A total of 119 patients were divided into 32 with spinal cord injury, and 68 controls with and 19 without nocturnal polyuria. Spinal cord injured patients showed no circadian rhythms in the diuresis rate or in the renal clearance of creatinine, free water, solutes, sodium or urea. Controls without nocturnal polyuria reported a lower nighttime diuresis rate and lower nighttime clearance of creatinine, solutes, sodium and urea compared to daytime levels. Controls with nocturnal polyuria had no circadian rhythms in the diuresis rate or creatinine clearance and a significant increase in nocturnal free water clearance compared to daytime levels.	Comparing the mechanisms underlying nocturnal urine production between patients with spinal cord injury and controls revealed important differences. Spinal cord injured patients showed absent circadian rhythms in the renal clearance of creatinine (glomerular filtration), free water (water diuresis) and solutes such as sodium and urea (solute diuresis). Future research must be done to evaluate the role of patient stratification to find the most effective and safe treatment or combination of treatments for spinal cord injured patients with complaints or complications related to nocturnal polyuria.	
27766649	The circadian pacemaker of the Madeira cockroach, Rhyparobia (Leucophaea) maderae, is located in the accessory medulla (AME). Ipsi- and contralateral histaminergic compound eyes are required for photic entrainment. Light pulses delay locomotor activity rhythm during the early night and advance it during the late night. Thus, different neuronal pathways might relay either light-dependent delays or advances to the clock. Injections of neuroactive substances combined with running-wheel assays suggested that GABA, pigment-dispersing factor, myoinhibitory peptides (MIPs), and orcokinins (ORCs) were part of both entrainment pathways, whereas allatotropin (AT) only delayed locomotor rhythms at the early night. To characterize photic entrainment further, histamine and corazonin were injected. Histamine injections resulted in light-like phase delays and advances, indicating that the neurotransmitter of the compound eyes participates in both entrainment pathways. Because injections of corazonin only advanced during the late subjective night, it was hypothesized that corazonin is only part of the advance pathway. Multiple-label immunocytochemistry in combination with neurobiotin backfills demonstrated that a single cell expressed corazonin in the optic lobes that belonged to the group of medial AME interneurons. It colocalized GABA and MIP but not AT or ORC immunoreactivity. Corazonin-immunoreactive (-ir) terminals overlapped with projections of putatively light-sensitive interneurons from the ipsi- and contralateral compound eye. Thus, we hypothesize that the corazonin-ir medial neuron integrates ipsi- and contralateral light information as part of the phase-advancing light entrainment pathway to the circadian clock. J. Comp. Neurol. 525:1250-1272, 2017. © 2016 Wiley Periodicals, Inc.
27765071	Molecular clocks drive oscillations in leaf photosynthesis, stomatal conductance, and other cell and leaf-level processes over ~24 h under controlled laboratory conditions. The influence of such circadian regulation over whole-canopy fluxes remains uncertain; diurnal CO2 and H2O vapor flux dynamics in the field are currently interpreted as resulting almost exclusively from direct physiological responses to variations in light, temperature and other environmental factors. We tested whether circadian regulation would affect plant and canopy gas exchange at the Montpellier European Ecotron. Canopy and leaf-level fluxes were constantly monitored under field-like environmental conditions, and under constant environmental conditions (no variation in temperature, radiation, or other environmental cues).We show direct experimental evidence at canopy scales of the circadian regulation of daytime gas exchange: 20-79 % of the daily variation range in CO2 and H2O fluxes occurred under circadian entrainment in canopies of an annual herb (bean) and of a perennial shrub (cotton). We also observed that considering circadian regulation improved performance by 8-17 % in commonly used stomatal conductance models.	Our results show that circadian controls affect diurnal CO2 and H2O flux patterns in entire canopies in field-like conditions, and its consideration significantly improves model performance. Circadian controls act as a 'memory' of the past conditions experienced by the plant, which synchronizes metabolism across entire plant canopies.	
27615005	To investigate the radiation effects and acute damage in inoperable cervical cancer patients irradiated at different times as well as the underlying mechanisms.67 patients were randomized to a morning group (MG, 9:00 - 11:00 AM) and an evening group (EG, 9:00 - 11:00 PM) and both received external beam radiotherapy (RT) (50 Gy in 25 fractions) at different times. Brachytherapy (36 - 42 Gy in 6 - 7 fractions) was also performed to enhance the radiation response twice every week in all patients at the same time. Clinical therapeutic effects and acute toxicities were evaluated after RT. Flow cytometry was analyzed before and after RT.	Patients' response to radiation was similar in the two groups. Incidences of overall and high-grade (III - IV) diarrhea in the MG vs. the EG were 75.0% vs. 57.6% and 12.5% vs. 6.1%, respectively. The incidence of severe hematological toxicity in the EG was significantly increased compared to the MG group. Cell apoptosis in the EG was significantly higher at 9:00 - 11:00 PM than that at 9:00 - 11:00 AM after RT. No significant differences were found in Gap Phase 0/Gap Phase 1 (G0/G1), Gap Phase 2/Metaphase Phase (G2/M), and Synthesis Phase (S) phase between different times and groups, nor were expressions of Per1, Per2, and Clock. But expressions of Per1, Per2, and Clock were significantly negative with G2/M phase and positively correlated with cell apoptosis.	RT at different time intervals results in similar efficacy. However, RT in the morning reduces severe hematological toxicity. Radiation responses may be associated with circadian genes by influence of cell cycles and apoptosis.
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27763782	Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.
27763686	Dynamic aspects of melatonin's actions merit increasing future attention. This concerns particularly entirely different effects in senescent, weakened oscillators and in dysregulated oscillators of cancer cells that may be epigenetically blocked. This is especially obvious in the case of sirtuin 1, which is upregulated by melatonin in aged tissues, but strongly downregulated in several cancer cells. These findings are not at all controversial, but are explained on the basis of divergent changes in weakened and dysregulated oscillators. Similar findings can be expected to occur in other accessory oscillator components that are modulated by melatonin, among them several transcription factors and metabolic sensors. Another cause of opposite effects concerns differences between nocturnally active laboratory rodents and the diurnally active human. This should be more thoroughly considered in the field of metabolic syndrome and related pathologies, especially with regard to type 2 diabetes and other aspects of insulin resistance. Melatonin was reported to impair glucose tolerance in humans, especially in carriers of the risk allele of the MT2 receptor gene, MTNR1B, that contains the SNP rs10830963. These findings contrast with numerous reports on improvements of glucose tolerance in preclinical studies. However, the relationship between melatonin and insulin may be more complex, as indicated by loss-of-function mutants of the MT2 receptor that are also prodiabetic, by the age-dependent time course of risk allele overexpression, by progressive reduction in circadian amplitudes and melatonin secretion, which are aggravated in diabetes. By supporting high-amplitude rhythms, melatonin may be beneficial in preventing or delaying diabetes.
27762290	Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150-200lux):12 h dark (LD) schedule or a 12 h light (150-200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16-19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.
27761341	Talitrus saltator is an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean. T. saltator exhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species.We harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq.	We identified a comprehensive suite of circadian clock gene homologues in T. saltator including the 'core' clock genes period (Talper), cryptochrome 2 (Talcry2), timeless (Taltim), clock (Talclk), and bmal1 (Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period in Talper and Talbmal1. Of the clock-related genes, casein kinase IIβ (TalckIIβ), ebony (Talebony), jetlag (Taljetlag), pigment dispensing hormone (Talpdh), protein phosphatase 1 (Talpp1), shaggy (Talshaggy), sirt1 (Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression.	We report the sequences of principle genes that comprise the circadian clock of T. saltator and highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory of described comparative clocks. Expression profiling of the identified clock genes illuminates tantalising targets for experimental manipulation to elucidate the molecular and cellular control of clock-driven phenotypes in this crustacean.	
27760892	To understand sleep mechanisms and develop treatments for sleep disorders, investigations using animal models are essential. The sleep architecture of rodents differs from that of diurnal mammals including humans and non-human primates. Sleep studies have been conducted in non-human primates; however, these sleep assessments were performed on animals placed in a restraint chair connected via the umbilical area to the recording apparatus. To avoid restraints, cables, and other stressful apparatuses and manipulations, telemetry systems have been developed. In the present study, sleep recordings in unrestrained cynomolgus monkeys (Macaca fascicularis) and common marmoset monkeys (Callithrix jacchus) were conducted to characterize normal sleep. For the analysis of sleep-wake rhythms in cynomolgus monkeys, telemetry electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) signals were used. For the analysis of sleep-wake rhythms in marmosets, telemetry EEG and EOG signals were used. Both monkey species showed monophasic sleep patterns during the dark phase. Although non-rapid eye movement (NREM) deep sleep showed higher levels at the beginning of the dark phase in cynomolgus monkeys, NREM deep sleep rarely occurred during the dark phase in marmosets. Our results indicate that the use of telemetry in non-human primate models is useful for sleep studies, and that the different NREM deep sleep activities between cynomolgus monkeys and common marmoset monkeys are useful to examine sleep functions.
27760556	We present a novel approach, the Local Edge Machine, for the inference of regulatory interactions directly from time-series gene expression data. We demonstrate its performance, robustness, and scalability on in silico datasets with varying behaviors, sizes, and degrees of complexity. Moreover, we demonstrate its ability to incorporate biological prior information and make informative predictions on a well-characterized in vivo system using data from budding yeast that have been synchronized in the cell cycle. Finally, we use an atlas of transcription data in a mammalian circadian system to illustrate how the method can be used for discovery in the context of large complex networks.
27760313	To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet. The model reproduces the dampened clock gene expression and NAD+ rhythms reported for mice on a high-fat diet and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects and suggests a pharmacological approach to resetting the clock in obesity.
27759059	Animals that use astronomical cues to orientate must make continuous adjustment to account for temporal changes in azimuth caused by Earth's rotation. For example, the Monarch butterfly possesses a time-compensated sun compass dependent upon a circadian clock in the antennae. The amphipod Talitrus saltator possesses both a sun compass and a moon compass. We reasoned that the time-compensated compass mechanism that enables solar orientation of T. saltator is located in the antennae, as is the case for Monarch butterflies. We examined activity rhythms and orientation of sandhoppers with antennae surgically removed, or unilaterally occluded with black paint. Removing or painting the antennae did not affect daily activity rhythms or competence to orientate using the sun. However, when tested at night these animals were unable to orientate correctly to the moon. We subsequently measured circadian gene expression in the antennae and brain of T. saltator and show the clock genes period and cryptochrome 2 are rhythmically expressed in both tissues, reminiscent of other arthropods known to possess antennal clocks. Together, our behavioural and molecular data suggest that, T. saltator has anatomically discrete lunar and solar orientation apparatus; a sun compass, likely located in the brain and a moon compass in the antennae.
27756900	Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status.
27756446	The circadian clock system enables organisms to anticipate the rhythmic environmental changes and to manifest behavior and physiology at advantageous times of the day. Transcriptional/translational feedback loop (TTFL) is the basic feature of the eukaryotic circadian clock and is based on the rhythmic association of circadian transcriptional activator and repressor. In Drosophila, repression of dCLOCK/CYCLE (dCLK/CYC) mediated transcription by PERIOD (PER) is critical for inducing circadian rhythms of gene expression. Pacemaker neurons in the brain control specific circadian behaviors upon environmental timing cues such as light and temperature cycle. We show here that amino acids 657-707 of dCLK are important for the transcriptional activation and the association with PER both in vitro and in vivo. Flies expressing dCLK lacking AA657-707 in Clkout genetic background, homologous to the mouse Clock allele where exon 19 region is deleted, display pacemaker-neuron-dependent perturbation of the molecular clockwork. The molecular rhythms in light-cycle-sensitive pacemaker neurons such as ventral lateral neurons (LNvs) were significantly disrupted, but those in temperature-cycle-sensitive pacemaker neurons such as dorsal neurons (DNs) were robust. Our results suggest that the dCLK-controlled TTFL diversify in a pacemaker-neuron-dependent manner which may contribute to specific functions such as different sensitivities to entraining cues. [BMB Reports 2016; 49(11): 587-589].
27592174	To examine the coordination between photosystem II (PSII) and photosystem I (PSI) in response to varying environmental conditions, both diurnal fluctuations and seasonal variability of photosynthetic electron transport activity in ivy (Hedera nepalensis, Araliaceae) were investigated: by measuring prompt fluorescence, delayed fluorescence (DF) and modulated reflection of 820 nm light (MR). During diurnal fluctuations, the PSII electron donor side was damaged, as evidenced by decreases of the fast amplitude of DF decay kinetics at I1, although there was no significant change in relative variable fluorescence at K-step to amplitude of FJ - Fo. Decreases in the maximum photochemical efficiency (i.e., PSII photoinactivation) were accompanied by an increased maximum decrease in the slope of MR/MRo (i.e., PSI photoactivation). Subsequently, PSII recovery and PSI relaxation occurred in the afternoon. Throughout the season, alternations between PSII and PSI were also suggested by the down-regulation of PSII and the up-regulation of PSI from summer to winter. Significant negative linear correlations between the activity of PSII and PSI across both diurnal fluctuations and seasonal variability were verified by correlation analyses. In addition, PSI was active throughout the year, suggesting PSI is independent from high temperatures. High PSI activity may maintain the functional integrity of the photosynthetic apparatus in overwintering ivy. The alternation between PSII and PSI activity may regulate the distribution of excitation energy between the two photosystems and balance the redox state of the electron transport change, thereby enabling ivy to respond to varying environmental conditions.
27754956	Circadian oscillators found across a variety of species are subject to periodic external light-dark forcing. Entrainment to light-dark cycles enables the circadian system to align biological functions with appropriate times of day or night. Phase response curves (PRCs) have been used for decades to gain valuable insights into entrainment; however, PRCs may not accurately describe entrainment to photoperiods with substantial amounts of both light and dark due to their reliance on a single limit cycle attractor. We have developed a new tool, called an entrainment map, that overcomes this limitation of PRCs and can assess whether, and at what phase, a circadian oscillator entrains to external forcing with any photoperiod. This is a 1-dimensional map that we construct for 3 different mathematical models of circadian clocks. Using the map, we are able to determine conditions for existence and stability of phase-locked solutions. In addition, we consider the dependence on various parameters such as the photoperiod and intensity of the external light as well as the mismatch in intrinsic oscillator frequency with the light-dark cycle. We show that the entrainment map yields more accurate predictions for phase locking than methods based on the PRC. The map is also ideally suited to calculate the amount of time required to achieve entrainment as a function of initial conditions and the bifurcations of stable and unstable periodic solutions that lead to loss of entrainment.
27754419	This project was designed to assess the effects of time of day and training status on the benefits of caffeine supplementation for cycling performance. Twenty male subjects (Age, 25 years; Peak oxygen consumption, 57 mL·kg-1·min-1) were divided into tertiles based on training levels, with top and bottom tertiles designated as 'trained' (n = 7) and 'untrained' (n = 7). Subjects completed two familiarization trials and four experimental trials consisting of a computer-simulated 3-km cycling time trial (TT). The trials were performed in randomized order for each combination of time of day (morning and evening) and treatment (6mg/kg of caffeine or placebo). Magnitude-based inferences were used to evaluate all treatment effects. For all subjects, caffeine enhanced TT performance in the morning (2.3% ± 1.7%, 'very likely') and evening (1.4% ± 1.1%, 'likely'). Both untrained and trained subjects improved performance with caffeine supplementation in the morning (5.5% ± 4.3%, 'likely'; 1.0% ± 1.7%, 'likely', respectively), but only untrained subjects rode faster in the evening (2.9% ± 2.6%, 'likely'). Altogether, our observations indicate that trained athletes are more likely to derive ergogenic effects from caffeine in the morning than the evening. Further, untrained individuals appear to receive larger gains from caffeine in the evening than their trained counterparts.
27752300	The circadian oscillations of muscle genes are controlled either directly by the intrinsic muscle clock or by extrinsic factors, such as feeding, hormonal signals, or neural influences, which are in turn regulated by the central pacemaker, the suprachiasmatic nucleus of the hypothalamus. A unique feature of circadian rhythms in skeletal muscle is motor neuron-dependent contractile activity, which can affect the oscillation of a number of muscle genes independently of the muscle clock. The role of the intrinsic muscle clock has been investigated using different Bmal1 knockout (KO) models. A comparative analysis of these models reveals that the dramatic muscle wasting and premature aging caused by global conventional KO are not present in muscle-specific Bmal1 KO or in global Bmal1 KO induced in the adult, therefore must reflect the loss of Bmal1 function during development in non-muscle tissues. On the other hand, muscle-specific Bmal1 knockout causes impaired muscle glucose uptake and metabolism, supporting a major role of the muscle clock in anticipating the sleep-to-wake transition, when glucose becomes the predominant fuel for the skeletal muscle.
27751889	Some major aspects of insect life, like development time and reproduction, can benefit from fluctuating temperatures rather than a constant temperature regime. The benefit of fluctuating temperature has generally been attributed to the non-linear properties of the relationship of many life history traits with temperature. Daily temperature rise, however, usually coincide with the light phase of the photoperiodic cycle and there could be a benefit in linking daily temperature fluctuations with light and dark phases e.g. to anticipate the change in temperature. Such synergistic effects have primarily been studied in the light of activity patterns and gene expression, but have not yet been shown to extend to population dynamics and aspects of individual fitness like oviposition behavior. We therefore explored possible synergistic effects on life history traits of the springtail Orchesella cincta. We first test the primary effect of ecologically relevant temperature fluctuations of different amplitudes on population growth and total population mass. The slowest population growth was observed in the constant temperature regime treatment and the highest population growth in the regime with high amplitude fluctuations. In a second experiment, population growth and oviposition rhythm were measured under four different regimes; a constant light and temperature regime, thermoperiod only, photoperiod only and thermoperiod and photoperiod aligned as under natural conditions. The regime in which thermoperiod was aligned with photoperiod resulted in a higher population growth than could be realized by either factor alone. Also, significantly fewer eggs were laid in the constant temperature/light regime than in the other three regimes, strongly suggesting that this regime is stressful to O. cincta. Additionally, the fraction of eggs laid at night was highest in the regime with the combined temperature and light cycle. In conclusion, our results show that under these experimental conditions there is a synergistic effect of daily temperature fluctuations in combination with light/dark phases that can considerably influence important life history traits and affect behavior. Such effects are likely to be relevant under natural conditions.

27040022	To analyse the effect of cataract surgery on diurnal intra-ocular pressure (IOP) fluctuation in primary angle-closure glaucoma (PACG) eyes.Thirty-nine eyes of 24 patients with PACG scheduled for cataract surgery were enrolled to this prospective study. A record was made which included mean IOP measurement, anterior chamber depth (ACD), anterior chamber angle (ACA), number of antiglaucomatous medications, visual field analysis (mean deviation - MD and pattern standard deviation - PSD) and responses to the Glaucoma Quality of Life-15 (GQL-15) questionnaires. The eyes were re-evaluated at 2 and 3 months of cataract surgery.	IOP fluctuation was decreased from 4.58 ± 2.07 mmHg to 2.84 ± 1.5 mmHg (p < 0.001). The decrease in mean IOP, the number of glaucoma eye drops required (p < 0.001, p = 0.012, respectively) and the increase in mean ACD, ACA grading and SITA-standard MD (p < 0.001, p < 0.001, and p = 0.01, respectively) were statistically significant. The mean GQL-15 score was also improved (p < 0.001). The change in IOP fluctuation correlated positively with the preoperative IOP fluctuation (r = 0.56 p = 0.00), the change in ACD (r = 0.703, p < 0.001) and the change in ACA (r = 0.664, p < 0.001). In multivariate analysis, preoperative IOP fluctuation and postoperative increase in ACD were significantly associated with a reduction in IOP fluctuation of an average of 1.1 mmHg per unit change (p = 0.00 and p = 0.019, respectively).	Cataract surgery in PACG provides the opportunity to address many pathologies with one intervention; improving vision, diminishing IOP, blunting IOP fluctuation, reducing need for medications, eliminating a narrow angle and improving GQL-15 scores.	
27749086	Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment.
27747302	To establish a connection between microRNA (miRNAs), circadian rhythm, and colorectal cancer patient survival.Genomic and clinical data were extracted from The Cancer Genome Atlas (TCGA) colorectal cancer database, and the expression levels of candidate miRNAs and a set of circadian rhythm-related genes (Per1, Per2, Per3, Bmal1), and genes associated with chemosensitivity (thymidylate synthase, dihydrofolate reductase) were assessed for any correlations among their expression. In addition, survival analyses specific to different colorectal cancer stages were performed to determine if these genes contribute to patient outcomes.	Significant inverse correlation between the expression of Per1 and that of miR-192 and miR-194 was observed. In survival analyses, high miR-192 and miR-194 correlate with better overall survival in Stage II patients, but worse survival in more advanced Stage III/IV patients. The expression of Per1, but Per2 or Bmal1, is marginally associated with patient survival for Stage II patients. Low thymidylate synthase expression correlates with better overall survival in Stage II patients but worse survival in Stage III/IV patients.	This study establishes a foundation based on a large genomic database of colorectal cancer, for further investigation into the importance of regulatory mechanisms of circadian rhythm by miRNAs in colorectal cancer.	
27747290	Cardiovascular disease is the number one cause of death worldwide. A powerful strategy for cardioprotection would be to identify specific molecules or targets that mimic ischemic preconditioning (IP), where short non-lethal episodes of ischemia and reperfusion prior to myocardial infarction result in dramatic reduction of infarct sizes. Since 1960 researchers believed that adenosine has a strong cardio-protective potential. In fact, with the discovery of cardiac IP in 1986 by Murry et al., adenosine was the first identified molecule that was used in studying the underlying mechanism of IP. Today we know, based on genetic studies, that adenosine is crucial for IP mediated cardio-protection and that the adenosine receptors ADORA1, ADORA2a and ADORA2b play an important role. However, the ADORA2b receptor is the only receptor so far which has been found to play a role in human and murine myocardial ischemia. With recent advances using tissue specific mice for the ADORA2b, we were able to uncover cardiomyocytes and endothelia as the responsible cell type for cardiac IP. Using a wide search for ADORA2b downstream targets, our group identified the circadian rhythm protein, Period 2 (PER2), as a novel target for IP mediated cardioprotection. Mechanistic studies on PER2 mediated cardioprotection revealed an important role for PER2 in optimizing cardiac metabolism through activation of oxygen saving pathways. Thus, cardiomyocyte or endothelial expressed ADORA2b or the downstream circadian rhythm protein PER2 are key targets for cardiac IP and could represent novel strategies to treat or prevent MI.
27746588	Background: There is barely any evidence of antipsychotic drugs affecting the molecular clockwork in human, yet it is suggested that clock genes are associated with dopaminergic transmission, i.e. the main target of this therapeutics. We decided to verify if haloperidol and olanzapine affect expression of CLOCK, BMAL1, PER1 and CRY1 in a human central nervous system cell line model. Methods: U-87MG human glioblastoma cell line was used as an experimental model. The cells were incubated with or without haloperidol and olanzapine in the concentration of 5 and 20 μM for 24 h. Real-time quantitative polymerase chain reaction with the ΔCT analysis was used to examine the effect of haloperidol and olanzapine on the mRNA expression of the genes. Results: At 5 μM, haloperidol decreased expression of CRY1 almost 20-fold. There was nearly a 1.5-fold increase in expression of PER1. Considering the 20 μM haloperidol concentration and both olanzapine concentrations, no other statistically significant effect was observed. Conclusions: At certain concentration, haloperidol seems to affect expression of particular clock genes in a human central nervous system cell line model, yet mechanism underlying this phenomenon remains elusive.
27534836	The International Conference on Harmonisation's (ICH) Tripartite Guideline on Safety Pharmacology Studies for Human Pharmaceuticals has adopted the requirement that each new test substance must be tested for effects on the central nervous system prior to "first dose in man". This assessment is required to measure, at a minimum, the effects of the substance on general motor activity, behavioral changes, coordination, sensory/motor reflex responses, and body temperatures. To achieve this goal, ICH S7A recommends a neurobehavioral assessment (usually a functional observational battery (FOB) or modified Irwin test), which is generally undertaken in the rat. There seems to be a growing lack of consensus on the value of the FOB to determine CNS safety. This review highlights the importance of the time, effort and cost of training technicians to familiarize with their instrument of measure, so that each observer is better able to identify and document very subtle changes in behavior that will serve to increase the reliability and validity of these assays with respect to CNS safety assessments.
25101831	Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC0-∞, Cmax, Tmax, t1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10 h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.
27742378	Alterations in hepatic free fatty acid (FFA) uptake and metabolism contribute to the development of prevalent liver disorders such as hepatosteatosis. However, detecting dynamic changes in FFA uptake by the liver in live model organisms has proven difficult. To enable noninvasive real-time imaging of FFA flux in the liver, we generated transgenic mice with liver-specific expression of luciferase and performed bioluminescence imaging with an FFA probe. Our approach enabled us to observe the changes in FFA hepatic uptake under different physiological conditions in live animals. By using this method, we detected a decrease in FFA accumulation in the liver after mice were given injections of deoxycholic acid and an increase after they were fed fenofibrate. In addition, we observed diurnal regulation of FFA hepatic uptake in living mice. Our imaging system appears to be a useful and reliable tool for studying the dynamic changes in hepatic FFA flux in models of liver disease.
27740710	The hypothalamic suprachiasmatic nucleus (SCN), locus of the master circadian clock, bears many neuronal types. At the cellular-molecular level, the clock is comprised of feedback loops involving 'clock' genes including Period1 and Period2, and their protein products, PERIOD1 and PERIOD2 (PER1/2). In the canonical model of circadian oscillation, the PER1/2 proteins oscillate together. While their rhythmic expression in the SCN as a whole has been described, the possibility of regional differences remains unknown. To explore these clock proteins in distinct SCN regions, we assessed their expression through the rostro-caudal extent of the SCN in sagittal sections. We developed an automated method for tracking three fluorophores in digital images of sections triply labeled for PER1, PER2, and gastrin-releasing peptide (used to locate the core). In the SCN as a whole, neurons expressing high levels of PER2 were concentrated in the rostral, rostrodorsal, and caudal portions of the nucleus, and those expressing high levels of PER1 lay in a broad central area. Within these overall patterns, adjacent cells differed in expression levels of the two proteins. The results demonstrate spatially distinct localization of high PER1 vs. PER2 expression, raising the possibility that their distribution is functionally significant in encoding and communicating temporal information. The findings provoke the question of whether there are fundamental differences in PER1/2 levels among SCN neurons and/or whether topographical differences in protein expression are a product of SCN network organization rather than intrinsic differences among neurons.
27739341	The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ between bipolar disorder (BD) and controls.The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5' region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls.	Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073).	Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.	
27738003	Circadian clocks are cell-autonomous timing mechanisms that organize cell functions in a 24-h periodicity. In mammals, the main circadian oscillator consists of transcription-translation feedback loops composed of transcriptional regulators, enzymes, and scaffolds that generate and sustain daily oscillations of their own transcript and protein levels. The clock components and their targets impart rhythmic functions to many gene products through transcriptional, posttranscriptional, translational, and posttranslational mechanisms. This, in turn, temporally coordinates many signaling pathways, metabolic activity, organelles' structure and functions, as well as the cell cycle and the tissue-specific functions of differentiated cells. When the functions of these circadian oscillators are disrupted by age, environment, or genetic mutation, the temporal coordination of cellular functions is lost, reducing organismal health and fitness.
27737865	Disruption of the biological rhythm in patients with bipolar disorder is a known risk factor for a switch in mood. This case study describes how modern techniques using ambulatory assessment of sleep parameters can help in signalling a mood switch and start early treatment. We studied a 40-year-old woman with bipolar disorder experiencing a life event while wearing an actigraph to measure sleep-wake parameters. The night after the life event the woman had sleep later and shorter sleep duration. Adequate response of both the woman and the treating psychiatrist resulted in two normal nights with the use of 1 mg lorazepam, possibly preventing further mood disturbances. Ambulatory assessment of the biological rhythm can function as an add-on to regular signalling plans for prevention of episodes in patients with bipolar disorder. More research should be conducted to validate clinical applicability, proper protocols and to understand underlying mechanisms.
27737649	Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.	A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.	Our data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.	
27737315	The objective of this study was to evaluate the alterations in sleep and circadian parameters during the aging process. The study sample comprises volunteers older than 18 up to 90 years of age that answered the Pittsburgh Sleep Quality Index (PSQI) and the Horne and Östberg circadian preference questionnaire. We observed that the shift to morningness with increasing age is associated with a significant worsening in sleep quality. We discuss that this sleep profile characterized by morningness and worse sleep quality observed in elderly, when compared to younger people, reflects not necessarily a pathological state, but an expected profile for this age group.
27736199	Chronotype is a stable trait presenting one's circardian preference. Since chronotype disturbances are common in patients with affective disorders, our aim is to evaluate chronotypes related to affective temperaments, measured with the temperament evaluation of Memphis, Pisa and San Diego-Autoquestionnaire (TEMPS-A). The study included 618 subjects (151 men and 467 women) within the framework of web-based design. They all fulfilled a questionnaire, consisting of the Composite Scale of Morningness (CSM), Sleep Wake Pattern Assessment Questionnaire (SWPAQ), and the TEMPS-A scale. Multiple regression models revealed that after controlling for age and gender: irritable and cyclothymic temperaments were negatively associated with total CSM score, CSM morning affect and circadian preference components, Sleepability (S), Vigilance (V), Wakeability (W) and positively with Morningness (M) and Eveningness (E) subscales of SWPAQ; anxious temperament was negatively associated with total CSM scores, CSM morning affect and with S, V, W subscales of SWPAQ; depressive temperament was negatively associated with Falling asleep, S, V, W subscales of SWPAQ; hyperthymic temperament was positively associated with CSM morning affect and V, W and negatively with M subscales of SWPAQ. The results show distinctiveness of the associations between hyperthymic temperament and circadian preferences, compared to all other TEMPS-A temperaments (depressive, cyclothymic, irritable and anxious). In the CMS scale, only hyperthymic temperament was related to morning affect. In the SWPAQ scale, hyperthymic temperament was the only one associated with earlier morningness (earlier wake up time preference), increased parameters of vigor - wakeability, vigilance, and also the only one not associated with decreased plasticity of circadian rhythm (sleepability and falling asleep). Results also point to some similarities between cyclothymic and irritable temperaments in some aspects of the chronotype.
27736193	Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2-/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT100 = QT/(RR/100)1/2). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QTmean-RR). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2-/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2-/- mice. Circadian rhythms in QT100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2-/-, respectively (p = 0.15). A diurnal rhythm in QT100 intervals was only found in WT mice. QTmean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2-/-. The amplitude of the circadian rhythm in QTmean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2-/-, respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.
27736010	Despite state-of-the-art pharmaceutical regimens, continuous improvements in diagnostic techniques as well as refinements in equipment and interventional procedures, many diseases remain refractory to conventional therapies. Recent advances in stem cell (SC) biology have opened an avenue to exploring its therapeutic potential in various disease entities, especially those that are ischemia-related and refractory to conventional treatment. A number of experimental studies and clinical trials have already demonstrated promising outcomes. On the other hand, SC therapy is associated with major problems. For instance, ischemia, inflammation, and oxidative stress are some of the factors unfavorable for SC survival once SCs are implanted into the ischemic area in an attempt to enhance tissue regeneration and restore organ function. Melatonin, which is originally derived from pineal gland in the regulation of human circadian rhythms and sleep, is a potent free radical scavenger and metal chelator with the capacity to alleviate oxidative stress and inflammatory reactions as well as stabilizing cell membranes. Accumulating data have demonstrated that melatonin-supported SC therapy is superior to SC alone for improving ischemia-related organ dysfunction. In this review, we describe and interpret the potential role of melatonin in sustaining the survival and preserving the functional integrity of SC.
27733449	The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (Meth) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-surgery and SCNX mice were treated with either Meth (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW. Only the association of Meth treatment and restricted RW access successfully reestablished entrained circadian rhythms in mice with SCNX. RW-likely acting as a link between the circadian and reward systems-promotes circadian entrainment of activity. We conclude that a conditioned drug response is a powerful tool to entrain, drive, and restore circadian physiology. Furthermore, an RW should be recognized as a potent input signal in addition to the conventional use as an output signal.-Rawashdeh, O., Clough, S. J., Hudson, R. L., Dubocovich, M. L. Learned motivation drives circadian physiology in the absence of the master circadian clock.
27733386	Diurnal or circadian rhythms are fundamentally important for healthy cardiovascular physiology and play a role in timing of onset and tolerance to myocardial infarction (MI) in patients. Whether time of day of MI triggers different molecular and cellular responses that can influence myocardial remodeling is not known. This study was designed to test whether time of day of MI triggers different gene expression, humoral, and innate inflammatory responses that contribute to cardiac repair after MI. Mice were infarcted by left anterior descending coronary artery ligation (MI model) within a 2-h time window either shortly after lights on or lights off, and the early remodeling responses at 8 h postinfarction were examined. We found that sleep-MI preferentially triggers early expression of genes associated with inflammatory responses, whereas wake-MI triggers more genes associated with metabolic pathways and transcription/translation, by microarray analyses. Homozygous clock mutant mice exhibit altered diurnal gene expression profiles, consistent with their cycling before onset of MI. In the first 8 h, crucial for innate immune responses to MI, there are also significant differences in sleep-MI and wake-MI serum cytokine responses and in neutrophil infiltration to infarcted myocardium. By 1-wk post-MI, there are differences in survivorship between the sleep and wake MI mice that could be explained by the different molecular and cellular responses. Our whole body physiology, tissues, and cells exhibit endogenous daily rhythms, and understanding their role in triggering effective responses after MI could lead to new strategies to benefit patients with cardiovascular disease.
27732848	Circadian clocks generate 24-hr rhythms in physiology and behavior. Despite numerous studies, it is still uncertain how circadian rhythms emerge from their molecular and neural constituents. Here, we demonstrate a tight connection between the molecular and neuronal circadian networks. Using fluorescent transcriptional reporters in a Drosophila ex vivo brain culture system, we identified a reciprocal negative regulation between the master circadian regulator CLK and expression of pdf, the main circadian neuropeptide. We show that PDF feedback is required for maintaining normal oscillation pattern in CLK-driven transcription. Interestingly, we found that CLK and neuronal firing suppresses pdf transcription, likely through a common pathway involving the transcription factors DHR38 and SR, establishing a direct link between electric activity and the circadian system. In sum, our work provides evidence for the existence of an uncharacterized CLK-PDF feedback loop that tightly wraps together the molecular oscillator with the circadian neuronal network in Drosophila.
27732604	The lack of sleep, both in quality and quantity, is an increasing problem in modern society, often related to workload and stress. A number of studies have addressed the effects of acute (total) sleep deprivation on postural control. However, up to date, the effects of chronic sleep deficits, either in quantity or quality, have not been analyzed. Thirty healthy adults participated in the study that consisted of registering activity with a wrist actigraph for more than a week before performing a series of postural control tests. Sleep and circadian rhythm variables were correlated and the sum of activity of the least active 5-h period, L5, a rhythm variable, obtained the greater coefficient value with sleep quality variables (wake after sleep onset WASO and efficiency sleep). Cluster analysis was performed to classify subjects into two groups based on L5 (low and high). The balance tests scores used to asses postural control were measured using Biodex Balance System and were compared between the two groups with different sleep quality. The postural tests were divided into dynamic (platform tilt with eyes open, closed and cursor) and static (clinical test of sensory integration). The results showed that during the tests with eyes closed, the group with worse sleep quality had also worse postural control performance. Lack of vision impairs postural balance more deeply in subjects with chronic sleep inefficiency. Chronic poor sleep quality impairs postural control similarly to total sleep deprivation.
27731339	Some cyanobacteria exhibit compaction of DNA in synchrony with their circadian rhythms accompanying cell division. Since the structure is transient, it has not yet been described in detail. Here, we successfully visualize the ultrastructure of compacted DNA in the cyanobacterium Synechococcus elongatus PCC 7942 under rigorous synchronized cultivation by means of high-voltage cryo-electron tomography. In 3D reconstructions of rapidly frozen cells, the compacted DNA appears as an undulating rod resembling a eukaryotic condensed chromosome. The compacted DNA also includes many small and paired polyphosphate bodies (PPBs), some of which seem to maintain contact with DNA that appears to twist away from them, indicating that they may act as interactive suppliers and regulators of phosphate for DNA synthesis. These observations throw light on the duplication and segregation mechanisms of cyanobacterial DNA and point to an important role for PPBs.
27728899	We sought to investigate the temporal patterns and sleep-wake cycle-related epileptiform discharges (EDs) in genetic generalized epilepsies (GGEs).We studied 24-hour ambulatory electroencephalography (EEG) recordings of patients with GGE, diagnosed and classified according to the International League against Epilepsy criteria. We manually coded the type of discharge, time of occurrence, duration, and arousal state of each ED. We employed mixed effects Poisson regression modeling to study the temporal distribution of epileptiform discharges. Additionally, we used multinomial regression analysis to explore the significance of the relationship between different states of arousal and types of epileptiform discharges.	We analyzed 6923 EDs from 105 abnormal 24-hour EEGs. Mixed effects Poisson regression analysis demonstrated significant changes in ED counts across time blocks. This distribution was largely influenced by the state of arousal. Generalized fragments (duration<2s) and focal discharges were more frequent during non-REM sleep while paroxysms (duration≥2s) were more frequent in wakefulness. Overall, 67% of epileptiform discharges occurred in non-REM sleep and only 33% occurred in wakefulness. Twenty-four patients (23%) had ED exclusively in sleep. Epileptiform discharges peaked from 23:00 through 07:00h.	There is a time-of-day dependency of ED with a significant influence exerted by the state of arousal. Our observations suggest that the generation of epileptiform discharges is not a random process but is the result of complex interactions among biological rhythms such as the sleep-wake cycle and the intrinsic circadian pacemaker. High density of ED in sleep suggests that 24-hour EEG recording with the capture of natural sleep may be more useful than routine EEG to diagnose GGE.	
27728793	A new study shows that nocturnal courtship vocalization is regulated by a circadian rhythm and potentiated by melatonin at multiple timescales. These findings are in contrast to those in diurnal vocalizers and provide a striking example of melatonin's niche-specific functions.
27727308	The energy metabolism of the retina might comply with daily changes in energy demand and is impaired in diabetic retinopathy-one of the most common causes of blindness in Europe and the USA. The aim of this study was to investigate putative adaptation of energy metabolism in healthy and diabetic retina. Hence expression analysis of metabolic pathway genes was performed using quantitative polymerase chain reaction, semi-quantitative western blot and immunohistochemistry. Transcriptional profiling of key enzymes of energy metabolism identified transcripts of mitochondrial fatty acid β-oxidation enzymes, i.e. carnitine palmitoyltransferase-1α (Cpt-1α) and medium chain acyl-CoA dehydrogenase (Acadm) to display daily rhythms with peak values during daytime in preparations of the whole retina and microdissected photoreceptors. The cycling of both enzymes persisted in constant darkness, was dampened in mice deficient for dopamine D4 (D4) receptors and was altered in db/db mice-a model of diabetic retinopathy. The data of the present study are consistent with circadian clock-dependent and dopaminergic regulation of fatty acid oxidation in retina and its putative disturbance in diabetic retina.
27726448	Continuous recordings of core body temperature (CBT) are a well-established approach in describing circadian rhythms. Given the discomfort of invasive CBT measurement techniques, the use of skin temperature recordings has been proposed as a surrogate. More recently, we proposed a heat-flux approach (the so-called Double Sensor) for monitoring CBT. Studies investigating the reliability of the heat-flux approach over a 24-hour period, as well as comparisons with skin temperature recordings, are however lacking. The first aim of the study was therefore to compare rectal, skin, and heat-flux temperature recordings for monitoring circadian rhythm. In addition, to assess the optimal placement of sensor probes, we also investigated the effect of different anatomical measurement sites, i.e. sensor probes positioned at the forehead vs. the sternum. Data were collected as part of the Berlin BedRest study (BBR2-2) under controlled, standardized, and thermoneutral conditions. 24-hours temperature data of seven healthy males were collected after 50 days of -6° head-down tilt bed-rest. Mean Pearson correlation coefficients indicated a high association between rectal and forehead temperature recordings (r > 0.80 for skin and Double Sensor). In contrast, only a poor to moderate relationship was observed for sensors positioned at the sternum (r = -0.02 and r = 0.52 for skin and Double Sensor, respectively). Cross-correlation analyses further confirmed the feasibility of the forehead as a preferred monitoring site. The phase difference between forehead Double Sensor and rectal recordings was not statistically different from zero (p = 0.313), and was significantly smaller than the phase difference between forehead skin and rectal temperatures (p = 0.016). These findings were substantiated by cosinor analyses, revealing significant differences for mesor, amplitude, and acrophase between rectal and forehead skin temperature recordings, but not between forehead Double Sensor and rectal temperature measurements. Finally, Bland-Altman analysis indicated narrower limits of agreement for rhythm parameters between rectal and Double Sensor measurements compared to between rectal and skin recordings, irrespective of the measurement site (i.e. forehead, sternum). Based on these data we conclude that (1) Double Sensor recordings are significantly superior to skin temperature measurements for non-invasively assessing the circadian rhythm of rectal temperature, and (2) temperature rhythms from the sternum are less reliable than from the forehead. We suggest that forehead Double Sensor recordings may provide a surrogate for rectal temperature in circadian rhythm research, where constant routine protocols are applied. Future studies will be needed to assess the sensor's ecological validity outside the laboratory under changing environmental and physiological conditions.

27721804	The core circadian oscillator in mammals is composed of transcription/translation feedback loop, in which cryptochrome (CRY) proteins play critical roles as repressors of their own gene expression. Although post-translational modifications, such as phosphorylation of CRY1, are crucial for circadian rhythm, little is known about how phosphorylated CRY1 contributes to the molecular clockwork. To address this, we created a series of CRY1 mutants with single amino acid substitutions at potential phosphorylation sites and performed a cell-based, phenotype-rescuing screen to identify mutants with aberrant rhythmicity in CRY-deficient cells. We report 10 mutants with an abnormal circadian period length, including long period (S280D and S588D), short period (S158D, S247D, T249D, Y266D, Y273D, and Y432D), and arrhythmicity (S71D and S404D). When expressing mutated CRY1 in HEK293 cells, we show that most of the mutants (S71D, S247D, T249D, Y266D, Y273D, and Y432D) exhibited reduction in repression activity compared with wild-type (WT) CRY1, whereas other mutants had no obvious change. Correspondingly, these mutants also showed differences in protein stability and cellular localization. We show that most of mutants are more stable than WT, except S158D, T249D, and S280D. Although the characteristics of the 10 mutants are various, they all impair the ratio balance of intracellular CRY1 protein. Thus, we conclude that the mutations caused distinct phenotypes most likely through the ratio of functional CRY1 protein in cells.
27721414	Circadian rhythms controlled by clock genes affect plasma lipids. Here we show that global ablation of Bmal1 in Apoe-/- and Ldlr-/- mice and its liver-specific ablation in Apoe-/- (L-Bmal1-/-Apoe-/-) mice increases, whereas overexpression of BMAL1 in L-Bmal1-/-Apoe-/- and Apoe-/-mice decreases hyperlipidaemia and atherosclerosis. Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Further, Bmal1 deficiency reduces expression of Shp and Gata4. Reductions in Shp increase Mtp expression and lipoprotein production, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and biliary cholesterol excretion. Forced SHP expression normalizes lipoprotein secretion with no effect on biliary cholesterol excretion, while forced GATA4 expression increases cholesterol excretion to the bile and reduces plasma lipids in L-Bmal1-/-Apoe-/- and Apoe-/- mice. Thus, our data indicate that Bmal1 modulates lipoprotein production and biliary cholesterol excretion by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4.
27721187	Dysfunctions in the intrinsic clocks are suggested in patients with depressive disorders. The cryptochrome circadian clocks 1 and 2 (CRY1 and CRY2) proteins modulate circadian rhythms in a cell and influence emotional reactions and mood in an individual. The protein kinase C delta binding protein (PRKCDBP, or CAVIN3), similar to the serum deprivation response protein (SDPR, or CAVIN2), reduces metabolic stability of the PER2-CRY2 transcription factor complex that plays a role in the circadian rhythm synchronization. Our aim was to study SDPR, PRKCDBP, CRY1 and CRY2 genetic variants in depressive disorders.The sample included 5910 Finnish individuals assessed with the Munich-Composite International Diagnostic Interview (M-CIDI) in year 2000. In year 2011, 3424 individuals were assessed again. After genotype quality control, there were 383 subjects with major depressive disorder, 166 with dysthymia, and 479 with depressive disorders (major depressive disorder, dysthymia or both), and 4154 healthy controls. A total of 48 single-nucleotide polymorphisms from SDPR, PRKCDBP, CRY1 and CRY2 genes were analyzed using logistic regression models controlling for age and gender.	The earlier reported association of CRY2 variants with dysthymia was confirmed and extended to major depressive disorder (q<0.05). In addition, novel associations of PRKCDBP rs1488864 with depressive disorders (q=0.02) and with major depressive disorder in specific (q=0.007) were found.	The number of cases was moderate and coverage of PRKCDB was limited.	CRY2 and PRKCDBP variants may be risk factors of major depressive disorder and provide information for diagnosis.	
27720226	A daily rhythm that is not in synchrony with the environmental light-dark cycle (as in jetlag and shift work) is known to affect mood and health through an as yet unresolved neural mechanism. Here, we combine Bayesian probabilistic 'cue-conflict' theory with known physiology of the biological clock of the brain, entailing the insight that, for a functional pacemaker, it is sufficient to have two interacting units (reflecting environmental and internal time-of-day cues), without the need for an extra homuncular directing unit. Unnatural light-dark cycles cause a time-of-day cue-conflict that is reflected by a desynchronization between the ventral (environmental) and dorsal (internal) pacemaking signals of the pacemaker. We argue that this desynchronization, in-and-of-itself, produces health issues that we designate as 'circadian-time sickness', analogous to 'motion sickness'.
27718292	Twenty-four-hour ambulatory blood pressure and heart rate monitoring (24-h ABPM) can provide vital information on circadian blood pressure (BP) profiles, which are commonly abnormal in Parkinson's disease with and without autonomic failure (PD + AF and PD) and multiple system atrophy (MSA). Twenty-four-hour ABPM has not been directly compared between these disorders regarding cardiovascular autonomic function. Our aim was to determine the usefulness of 24-h ABPM with diary compared to head-up tilting (HUT) in diagnosing orthostatic hypotension (OH) in these patients.Seventy-four patients (23 MSA, 18 PD + AF, 33 PD) underwent cardiovascular autonomic screening followed by 24-h ABPM with diary. Standing tests were included during 24-h ABPM. The sensitivity and specificity in detecting OH from the 24-h ABPM standing test were compared with HUT.	There was no difference in OH during HUT between MSA and PD + AF (P > 0.05). There was a higher proportion of abnormal BP circadian rhythms in MSA and PD + AF compared to PD (P < 0.05) but not between MSA and PD + AF (P > 0.05). Patients were divided into groups with OH (OH+) and without OH (OH-) on HUT. Using the standing test during 24-h ABPM, a systolic BP fall of >20 mmHg showed a sensitivity and specificity of 82% and 100% (area under the curve 0.91, 95% confidence interval 0.84-0.98) in differentiating OH+ from OH-.	Parkinson's disease with autonomic failure and MSA patients had similar circadian BP patterns suggesting that autonomic dysfunction influences abnormal BP circadian patterns similarly in these disorders. The higher sensitivity and specificity in detecting OH using a systolic BP fall of >20 mmHg compared to a diastolic BP fall of >10 mmHg during the standing test supports its usefulness to assess autonomic function in MSA and PD.	
27716936	We investigated the signalling pathways that regulate chloroplast transcription in response to environmental signals. One mechanism controlling plastid transcription involves nuclear-encoded sigma subunits of plastid-encoded plastid RNA polymerase. Transcripts encoding the sigma factor SIG5 are regulated by light and the circadian clock. However, the extent to which a chloroplast target of SIG5 is regulated by light-induced changes in SIG5 expression is unknown. Moreover, the photoreceptor signalling pathways underlying the circadian regulation of chloroplast transcription by SIG5 are unidentified. We monitored the regulation of chloroplast transcription in photoreceptor and sigma factor mutants under controlled light regimes in Arabidopsis thaliana. We established that a chloroplast transcriptional response to light intensity was mediated by SIG5; a chloroplast transcriptional response to the relative proportions of red and far red light was regulated by SIG5 through phytochrome and photosynthetic signals; and the circadian regulation of chloroplast transcription by SIG5 was predominantly dependent on blue light and cryptochrome. Our experiments reveal the extensive integration of signals concerning the light environment by a single sigma factor to regulate chloroplast transcription. This may originate from an evolutionarily ancient mechanism that protects photosynthetic bacteria from high light stress, which subsequently became integrated with higher plant phototransduction networks.
27716514	It is known that sleep disturbance has been considered a trait-marker of mood disorders. However, the role of disruptions in biological rhythms, such as eating, activity, and social patterns, needs to be better understood.To assess the differences in biological rhythms in subjects with bipolar disorder, major depressive disorder, and healthy controls. We also tested the association between disruptions of biological rhythms and circadian preferences.	A cross-sectional, population-based study with a representative sample of 1023 young adults. Bipolar disorder and depression were diagnosed using The Mini International Neuropsychiatric Interview - PLUS and DSM Structured Clinical Interview. Self-reported biological rhythms and circadian preference were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN).	Bipolar disorders and depression subjects presented higher rates of disruption in biological rhythms when compared to healthy controls even after adjusting for sex, socioeconomic status, alcohol, tobacco, illicit drug use, anxiety disorder and psychotropic medication use. Euthymic subjects showed higher biological rhythm disruption when compared to controls. Higher disruption in biological rhythms was observed in subjects with evening preferences.	Higher disruption in biological rhythms occurs in individuals with depression and bipolar disorder even on periods of euthymia.	
27715334	The study investigates the distribution of chronotypes among alcohol-dependent subjects and the relationship between personality and chronotype. Fifty-eight alcohol-dependent patients and 29 age-matched healthy controls were studied using Ogińska's Chronotype Questionnaire (ChQ), Eysenck's Personality Questionnaire - Revised (EPQ-R), Selzer's Michigan Alcoholism Screening Test (MAST) and a sociodemographic status questionnaire designed by the authors. The alcohol-dependent patients tended to be morning type, based on the morningness-eveningness ChQ scale, with a weakly marked rhythm, based on the distinctness ChQ scale. Preference towards morningness was associated with older age, but no relation between chronotype and severity of alcohol dependence was found. A high amplitude of the rhythm was associated with higher neuroticism. Therefore, despite being in the minority, patients with a distinct circadian rhythm (i.e. with a high amplitude) are at greater risk of mood and anxiety disorders and hence should be given special consideration.
27715321	Night work is associated with a large range of acute health problems and possibly also health consequences in the long run. Yet, only very few field studies specifically investigate the effects of consecutive night shift on key physiological regulatory systems. In this field study, we investigated the effects of consecutive night shifts on three hormones, melatonin, cortisol, and testosterone, among police officers at work. More specifically, the aim was to investigate how the diurnal rhythms of melatonin, cortisol, and testosterone responded to two, four, and seven consecutive night shifts and a corresponding number of days for recovery. The study was part of the "In the Middle of the Night" project and included 73 male police officers from five different police districts. The participants were exposed to three intervention conditions: "2+2": two consecutive night shifts followed by two consecutive day recovery days; "4+4": four consecutive night shifts followed by four consecutive recovery days; "7+7": seven consecutive night shifts followed by seven consecutive recovery days. On the last day with night shift and the last recovery day in each intervention, the participants collected saliva samples every 4th hour when awake. The diurnal rhythms of melatonin, cortisol, and testosterone were all affected differently by an increasing number of consecutive night shifts: the amplitude of the melatonin rhythm was suppressed by 4.9% per day (95% CI 1.4-8.2% per day; p = 0.006). The diurnal rhythm of cortisol phase was delayed with an increasing number of night shifts by 33 min/day (95% CI 18-48 min per day; p ≤ 0.001), but did not show any changes in amplitude. For the diurnal rhythm of testosterone, there was no effect of the number of consecutive night shifts and the diurnal rhythm completely followed the sleep/wake cycle. We found that there were no differences in the rhythms of melatonin, cortisol, and testosterone after 2, 4, and 7 recovery days, respectively. In conclusion, we found signs of desynchronization in terms of suppressed amplitude of melatonin and phase delay of salivary cortisol as a consequence of the increasing number of consecutive night shifts among police officers at work. Lack of synchronization has been suggested as a possible mechanism linking night work to disease, but this remains to be determined.
27715142	The aim of this study was to gain a comprehensive insight into the use of night-time compression in the management of lymphoedema in patients who had been suffering from chronic lymphoedema for over 12 months. Data were collected and analysed from 94 patients, across five countries. Understanding user characteristics provided insight and understanding into how night-time compression regimens were initiated, products were used and benefits to the patient were reported. In addition to gaining an insight into user habits and night-time compression benefits, unmet needs were also identified. Positive outcomes from the use of night-time compression were reported, with all patients identifying benefits of using night-time compression. An increase in swelling was documented in 89% of all patients in this study group when night-time compression was not used. The study provided an opportunity to explore how lymphoedema affects patients, and how night-time compression can form part of a beneficial regime.
27712958	T cells have dramatic functional and proliferative shifts in the course of maintaining immune protection from pathogens and cancer. To support these changes, T cells undergo metabolic reprogramming upon stimulation and again after antigen clearance. Depending on the extrinsic cell signals, T cells can differentiate into functionally distinct subsets that utilize and require diverse metabolic programs. Effector T cells (Teff) enhance glucose and glutamine uptake, whereas regulatory T cells (Treg) do not rely on significant rates of glycolysis. The dependence of these subsets on specific metabolic programs makes T cells reliant on these signaling pathways and nutrients. Metabolic pathways, such as those regulated by mTOR and Myc, augment T cell glycolysis and glutaminolysis programs to promote T cell activity. These pathways respond to signals and control metabolism through both transcriptional or post-transcriptional mechanisms. Epigenetic modifications also play an important role by stabilizing the transcription factors that define subset specific reprogramming. In addition, circadian rhythm cycling may also influence energy use, immune surveillance, and function of T cells. In this review, we focus on the metabolic and nutrient requirements of T cells, and how canonical pathways of growth and metabolism regulate nutrients that are essential for T cell function.
27712846	The consequences of exposure to particulate matter (PM) have been thoroughly investigated in humans and other model species, but there is a dearth of studies of the effects of PM on physiology and life-history traits of non-human organisms living in natural or semi-natural environments. Besides toxicological relevance, PM has been recently suggested to exert epigenetic effects by altering DNA methylation patterns. Here, we investigated for the first time the association between the exposure to free-air PM10 and DNA methylation at two loci ('poly-Q exon' and '5'-UTR') of the Clock gene in blood cells of the nestlings of a synanthropic passerine bird, the barn swallow (Hirundo rustica). The Clock gene is a phylogenetically highly conserved gene playing a major role in governing circadian rhythms and circannual life cycles of animals, implying that change in its level of methylation can impact on important fitness traits. We found that methylation at both loci significantly increased with PM10 levels recorded few days before blood sampling, and also with PM10 exposure experienced by the mother during or shortly before egg laying. This study is the first where methylation at a functionally important gene has been shown to vary according to the concentration of anthropogenic pollutants in any animal species in the wild. Since early-life environmental conditions produce epigenetic effects that can transgenerationally be transmitted, DNA methylation of genes controlling photoperiodic response can have far reaching consequences for the ecology and the evolution of wild animal populations.
27712099	Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.
27709392	Circadian peculiarities of HR regulation and functional capacities of the heart in WAG/Rij rats with genetically determined absence epilepsy are related to spike-wave activity of the brain. The number of spike-wave discharges (SWD) is maximum at night, early morning, and evening time and decreases to minimum at 08.00-16.00. At night, functional capacities of the heart are reduced and stress test at night induces ischemic changes in the myocardium at a lower functional load than in the daytime (low level of SWD activity). The decrease in the number of SWD and spike-wave index during the daytime contributes to the central mechanisms of autonomic regulation of the heart. However, these capacities are reduced against the background of increased seizure activity during nighttime.
27708309	Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep. The ability to initiate and terminate sleep on command will also help us to elucidate its functions within and beyond the brain.
27708112	Circadian clocks keep organisms in synchrony with external day-night cycles. The free running period (FRP) of the clock, however, is usually only close to-not exactly-24 h. Here, we explored the geographical variation in the FRP of the linden bug, Pyrrhocoris apterus, in 59 field-lines originating from a wide variety of localities representing geographically different environments. We have identified a remarkable range in the FRPs between field-lines, with the fastest clock at ~21 h and the slowest close to 28 h, a range comparable to the collections of clock mutants in model organisms. Similarly, field-lines differed in the percentage of rhythmic individuals, with a minimum of 13.8% and a maximum of 86.8%. Although the FRP correlates with the latitude and perhaps with the altitude of the locality, the actual function of this FRP diversity is currently unclear. With the recent technological progress of massive parallel sequencing and genome editing, we can expect remarkable progress in elucidating the genetic basis of similar geographic variants in P. apterus or in similar emerging model species of chronobiology.
27707754	Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept.Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain.	In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters.	Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes.	
27706126	RORγt is a nuclear hormone receptor that has followed an exponential success carrier. Its modest origins as an orphan receptor cloned from human pancreas blossomed within 15 years into a critical regulator of anti-microbial immunity and a major target in the fight against inflammatory pathologies. Here, I review its role as a transcription factor required for the generation of type 3 lymphoid cells, which induce the development of lymphoid tissues, provide resistance of epithelial stem cells to injury, maintain homeostasis with the symbiotic microbiota, orchestrate defense against extracellular microbes, and regulate allergic responses. RORγt is also an intriguing molecule that is regulated by the circadian rhythm and includes cholesterol metabolites as ligands. RORγt therefore links anti-microbial immunity with circadian rhythms and steroids, the logic of which remains to be understood.
27706103	SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is marketed in illicit products. Therefore, the aim was to identify potential diagnostic metabolites via in vitro metabolic studies to ensure effective (doping) control. The presence of SR9009 could be demonstrated in a black market product purchased over the Internet. Via human liver microsomal metabolic assays, eight metabolites were detected for SR9009 and fourteen metabolites for SR9011 by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Structure elucidation was performed for all metabolites by LC-HRMS product ion scans in both positive and negative ionization mode. Retrospective data analysis was applied to 1511 doping control samples previously analyzed by a full-scan LC-HRMS screening method to verify the presence of SR9009, SR9011 and their metabolites. So far, the presence of neither the parent compound nor the metabolites could be detected in routine urine samples. However, to further discourage use of these potentially harmful compounds, incorporation of SR9009 and SR9011 into screening methods is highly recommended.
27704948	Circadian rhythms synchronize physiological processes with the light-dark cycle and are regulated by a hierarchical system initiated in the suprachiasmatic nucleus, a hypothalamic region that receives direct photic input. The suprachiasmatic nucleus then entrains additional oscillators in the periphery. Circadian rhythms are maintained by a molecular transcriptional feedback loop, of which brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a key member. Disruption of circadian rhythms by deletion of the BMAL1 gene (Bmal1 knockout [KO]) induces a variety of disease states, including infertility in males, due to unidentified mechanisms. We find that, despite normal sperm function, Bmal1 KO males fail to mate with receptive females, indicating a behavioral defect. Mating is dependent on pheromone detection, as are several other behaviors. We determined that Bmal1 KO males also fail to display aggression and avoidance of predator scent, despite intact main olfactory function. Moreover, the vomeronasal organ, a specialized pheromone-responsive organ, was also functionally intact, as determined by calcium imaging in response to urine pheromone stimulus. However, neural circuit tracing using c-FOS activation revealed that, although Bmal1 KO males displayed appropriate activation in the olfactory bulb and accessory olfactory bulb, the bed nucleus of the stria terminalis and the medial preoptic area (areas responsible for integration of copulatory behaviors) failed to activate highly in response to the female scent. This indicates that neural signaling in select behavioral centers is impaired in the absence of BMAL1, likely underlying Bmal1 KO male copulatory defects, demonstrating the importance of the BMAL1 protein in the maintenance of neural circuits that drive pheromone-mediated mating behaviors.
27703451	Phosphorus (P) is a limiting macronutrient for diatom growth and productivity in the ocean. Much effort has been devoted to the physiological response of marine diatoms to ambient P change, however, the whole-genome molecular mechanisms are poorly understood. Here, we utilized RNA-Seq to compare the global gene expression patterns of a marine diatom Skeletonema costatum grown in inorganic P-replete, P-deficient, and inorganic- and organic-P resupplied conditions. In total 34,942 unique genes were assembled and 20.8% of them altered significantly in abundance under different P conditions. Genes encoding key enzymes/proteins involved in P utilization, nucleotide metabolism, photosynthesis, glycolysis, and cell cycle regulation were significantly up-regulated in P-deficient cells. Genes participating in circadian rhythm regulation, such as circadian clock associated 1, were also up-regulated in P-deficient cells. The response of S. costatum to ambient P deficiency shows several similarities to the well-described responses of other marine diatom species, but also has its unique features. S. costatum has evolved the ability to re-program its circadian clock and intracellular biological processes in response to ambient P deficiency. This study provides new insights into the adaptive mechanisms to ambient P deficiency in marine diatoms.
27703199	The peripheral circadian clock is entrained by factors in the external environment such as scheduled feeding, exercise, and mental and physical stresses. In addition, recent studies in mice demonstrated that some food components have the potential to control the peripheral circadian clock during scheduled feeding, although information about these components remains limited. l-Ornithine is a type of non-protein amino acid that is present in foods and has been reported to have various physiological functions. In human trials, for example, l-ornithine intake improved a subjective index of sleep quality. Here we demonstrate, using an in vivo monitoring system, that repeated oral administration of l-ornithine at an early inactive period in mice induced a phase advance in the rhythm of PER2 expression. By contrast, l-ornithine administration to mouse embryonic fibroblasts did not affect the expression of PER2, indicating that l-ornithine indirectly alters the phase of PER2. l-Ornithine also increased plasma levels of insulin, glucose and glucagon-like peptide-1 alongside mPer2 expression, suggesting that it exerts its effects probably via insulin secretion. Collectively, these findings demonstrate that l-ornithine affects peripheral clock gene expression and may expand the possibilities of L-ornithine as a health food.
27703142	Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD.
27702781	The daily timing of mammalian physiology is coordinated by circadian clocks throughout the body. Although measurements of clock gene expression indicate that these clocks in mice are normally in phase with each other, the situation in humans remains unclear. We used publicly available data from five studies, comprising over 1000 samples, to compare the phasing of circadian gene expression in human brain and human blood. Surprisingly, after controlling for age, clock gene expression in brain was phase-delayed by ~8.5 h relative to that of blood. We then examined clock gene expression in two additional human organs and in organs from nine other mammalian species, as well as in the suprachiasmatic nucleus (SCN). In most tissues outside the SCN, the expression of clock gene orthologs showed a phase difference of ~12 h between diurnal and nocturnal species. The exception to this pattern was human brain, whose phasing resembled that of the SCN. Our results highlight the value of a multi-tissue, multi-species meta-analysis, and have implications for our understanding of the human circadian system.
27701007	Sleep and circadian rhythms studies have recently benefited from metabolomics analyses, uncovering new connections between chronobiology and metabolism. From untargeted mass spectrometry to quantitative nuclear magnetic resonance spectroscopy, a diversity of analytical approaches has been applied for biomarker discovery in the field. In this review we consider advances in the application of metabolomics technologies which have uncovered significant effects of sleep and circadian cycles on several metabolites, namely phosphatidylcholine species, medium-chain carnitines, and aromatic amino acids. Study design and data processing measures essential for detecting rhythmicity in metabolomics data are also discussed. Future developments in these technologies are anticipated vis-à-vis validating early findings, given metabolomics has only recently entered the ring with other systems biology assessments in chronometabolism studies.
27699411	Zebrafish neurons regenerate from Müller glia following retinal lesions. Genes and signaling pathways important for retinal regeneration in zebrafish have been described, but our understanding of how Müller glial stem cell properties are regulated is incomplete. Mammalian Müller glia possess a latent neurogenic capacity that might be enhanced in regenerative therapies to treat degenerative retinal diseases.To identify transcriptional changes associated with stem cell properties in zebrafish Müller glia, we performed a comparative transcriptome analysis from isolated cells at 8 and 16 hours following an acute photic lesion, prior to the asymmetric division that produces retinal progenitors.	We report a rapid, dynamic response of zebrafish Müller glia, characterized by activation of pathways related to stress, nuclear factor-κB (NF-κB) signaling, cytokine signaling, immunity, prostaglandin metabolism, circadian rhythm, and pluripotency, and an initial repression of Wnt signaling. When we compared publicly available transcriptomes of isolated mouse Müller glia from two retinal degeneration models, we found that mouse Müller glia showed evidence of oxidative stress, variable responses associated with immune regulation, and repression of pathways associated with pluripotency, development, and proliferation.	Categories of biological processes/pathways activated following photoreceptor loss in regeneration-competent zebrafish Müller glia, which distinguished them from mouse Müller glia in retinal degeneration models, included cytokine signaling (notably NF-κB), prostaglandin E2 synthesis, expression of core clock genes, and pathways/metabolic states associated with pluripotency. These regulatory mechanisms are relatively unexplored as potential mediators of stem cell properties likely to be important in Müller glial cells for successful retinal regeneration.	
27698681	Pain and anxiety are the most common neurological responses to many harmful or noxious stimuli and their management clinically is often challenging. Many of the frequently used morphine-based drugs, non-steroid anti-inflammatory drugs and acetaminophen, while efficient for treating pain, lead to patients suffering from several unwanted side effects. Melatonin, produced from the pineal body is a hormone of darkness, is involved in the control of circadian rhythms, and exerts a number of pharmacological effects. Melatonin mediates its actions through MT1/MT2 melatonin receptors on the cell membrane and also through RZR/ROR nuclear orphan receptors. Chronic pain syndromes are often associated with the desynchronization of circadian and biological rhythms, which also cause disturbances in the sleep-wake cycle. Melatonin-mediated analgesic effects seem to involve β-endorphins, GABA receptor, opioid receptors and the nitric oxide-arginine pathway. The effectiveness of melatonin as an analgesic and anxiolytic agent has been demonstrated in various animal models of pain and this led to the use of melatonin clinically in different pathological conditions and also in patients undergoing surgery. Melatonin was found to be effective in many of these cases as an anxiolytic and analgesic agent, indicating its clinical application.
27698436	Synchronization of biological rhythms to the 24-hour day/night has long been studied with model organisms, under artificial light/dark cycles in the laboratory. The commonly used rectangular light/dark cycles, comprising hours of continuous light and darkness, may not be representative of the natural light exposure for most species, including humans. Subterranean rodents live in dark underground tunnels and offer a unique opportunity to investigate extreme mechanisms of photic entrainment in the wild. Here, we show automated field recordings of the daily light exposure patterns in a South American subterranean rodent, the tuco-tuco (Ctenomys aff. knighti ). In the laboratory, we exposed tuco-tucos to a simplified version of this natural light exposure pattern, to determine the minimum light timing information that is necessary for synchronization. As predicted from our previous studies using mathematical modeling, the activity rhythm of tuco-tucos synchronized to this mostly simplified light/dark regimen consisting of a single light pulse per day, occurring at randomly scattered times within a day length interval. Our integrated semi-natural, lab and computer simulation findings indicate that photic entrainment of circadian oscillators is robust, even in face of artificially reduced exposure and increased phase instability of the synchronizing stimuli.
27697884	One feature of the mammalian circadian clock, situated in the suprachiasmatic nucleus (SCN), is its ability to measure day length and thereby contribute to the seasonal adaptation of physiology and behavior. The timing signal from the SCN, namely the 24 hr pattern of electrical activity, is adjusted according to the photoperiod being broader in long days and narrower in short days. Vasoactive intestinal peptide and gamma-aminobutyric acid play a crucial role in intercellular communication within the SCN and contribute to the seasonal changes in phase distribution. However, little is known about the underlying ionic mechanisms of synchronization. The present study was aimed to identify cellular mechanisms involved in seasonal encoding by the SCN. Mice were adapted to long-day (light-dark 16:8) and short-day (light-dark 8:16) photoperiods and membrane properties as well as K+ currents activity of SCN neurons were measured using patch-clamp recordings in acute slices. Remarkably, we found evidence for a photoperiodic effect on the fast delayed rectifier K+ current, that is, the circadian modulation of this ion channel's activation reversed in long days resulting in 50% higher peak values during the night compared with the unaltered day values. Consistent with fast delayed rectifier enhancement, duration of action potentials during the night was shortened and afterhyperpolarization potentials increased in amplitude and duration. The slow delayed rectifier, transient K+ currents, and membrane excitability were not affected by photoperiod. We conclude that photoperiod can change intrinsic ion channel properties of the SCN neurons, which may influence cellular communication and contribute to photoperiodic phase adjustment.
27697139	The hormone, melatonin is produced with circadian rhythm by the pineal gland in humans. The melatonin rhythm provides an endogenous synchronizer, modulating e.g. blood pressure, body temperature, cortisol rhythm, sleep-awake-cycle, immune function and anti-oxidative defence. Interestingly, a number of experimental animal studies demonstrate significant dose-dependent anti-nociceptive effects of exogenous melatonin. Similarly, recent experimental- and clinical studies in humans indicate significant analgesic effects. In study I, we systematically reviewed all randomized studies investigating clinical effects of perioperative melatonin. Meta-analyses demonstrated significant analgesic and anxiolytic effects of melatonin in surgical patients, equating reductions of 20 mm and 19 mm, respectively on a VAS, compared with placebo. Profound heterogeneity between the included studies was, however, present. In study II, we aimed to investigate the analgesic, anti-hyperalgesic and anti-inflammatory effects of exogenous melatonin in a validated human inflammatory pain model, the human burn model. The study was performed as a randomized, double blind placebo-controlled crossover study. Primary outcomes were pain during the burn injury and areas of secondary hyperalgesia. No significant effects of exogenous melatonin were observed with respect to primary or secondary outcomes, compared to placebo. Study III and IV estimated the pharmacokinetic variables of exogenous melatonin. Oral melatonin demonstrated a tmax value of 41 minutes. Bioavailability of oral melatonin was only 3%. Elimination t1/2 were approximately 45 minutes following both oral and intravenous administration, respectively. High-dose intravenous melatonin was not associated with increased sedation, in terms of simple reaction times, compared to placebo. Similarly, no other adverse effects were reported. In Study V, we aimed to re-analyse data obtained from a randomized analgesic drug trial by a selection of standard statistical test. Furthermore, we presented an integrated assessment method of longitudinally measured pain intensity and opioid consumption. Our analyses documented that the employed statistical method impacted the statistical significance of post-operative analgesic outcomes. Furthermore, the novel integrated assessment method combines two interdependent outcomes, lowers the risk of type 2 errors, increases the statistical power, and provides a more accurate description of post-operative analgesic efficacy. Exogenous melatonin may offer an effective and safe analgesic drug. At this moment, however, the results of human studies have been contradictory. High-quality randomized experimental- and clinical studies are still needed to establish a "genuine" analgesic effect of the drug in humans. Other perioperative effects of exogenous melatonin should also be investigated, before melatonin can be introduced for clinical routine use in surgical patients. Despite promising experimental and clinical findings, several unanswered questions also relate to optimal dosage, timing of administration and administration route of exogenous melatonin.
27695372	Shift work is considered necessary to ensure continuity of care in hospitals and residential facilities. In particular, the night shift is one of the most frequent reasons for the disruption of circadian rhythms, causing significant alterations of sleep and biological functions that can affect physical and psychological well-being and negatively impact work performance.The aim of this study was to highlight if shift work with nights, as compared with day work only, is associated with risk factors predisposing nurses to poorer health conditions and lower job satisfaction.	This cross-sectional study was conducted from June 1, 2015 to July 31, 2015 in 17 wards of a general hospital and a residential facility of a northern Italian city. This study involved 213 nurses working in rotating night shifts and 65 in day shifts. The instrument used for data collection was the "Standard Shift Work Index," validated in Italian. Data were statistically analyzed.	The response rate was 86%. The nurses engaged in rotating night shifts were statistically significantly younger, more frequently single, and had Bachelors and Masters degrees in nursing. They reported the lowest mean score in the items of job satisfaction, quality and quantity of sleep, with more frequent chronic fatigue, psychological, and cardiovascular symptoms in comparison with the day shift workers, in a statistically significant way.	Our results suggest that nurses with rotating night schedule need special attention due to the higher risk for both job dissatisfaction and undesirable health effects.	
27692050	To examine the prevalence of circadian misalignment in clinically diagnosed DSPD, and compare mood and daytime functioning in those with and without a circadian basis for the disorder.182 DSPD patients aged 16 to 64 years, engaged in regular employment or school, underwent sleep-wake monitoring in the home, followed by a sleep laboratory visit for assessment of salivary dim light melatonin onset (DLMO). Based on the DLMO assessments, patients were classified into two groups: circadian DSPD, defined as DLMO occurring at or after desired bedtime, or non-circadian DSPD, defined as DLMO occurring before desired bedtime.	103 patients (57%) were classified as circadian DSPD and 79 (43%) as non-circadian DSPD. DLMO occurred 1.66 h later in circadian DSPD compared to non-circadian DSPD (p<0.001). Moderate-severe depressive symptoms (Beck Depression Inventory-II) were more prevalent in circadian DSPD (14.0%) than in non-circadian DSPD (3.8%; p<0.05). Relative to non-circadian DSPD patients, circadian DSPD patients had 4.31 times increased odds of at least mild depressive symptoms (95% CI 1.75 to 10.64, p<0.01). No group differences were found for daytime sleepiness or function, but DSPD symptoms were rated by clinicians to be more severe in those with circadian DSPD.	Almost half of patients clinically diagnosed with DSPD did not show misalignment between the circadian pacemaker and the desired bedtime, suggesting that the reported difficulties initiating sleep at the desired bedtime are unlikely to be explained by the (mis)timing of the circadian rhythm of sleep propensity. Circadian misalignment in DSPD is associated with increased depressive symptoms and DSPD symptom severity.	
27692049	Firefighters' schedules include extended shifts and long work weeks which cause sleep deficiency and circadian rhythm disruption. Many firefighters also suffer from undiagnosed sleep disorders, exacerbating fatigue. We tested the hypothesis that a workplace-based Sleep Health Program (SHP) incorporating sleep health education and sleep disorders screening would improve firefighter health and safety compared to standard practice.Prospective station-level randomized, field-based intervention.	US fire department.	1,189 firefighters.	Sleep health education, questionnaire-based sleep disorders screening and sleep clinic referrals for respondents who screened positive for a sleep disorder.	Firefighters were randomized by station. Using departmental records, in an intention-to-treat analysis, firefighters assigned to intervention stations which participated in education sessions and had the opportunity to complete sleep disorders screening reported 46% fewer disability days than those assigned to control stations (1.4±5.9 versus 2.6±8.5 days/firefighter, respectively; p=0.003). There were no significant differences in departmental injury or motor vehicle crash rates between the groups. In post-hoc analysis accounting for intervention exposure, firefighters who attended education sessions were 24% less likely to file at least one injury report during the study than those who did not attend, regardless of randomization [OR(95%CI) 0.76 (0.60,0.98); χ2=4.56; p=0.033]. There were no significant changes pre- versus post-study in self-reported sleep or sleepiness in those who participated in the intervention.	A firefighter workplace-based SHP providing sleep health education and sleep disorders screening opportunity can reduce injuries and work loss due to disability in firefighters.	
27689221	Circadian timekeeping is a ubiquitous mechanism that enables organisms to maintain temporal coordination between internal biological processes and time of the local environment. The molecular basis of circadian rhythms lies in a set of transcription-translation feedback loops (TTFLs) that drives the rhythmic transcription of core clock genes, whose level and phase of expression serve as the marker of circadian time. However, it has become increasingly evident that additional regulatory mechanisms impinge upon the TTFLs to govern the properties and behavior of the circadian clock. Such mechanisms include changes in chromatin architecture, interactions with other transcription factor networks, post-transcriptional control by RNA modifications, alternative splicing and microRNAs, and post-translational regulation of subcellular trafficking and protein degradation. In this review, we will summarize the current knowledge of circadian clock regulation-from transcriptional to post-translational-drawing from literature pertaining to the Drosophila and murine circadian systems.
27686624	Learning and memory depend on the time of day in various organisms, but it is not clear whether and how the circadian clock regulates memory performance. Here we show that consolidation of long-term recognition memory is a circadian-regulated process, which is blunted by disruption of the hippocampal clock. We focused on SCOP, a key molecule regulating hippocampus-dependent long-term memory for objects. The amounts of SCOP and its binding partner K-Ras in the hippocampal membrane rafts exhibit robust circadian changes, and SCOP knockdown in the hippocampal CA1 impairs long-term memory at night. Circadian changes in stimulus-dependent activation of ERK in the hippocampal neurons are dependent on the SCOP levels in the membrane rafts, while Scop knockout abrogates the activation rhythm. We conclude that long-term memory formation is regulated by the circadian clock through SCOP dynamics in the membrane rafts of the hippocampal CA1.
27686062	Preclinical Research Circadian rhythms are fundamental processes in all cells that coordinate a variety of cellular functions related to a specific time of the day. Disruption of circadian rhythms markedly impacts homeostasis. In this Commentary, we present data that disruption of circadian rhythm may lead to the pathogenesis of neurodegenerative states. In this context, we further argue that there is an urgent need of developing new generations of compounds, chronobiotics, to modulate the molecular substrates of circadian timing system. Chronobiotics conceptually offer an effective way for restoration and protection from the consequences of the circadian disruption. We also briefly discuss whether dysfunctional circadian rhythms are a major driver of aging. Drug Dev Res 77 : 469-473, 2016. © 2016 Wiley Periodicals, Inc.
27686043	Salivary cortisol is considered to be a safe and noninvasive measure of hypothalamic-pituitary-adrenal axis functioning, and is a commonly measured biomarker of the human stress response in pediatric research. However, cortisol is highly variable and sensitive to a wide range of factors, creating a challenge for reliable salivary cortisol collection in the community setting. Furthermore, the acceptability of salivary cortisol collection in community samples of children is largely unknown. The purpose of this integrative review was to investigate current evidence on the acceptability and feasibility of salivary cortisol collection in community samples of children. In an analysis framed by the Theory of Planned Behavior, data extracted from 31 studies revealed six categories of psychosocial influences on acceptability and feasibility: uncertainty and misconceptions, cultural and ethnic values, family rules and values, difficulty following protocols and procedures, burden of multiple samples, and child refusal or resistance. Further research is required to fully understand the factors that influence acceptability and feasibility of salivary cortisol collection in community samples of children. Understanding individual, family, and community perceptions of biobehavioral research will lead to more culturally sensitive and feasible community-based research methods. © 2016 Wiley Periodicals, Inc.
27684732	Diurnal primates typically give birth at night, when it is presumed that they are safer at a very vulnerable time, and this is reflected in an overwhelmingly nocturnal pattern of delivery in most species of Callitrichidae. However, over half (51.1%) of 88 births to pied tamarins (Saguinus bicolor) at Durrell Wildlife Park occurred during the day (0800-1700), almost always in the afternoon. Nearly three quarters of breeding females (17/23) had at least one diurnal birth, including females from all generations in captivity from wild-caught to fifth captive-born generation, and from all six matrilines represented at Durrell. The proportion of diurnal births has remained relatively stable over time despite management changes. We used generalized linear mixed modeling to investigate several factors that we hypothesized could affect time of birth: maternal experience, season, female rearing history, and whether or not the group was on public display. We fitted all possible models to the data, but none explained more than 7.5% of the variation. Daytime delivery had few statistically significant detrimental effects, although infant survival was somewhat lower and parental rejection increased in diurnal births. Pied tamarins do not seem to fit any of the hypotheses previously put forward to explain exceptions to the typical primate circadian pattern of delivery. Zoo Biol. 35:487-494, 2016. © 2016 Wiley Periodicals, Inc.
27684315	The plant circadian clock allows the anticipation of daily changes to the environment. This anticipation aids the responses to temporally predictable biotic and abiotic stress. Conversely, disruption of circadian timekeeping severely compromises plant health and reduces agricultural crop yields. It is therefore imperative that we understand the intricate regulation of circadian rhythms in plants, including the factors that affect motion of the transcriptional clockwork itself. Testing circadian defects in the model plant Arabidopsis thaliana (Arabidopsis) traditionally involves crossing specific mutant lines to a line rhythmically expressing firefly luciferase from a circadian clock gene promoter. This approach is laborious, time-consuming, and could be fruitless if a mutant has no circadian phenotype. The methodology presented here allows a rapid initial assessment of circadian phenotypes. Protoplasts derived from mutant and wild-type Arabidopsis are isolated, transfected with a rhythmically expressed luminescent reporter, and imaged under constant light conditions for 5 days. Luminescent traces will directly reveal whether the free-running period of mutant plants is different from wild-type plants. The advantage of the method is that any Arabidopsis line can efficiently be screened, without the need for generating a stably transgenic luminescent clock marker line in that mutant background. 
27680947	Curcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells.We examined the circadian clock's impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric.	Circadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium.	We propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying the circadian phase of the cancer cells. We confirmed the greater stability of the curcumin congeners, suggesting that they may produce sustained toxicity in cancer cells and should be considered for use in patient care.	
27680940	Circadian rhythms have evolved to anticipate and adapt animals to the constraints of the earth's 24-hour light cycle. Although the molecular processes that establish periodicity in clock neurons of the suprachiasmatic nucleus (SCN) are well understood, the mechanisms by which axonal projections from the central clock drive behavioural rhythms are unknown. Here we show that the sleep period in mice (Zeitgeber time, ZT0-12) is preceded by an increase in water intake promoted entirely by the central clock, and not motivated by physiological need. Mice denied this surge experienced significant dehydration near the end of the sleep period, indicating that this water intake contributes to the maintenance of overnight hydromineral balance. Furthermore, this effect relies specifically on the activity of SCN vasopressin (VP) neurons that project to thirst neurons in the OVLT (organum vasculosum lamina terminalis), where VP is released as a neurotransmitter. SCN VP neurons become electrically active during the anticipatory period (ZT21.5-23.5), and depolarize and excite OVLT neurons through the activation of postsynaptic VP V1a receptors and downstream non-selective cation channels. Optogenetic induction of VP release before the anticipatory period (basal period; ZT19.5-21.5) excited OVLT neurons and prompted a surge in water intake. Conversely, optogenetic inhibition of VP release during the anticipatory period inhibited the firing of OVLT neurons and prevented the corresponding increase in water intake. Our findings reveal the existence of anticipatory thirst, and demonstrate this behaviour to be driven by excitatory peptidergic neurotransmission mediated by VP release from central clock neurons.
27680939	Networks of organic chemical reactions are important in life and probably played a central part in its origin. Network dynamics regulate cell division, circadian rhythms, nerve impulses and chemotaxis, and guide the development of organisms. Although out-of-equilibrium networks of chemical reactions have the potential to display emergent network dynamics such as spontaneous pattern formation, bistability and periodic oscillations, the principles that enable networks of organic reactions to develop complex behaviours are incompletely understood. Here we describe a network of biologically relevant organic reactions (amide formation, thiolate-thioester exchange, thiolate-disulfide interchange and conjugate addition) that displays bistability and oscillations in the concentrations of organic thiols and amides. Oscillations arise from the interaction between three subcomponents of the network: an autocatalytic cycle that generates thiols and amides from thioesters and dialkyl disulfides; a trigger that controls autocatalytic growth; and inhibitory processes that remove activating thiol species that are produced during the autocatalytic cycle. In contrast to previous studies that have demonstrated oscillations and bistability using highly evolved biomolecules (enzymes and DNA) or inorganic molecules of questionable biochemical relevance (for example, those used in Belousov-Zhabotinskii-type reactions), the organic molecules we use are relevant to metabolism and similar to those that might have existed on the early Earth. By using small organic molecules to build a network of organic reactions with autocatalytic, bistable and oscillatory behaviour, we identify principles that explain the ways in which dynamic networks relevant to life could have developed. Modifications of this network will clarify the influence of molecular structure on the dynamics of reaction networks, and may enable the design of biomimetic networks and of synthetic self-regulating and evolving chemical systems.
27680326	The circadian clock is set up around a 24-h period in humans who are awake in the daytime and sleep in the nighttime, accompanied with physiological and metabolic rhythms. Most haplorhine primates, including humans, are diurnal, while most "primitive" strepsirrhine primates are nocturnal, suggesting primates have evolved from nocturnal to diurnal habits. The mechanisms of physiological changes causing the habits and of genetic changes causing the physiological changes are, however, unknown. To reveal these mechanisms, we focus on the nucleotide sequences of the regulatory region of the PERIOD1 (PER1) gene that is known as one of the key elements of the circadian clock in mammalians.We determined nucleotide sequences of the regulatory region of PER1 concerning the gene expression for six primates and compared those with those of eight primates from the international DNA database. Based on the sequence data, we constructed a phylogenetic tree including both the diurnal/nocturnal species and investigated the guanine and cytosine (GC) content in the regulatory region.	The motif sequences regulating gene expression were evolutionary conservative in the primates examined. The phylogenetic tree simply showed phylogenetic relationship among the species and no branching pattern distinguishable between the diurnal and nocturnal groups. We found two cores showing a statistically significant difference between the diurnal and the nocturnal habits related to the GC contents of the regulatory region of PER1.	Our results suggest the possibility that the two cores in the upstream region of PER1 are related to the regulation of gene expression leading to behavioral differences between diurnal and nocturnal primates.	
27677675	Sleep-wake disturbances are frequently reported following traumatic brain injury (TBI), but they remain poorly documented in the acute stage of injury. Little is known about their origin and evolution.This study presents the case of a patient in the acute phase of a severe TBI. The patient was injured at work when falling 12 m into a mine and was hospitalized in the regular wards of a level I trauma centre. From days 31 to 45 post-injury, once he had reached a level of medical stability and continuous analgosedation had been ceased, his sleep-wake cycle was monitored using actigraphy. Results showed significant sleep-wake disturbances and severe sleep deprivation. Indeed, the patient had an average nighttime sleep efficiency of 32.7 ± 15.4 %, and only an average of 4.8 ± 1.3 h of sleep per 24-h period. After hospital discharge to the rehabilitation centre, where he remained for 5 days, the patient was readmitted to the same neurological unit for paranoid delusions. During his second hospital stay, actigraphy recordings resumed from days 69 to 75 post-injury. A major improvement in his sleep-wake cycle was observed during this second stay, with an average nighttime sleep efficiency of 96.3 ± 0.9 % and an average of 14.1 ± 0.9 h of sleep per 24-h period.	This study is the first to extensively document sleep-wake disturbances in both the acute and subacute phases of severe TBI. Results show that prolonged sleep deprivation can be observed after TBI, and suggest that the hospital environment only partially contributes to sleep-wake disturbances. Continuous actigraphic monitoring may prove to be a useful clinical tool in the monitoring of patients hospitalized after severe TBI in order to detect severe sleep deprivation requiring intervention. The direct impact of sleep-wake disturbances on physiological and cognitive recovery is not well understood within this population, but is worth investigating and improving.	
27676300	A new study utilizes transgenic mice to elucidate the coupling between cells of a neuronal pacemaker that determines circadian period. 
27671869	The salivary glands (mandibular epidermal glands) of adult males and females of Lithobius forficatus (Myriapoda, Chilopoda) were isolated during spring, summer and autumn. In addition, the organs were isolated at different times of the day - at about 12:00 (noon) and about 00:00 (midnight). The ultrastructure of these organs depending on seasonal and circadian rhythms was analyzed using transmission and scanning electron microscopy and histochemical methods. The paired salivary glands of L. forficatus are situated in the vicinity of the foregut and they are formed by numerous acini that are surrounded by the fat body, hemocytes and tracheolae. The salivary glands are composed of a terminal acinar component and a system of tubular ducts that are lined with a cuticle. The glandular part is composed of secretory epithelial cells that are at various stages of their secretory activity. The saliva that is produced by the secretory cells of the acini is secreted into the salivary ducts, which are lined with a simple epithelium that is based on the non-cellular basal lamina. The ultrastructural variations suggest that salivary glands function differently depending on seasonal rhythms and prepare the animal for overwintering. Therefore, the salivary glands of the centipedes that were analyzed participate in the accumulation of proteins, lipids and polysaccharides during the spring, summer and autumn. Subtle differences in the ultrastructure of the secretory cells of the salivary glands during the circadian cycle must be related to the physiological reactions of the organism. The salivary ducts showed no differences in the specimens that were analyzed during the day/night cycle or during the seasonal cycle.
27671790	Nonobese diabetic (NOD) mice are a model for type 1 diabetes that displays defects in central immune tolerance, including impairment of thymocyte apoptosis and proliferation. Thymocyte apoptosis is decreased in NOD/Lt mice compared to nondiabetic C3H/HeJ and C57BL/6 mice. Analysis of a set of NOD.C3H and NOD.B6 congenic mouse strains for distal chromosome 6 localizes the phenotype to the 700 kb Idd6.3 interval. Idd6.3 contains the type 1 diabetes candidate gene aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2), encoding a circadian rhythm-related transcription factor. Newly generated Arntl2 -/- mouse strains reveal that inactivation of the B6 allele of Arntl2 is sufficient to both decrease thymocyte apoptosis and proliferation. When expressed from C3H or B6 alleles, ARNTL2 inhibits the transcription of interleukin 21 (Il21), a major player in the regulation of immune responses. IL-21 injection abolishes the B6 allele-mediated decrease of apoptosis and proliferation. Interestingly, IL-21 also leads to an increase in thymic proinflammatory Th17 helper cells. Our results identify Arntl2 as a gene controlling thymocyte apoptosis and proliferation along with Th17 development through the IL-21 pathway.
27669996	Sleep complaints are very common in bipolar disorders (BD) both during acute phases (manic and depressive episodes) and remission (about 80 % of patients with remitted BD have poor sleep quality). Sleep complaints during remission are of particular importance since they are associated with more mood relapses and worse outcomes. In this context, this review discusses the characterization and treatment of sleep complaints in BD.We examined the international scientific literature in June 2016 and performed a literature search with PubMed electronic database using the following headings: "bipolar disorder" and ("sleep" or "insomnia" or "hypersomnia" or "circadian" or "apnoea" or "apnea" or "restless legs").	Patients with BD suffer from sleep and circadian rhythm abnormalities during major depressive episodes (insomnia or hypersomnia, nightmares, nocturnal and/or early awakenings, non-restorative sleep) and manic episodes (insomnia, decreased need for sleep without fatigue), but also some of these abnormalities may persist during remission. These remission phases are characterized by a reduced quality and quantity of sleep, with a longer sleep duration, increased sleep latency, a lengthening of the wake time after sleep onset (WASO), a decrease of sleep efficiency, and greater variability in sleep/wake rhythms. Patients also present frequent sleep comorbidities: chronic insomnia, sleepiness, sleep phase delay syndrome, obstructive sleep apnea/hypopnea syndrome (OSAHS), and restless legs syndrome (RLS). These disorders are insufficiently diagnosed and treated whereas they are associated with mood relapses, treatment resistance, affect cognitive global functioning, reduce the quality of life, and contribute to weight gain or metabolic syndrome. Sleep and circadian rhythm abnormalities have been also associated with suicidal behaviors. Therefore, a clinical exploration with characterization of these abnormalities and disorders is essential. This exploration should be helped by questionnaires and documented on sleep diaries or even actimetric objective measures. Explorations such as ventilatory polygraphy, polysomnography or a more comprehensive assessment in a sleep laboratory may be required to complete the diagnostic assessment. Treatments obviously depend on the cause identified through assessment procedures. Treatment of chronic insomnia is primarily based on non-drug techniques (by restructuring behavior and sleep patterns), on psychotherapy (cognitive behavioral therapy for insomnia [CBT-I]; relaxation; interpersonal and social rhythm therapy [IPSRT]; etc.), and if necessary with hypnotics during less than four weeks. Specific treatments are needed in phase delay syndrome, OSAHS, or other more rare sleep disorders.	BD are defined by several sleep and circadian rhythm abnormalities during all phases of the disorder. These abnormalities and disorders, especially during remitted phases, should be characterized and diagnosed to reduce mood relapses, treatment resistance and improve BD outcomes.	
27668547	Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock (PER1) and clock-controlled (vasopressin) proteins. To determine if these SCN changes are due to the metabolic or timing cues of the restricted feeding, mice were challenged with an ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost <10% body mass (i.e. isocaloric) displayed 1.5-h phase-advance of body temperature rhythm, but remained mostly nocturnal, together with up-regulated vasopressin and down-regulated PER1 and PER2 levels in the SCN. Hepatic expression of clock genes (Per2, Rev-erbα, and Clock) and Fgf21 was, respectively, phase-advanced and up-regulated by ultradian feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.
27668457	Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder which has been associated with sleep and circadian rhythm disturbances. Numerous studies have linked evening circadian typology with traits and behaviours associated with the disorder, although a precise reason for this relationship has not been clarified. The current study examines ADHD symptoms, impulsivity, cognitive failures, sleep quality and chronotype in a cohort of healthy young adults (N = 396). Results show significant, small magnitude associations between mid-point of sleep on free days, social jetlag (SJL) and ADHD symptoms and impulsivity, although not with cognitive failures. Similarly, sleep quality is also associated with ADHD symptoms and impulsivity. Group-wise approaches show that higher SJL is associated with significantly more ADHD symptoms and impulsivity, and later mid-sleep on free days is also associated with more ADHD symptoms. Stepwise multiple linear regression reveals that, when controlling for age and sex, SJL but not mid-sleep on free days is a significant predictor of ADHD symptoms and impulsivity. These results indicate that SJL may be an important factor to consider when exploring circadian rhythm associations with ADHD symptoms.
27667263	Jet lag is common place amongst long-haul cabin crew. Timed food has been shown to reset the circadian rhythm in rodents. Implementation intentions have been used to change eating behaviour. Mealtimes could therefore be used as a countermeasure to reduce jet lag and improve alertness in long-haul cabin crew through forming an implementation intention to improve the regularity of meals on days off.Sixty long-haul crew took part in a randomised controlled trial, with two conditions: forming an implementation intention to eat regular meals on days off vs. no implementation intention. Pre-intervention measurements were taken at baseline (before a long-haul trip) and post-intervention measures were taken on the first and second days off post-trip.	Subjective jet lag (unidimensional and multidimensional) and objective alertness (Psychomotor Vigilance Task (PVT)).	Mixed ANOVA showed a significant condition x time interaction for unidimensional jet lag but not for multidimensional jet lag and objective alertness. In particular, the formation of an implementation intention to alter mealtimes resulted in a reduction of unidimensional jet lag.	Implementation intentions can be used to alleviate jet lag in long-haul crew through promoting a change in mealtimes.	
27666972	The patterning of social acoustic signaling at multiple timescales, from day-night rhythms to acoustic temporal properties, enhances sender-receiver coupling and reproductive success [1-8]. In diurnal birds, the nocturnal production of melatonin, considered the major vertebrate timekeeping hormone [9, 10], suppresses vocal activity but increases song syllable duration over circadian and millisecond timescales, respectively [11, 12]. Comparable studies are lacking for nocturnal vertebrates, including many teleost fish species that are also highly vocal during periods of reproduction [4, 13-20]. Utilizing continuous sound recordings, light cycle manipulations, hormone implants, and in situ hybridization, we demonstrate in a nocturnally breeding teleost fish that (1) courtship vocalization exhibits an endogenous circadian rhythm under constant dark conditions that is suppressed under constant light, (2) exogenous delivery of a melatonin analog under inhibitory constant light conditions rescues courtship vocal activity as well as the duration of single calls, and (3) melatonin receptor 1b is highly expressed in evolutionarily conserved neuroendocrine and vocal-acoustic networks crucial for patterning reproductive and vocal behaviors in fishes and tetrapods. Our findings, together with those in birds, show melatonin's remarkable versatility as a timing signal in distantly related lineages. It exerts opposing effects on vocalization in nocturnal versus diurnal species at the circadian timescale but comparable effects at the finer timescale of acoustic features. We propose that melatonin's separable effects at different timescales depends on its actions within distinct neural networks that control circadian rhythms, reproduction, and vocalization, which may be selected upon over evolutionary time as dissociable modules to pattern and coordinate social behaviors. VIDEO ABSTRACT.
27666286	Circadian rhythms are periodic patterns in biological processes that allow the organisms to anticipate changes in the environment. These rhythms are driven by the suprachiasmatic nucleus (SCN), the master circadian clock in vertebrates. At a molecular level, circadian rhythms are regulated by the so-called clock genes, which oscillate in a periodic manner. The protein products of clock genes are transcription factors that control their own and other genes' transcription, collectively known as "clock-controlled genes." Several brain regions other than the SCN express circadian rhythms of clock genes, including the amygdala, the olfactory bulb, the retina, and the cerebellum. Glia cells in these structures are expected to participate in rhythmicity. However, only certain types of glia cells may be called "glial clocks," since they express PER-based circadian oscillators, which depend of the SCN for their synchronization. This contribution summarizes the current information about clock genes in glia cells, their plausible role as oscillators and their medical implications.
27665709	The circadian system integrates environmental cues to regulate physiological functions in a temporal fashion. The suprachiasmatic nucleus, located in the hypothalamus, is the master clock that synchronizes central and peripheral organ clocks to orchestrate physiological functions. Recently, molecular clock machinery has been identified in the cochlea unravelling the potential involvement in the circadian regulation of auditory functions. Here, we present background information on the circadian system and review the recent findings that introduce circadian rhythms to the auditory field. Understanding the mechanisms by which circadian rhythms regulate auditory function will provide fundamental knowledge on the signalling networks that control vulnerability and resilience to auditory insults.
27664655	Melatonin is a neurohormone involved in the regulation of circadian rhythms in humans. Evidence has recently been found of its occurrence in wines and its role in the winemaking process. The yeast Saccharomyces cerevisiae is consequently thought to be important in Melatonin synthesis, but limited data and reference texts are available on this synthetic pathway. This paper aims to elucidate whether the synthetic pathway of Melatonin in Saccharomyces and non-Saccharomyces strains involves these intermediates. To this end, seven commercial strains comprising Saccharomyces cerevisiae (Red Fruit, ES488, Lalvin QA23, Uvaferm BC, and Lalvin ICV GRE) and non-Saccharomyces (Torulaspora delbrueckii and Metschnikowia pulcherrima) were monitored, under controlled fermentation conditions, in synthetic must, for seven days. Samples were analysed using a UHPLC-HRMS system (Qexactive). Five out of the seven strains formed Melatonin during the fermentation process: three S. cerevisiae strains and the two non-Saccharomyces. Additionally, other compounds derived from l-tryptophan occurred during fermentation. 
27664233	In mammals, rhythms in body temperature help to entrain and synchronize circadian rhythms throughout the organism, and the cold-inducible RNA-binding protein (CIRBP) is one of the mediators of these daily temperature changes. Cirbp mRNA expression is regulated by the daily subtle rhythms in body temperature, and a new study by Gotic and colleagues (pp. 2005-2017) reveals a surprising and novel mechanism that involves temperature-dependent enhancement of splicing efficiency. 
27662620	Arabidopsis thaliana is the most widely used model organism for research in plant biology. While significant advances in understanding plant growth and development have been made by focusing on the molecular genetics of Arabidopsis, extracting and understanding the functional framework of metabolism is challenging, both from a technical perspective due to losses and modification during extraction of metabolites from the leaves, and from the biological perspective, due to random variation obscuring how well the function is performed. The purpose of this work is to establish the in vivo metabolic profile directly from the Arabidopsis thaliana leaves without metabolite extraction, to reduce the complexity of the results by multivariate analysis, and to unravel the mitigation of cellular complexity by predominant functional periodicity. To achieve this, we use the circadian cycle that strongly influences metabolic and physiological processes and exerts control over the photosynthetic machinery. High resolution-magic angle spinning nuclear magnetic resonance (HR-MAS NMR) was applied to obtain the metabolic profile directly from intact Arabidopsis leaves. Combining one- and two-dimensional 1H HR-MAS NMR allowed the identification of several metabolites including sugars and amino acids in intact leaves. Multivariate analysis on HR-MAS NMR spectra of leaves throughout the circadian cycle revealed modules of primary metabolites with significant and consistent variations of their molecular components at different time points of the circadian cycle. Since robust photosynthetic performance in plants relies on the functional periodicity of the circadian rhythm, our results show that HR-MAS NMR promises to be an important non-invasive method that can be used for metabolomics of the Arabidopsis thaliana mutants with altered physiology and photosynthetic efficiency.
27662349	This study examined whether subjective measurements of in-flight sleep could be a reliable alternative to actigraphic measurements for monitoring pilot fatigue in a large-scale survey.Pilots (3-pilot crews) completed a 1-page survey on outbound and inbound long-haul flights crossing 1-7 time zones (N = 586 surveys) between 53 city pairs with 1-d layovers. Across each flight, pilots documented flight start and end times, break times, and in-flight sleep duration and quality if they attempted sleep. They also rated their fatigue (Samn-Perelli Crew Status Check) and sleepiness (Karolinska Sleepiness Scale) at top of descent (TOD). Mixed model ANCOVA was used to identify independent factors associated with sleep duration, quality, and TOD measures. Domicile time was used as a surrogate measure of circadian phase.	Sleep duration increased by 10.2 min for every 1-h increase in flight duration. Sleep duration and quality varied by break start time, with significantly more sleep obtained during breaks starting between (domicile) 22:00-01:59 and 02:00-05:59 compared to earlier breaks. Pilots were more fatigued and sleepy at TOD on flights arriving between 02:00-05:59 and 06:00-09:59 domicile time compared to other flights. With every 1-h increase in sleep duration, sleepiness ratings at TOD decreased by 0.6 points and fatigue ratings decreased by 0.4 points.	The present findings are consistent with previous actigraphic studies, suggesting that self-reported sleep duration is a reliable alternative to actigraphic sleep in this type of study, with use of validated measures, sufficiently large sample sizes, and where fatigue risk is expected to be low. van den Berg MJ, Wu LJ, Gander PH. Subjective measurements of in-flight sleep, circadian variation, and their relationship with fatigue. Aerosp Med Hum Perform. 2016; 87(10):869-875.	
27661417	Sleep and circadian abnormalities have been mostly demonstrated in bipolar patients. However, it is not clear whether these alterations are present in population at high risk for bipolar disorder (BD), indicating a possible risk factor for this condition.This systematic review aims to define current evidence about sleep and rhythm alterations in people at risk for BD and to evaluate sleep and circadian disorders as risk factor for BD.	The systematic review included all articles about the topic until February 2016. Two researchers performed an electronic search of PubMed and Cochrane Library. Keywords used were 'sleep' or 'rhythm' or 'circadian' AND 'bipolar disorder' or 'mania' or 'bipolar depression' AND 'high-risk' or 'risk'.	Thirty articles were analyzed (7451 participants at risk for BD). Sleep disturbances are frequent in studies using both subjective measures and actigraphy. High-risk individuals reported irregularity of sleep/wake times, poor sleep and circadian rhythm disruption. Poor sleep quality, nighttime awakenings, and inadequate sleep are possible predictive factors for BD. A unique study suggested that irregular rhythms increase risk of conversion. People at risk for BD showed high cortisol levels in different times of day. Studies about anatomopathology, melatonin levels, inflammatory cytokines and oxidative stress were not identified. The most important limitations were differences in sleep and rhythm measures, heterogeneity of study designs, and lack of consistency in the definition of population at risk.	Sleep and circadian disturbances are common in people at risk for BD. However, the pathophysiology of these alterations and the impact on BD onset are still unclear.	
27661138	Colonic function is controlled by an endogenous clock that allows the colon to optimize its function on the daytime basis. For the first time, this study provided evidence that the clock is synchronized by rhythmic hormonal signals. In rat colon, adrenalectomy decreased and repeated applications of dexamethasone selectively rescued circadian rhythm in the expression of the clock gene Per1. Dexamethasone entrained the colonic clock in explants from mPer2Luc mice in vitro. In contrast, pinealectomy had no effect on the rat colonic clock, and repeated melatonin injections were not able to rescue the clock in animals maintained in constant light. Additionally, melatonin did not entrain the clock in colonic explants from mPer2Luc mice in vitro. However, melatonin affected rhythmic regulation of Nr1d1 gene expression in vivo. The findings provide novel insight into possible beneficial effects of glucocorticoids in the treatment of digestive tract-related diseases, greatly exceeding their anti-inflammatory action.
27660641	Most biological functions are synchronized to the environmental light:dark cycle via a circadian timekeeping system. Bears exhibit shallow torpor combined with metabolic suppression during winter dormancy. We sought to confirm that free-running circadian rhythms of body temperature (Tb) and activity were expressed in torpid grizzly (brown) bears and that they were functionally responsive to environmental light. We also measured activity and ambient light exposures in denning wild bears to determine if rhythms were evident and what the photic conditions of their natural dens were. Lastly, we used cultured skin fibroblasts obtained from captive torpid bears to assess molecular clock operation in peripheral tissues. Circadian parameters were estimated using robust wavelet transforms and maximum entropy spectral analyses.Captive grizzly bears housed in constant darkness during winter dormancy expressed circadian rhythms of activity and Tb. The rhythm period of juvenile bears was significantly shorter than that of adult bears. However, the period of activity rhythms in adult captive bears was virtually identical to that of adult wild denning bears as was the strength of the activity rhythms. Similar to what has been found in other mammals, a single light exposure during the bear's active period delayed subsequent activity onsets whereas these were advanced when light was applied during the bear's inactive period. Lastly, in vitro studies confirmed the expression of molecular circadian rhythms with a period comparable to the bear's own behavioral rhythms.	Based on these findings we conclude that the circadian system is functional in torpid bears and their peripheral tissues even when housed in constant darkness, is responsive to phase-shifting effects of light, and therefore, is a normal facet of torpid bear physiology.	
27660402	The androgen receptor (AR) plays a key role in the development and progression of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out higher incidences of CaP in some select groups, such as airline pilots and night shift workers in comparison with those working regular hours. The common finding in these 'high-risk' groups was that they all experienced a deregulation of the body's internal circadian rhythm. Here, we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumour-suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT). In addition, a large-scale study found that high-dose radiation was more effective in CaP patients when it was delivered before 17:00 h, compared with those delivered after 17:00 h, suggesting that the therapy was more effective when delivered in synchrony with the patient's circadian clock. As CaP patients are shown to become easily resistant to new therapies, perhaps circadian delivery of these therapeutic agents or delivery in conjunction with melatonin and its novel analogs should be tested to see if they prevent this resistance.
27660201	In modern societies, the risk of developing a whole array of affective and somatic disorders is associated with the prevalence of frequent psychosocial stress. Therefore, a better understanding of adaptive stress responses and their underlying molecular mechanisms is of high clinical interest. In response to an acute stressor, each organism can either show passive freezing or active fight-or-flight behaviour, with activation of sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis providing the necessary energy for the latter by releasing catecholamines and glucocorticoids (GC). Recent data suggest that stress responses are also regulated by the endogenous circadian clock. In consequence, the timing of stress may critically affect adaptive responses to and/or pathological effects of repetitive stressor exposure. In this article, we characterize the impact of predictable social defeat stress during daytime versus nighttime on bodyweight development and HPA axis activity in mice. While 19 days of social daytime stress led to a transient reduction in bodyweight without altering HPA axis activity at the predicted time of stressor exposure, more detrimental effects were seen in anticipation of nighttime stress. Repeated nighttime stressor exposure led to alterations in food metabolization and reduced HPA axis activity with lower circulating adrenocorticotropic hormone (ACTH) and GC concentrations at the time of predicted stressor exposure. Our data reveal a circadian gating of stress adaptation to predictable social defeat stress at the level of the HPA axis with impact on metabolic homeostasis underpinning the importance of timing for the body's adaptability to repetitive stress.
27659262	The present study was aimed to identify how age-related changes in some physiological and biochemical systems are related to changes in the life span of rats with long-term pineal gland hypo- and hyperfunction induced by constant light and constant darkness, respectively.At the age of 25 days the rats were randomly divided into 3 groups: standard light/dark regimen (LD), constant light (LL) and constant darkness (DD). Age-related Antioxidant System (AOS) changes in liver tissues, alteration of immunoreactivity in blood smears were investigated, pubescence and lifespan of the animals were determined.	Modification of the level of melatonin synthesis induced by constant light results in interrelated rearrangements in the functioning of the investigated physiological systems. Elevated activity of the antioxidant system extends the lifespan, while at the same time slowing down pubescence and altering the morpho-functional properties of leukocytes in blood.	The absence of light/dark alternation (constant light and constant darkness) affects only those physiological indices that follow the organism's circadian rhythms (Activity of Antioxidant Enzymes (AOE), levels of individual immune system cell types), whereas changes in the parameters not governed by circadian fluctuations (vitamin concentrations, pubescence, and aging) depend on the level of melatonin produced by the pineal gland.	

27658441	Circadian rhythms are essential for health and are frequently disturbed in disease. A full understanding of the causal relationships between behavioural and molecular circadian rhythms requires simultaneous longitudinal observations over time in individual organisms. Current experimental paradigms require the measurement of each rhythm separately across distinct populations of experimental organisms, rendering the comparability of the resulting datasets uncertain. We therefore developed FLYGLOW, an assay using clock gene controlled luciferase expression detected by exquisitely sensitive EM-CCD imaging, to enable simultaneous quantification of parameters including locomotor, sleep consolidation and molecular rhythms in single flies over days/weeks. FLYGLOW combines all the strengths of existing techniques, and also allows powerful multiparametric paired statistics. We found the age-related transition from rhythmicity to arrhythmicity for each parameter occurs unpredictably, with some flies showing loss of one or more rhythms during middle-age. Using single-fly correlation analysis of rhythm robustness and period we demonstrated the independence of the peripheral clock from circadian behaviours in wild type flies as well as in an Alzheimer's model. FLYGLOW is a useful tool for investigating the deterioration of behavioural and molecular rhythms in ageing and neurodegeneration. This approach may be applied more broadly within behavioural neurogenetics research.
27657167	Many animals display morning and evening bimodal activities in the day/night cycle. However, little is known regarding the potential components involved in the regulation of bimodal behavioral rhythms in mammals. Here, we identified that the zinc finger protein gene Zbtb20 plays a crucial role in the regulation of bimodal activities in mice. Depletion of Zbtb20 in nerve system resulted in the loss of early evening activity, but the increase of morning activity. We found that Zbtb20-deficient mice exhibited a pronounced decrease in the expression of Prokr2 and resembled phenotypes of Prok2 and Prokr2-knockout mice. Injection of adeno-associated virus-double-floxed Prokr2 in suprachiasmatic nucleus could partly restore evening activity in Nestin-Cre; Zbtb20fl/fl (NS-ZB20KO) mice. Furthermore, loss of Zbtb20 in Foxg1 loci, but intact in the suprachiasmatic nucleus, was not responsible for the unimodal activity of NS-ZB20KO mice. Our study provides evidence that ZBTB20-mediated PROKR2 signaling is critical for the evening behavioral rhythms.
27656887	Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies.
27656401	A disturbed day-night rhythm is associated with metabolic perturbations that can lead to obesity and type 2 diabetes mellitus (T2DM). In skeletal muscle, a reduced oxidative capacity is also associated with the development of T2DM. However, whether oxidative capacity in skeletal muscle displays a day-night rhythm in humans has so far not been investigated.Lean, healthy subjects were enrolled in a standardized living protocol with regular meals, physical activity and sleep to reflect our everyday lifestyle. Mitochondrial oxidative capacity was examined in skeletal muscle biopsies taken at five time points within a 24-hour period.	Core-body temperature was lower during the early night, confirming a normal day-night rhythm. Skeletal muscle oxidative capacity demonstrated a robust day-night rhythm, with a significant time effect in ADP-stimulated respiration (state 3 MO, state 3 MOG and state 3 MOGS, p < 0.05). Respiration was lowest at 1 PM and highest at 11 PM (state 3 MOGS: 80.6 ± 4.0 vs. 95.8 ± 4.7 pmol/mg/s). Interestingly, the fluctuation in mitochondrial function was also observed in whole-body energy expenditure, with peak energy expenditure at 11 PM and lowest energy expenditure at 4 AM (p < 0.001). In addition, we demonstrate rhythmicity in mRNA expression of molecular clock genes in human skeletal muscle.	Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.	
27656270	Despite progress in research concerning adolescent and young adult sleep and circadian preferences, several aspects have remained unexamined. This study explored gender and diurnal rhythms in relation to several sleep-related factors: sleep duration, bedtime, wake-up time, tiredness, sleepiness, and optimal subjective sleep duration.Circadian preferences and sleep were investigated in 555 (Females N=247) Finnish students aged 15-20. The self-report measures included a shortened version of the Horne-Östberg Morningness-Eveningness Scale, the Epworth Sleepiness Scale as well as items probing feelings of tiredness, optimal subjective sleep durations, and bedtime and wake-up time on the most recent day and a typical weekend. Data were collected from Tuesday to Thursday during an ordinary school week.	The most frequent chronotype was the intermediate type (54%), and compared to previous studies, the prevalence of evening-oriented individuals was high (37%), whereas only 9% of the participants were classified as morning oriented. No gender-specific or chronotype-specific differences in sleep durations were observed, but girls/women and evening-orientated individuals reported suffering more from sleepiness, compared to boys/men and more morning-typed participants, respectively. About 20% of the total sample indicated that their subjective need for sleep was not satisfied during the weekdays nor the weekend, indicating chronic sleep deprivation. Among girls/women and evening-oriented individuals, the subjective sleep need was greater for weekday nights.	

27655315	Rice flowering regulation is an extremely complex process, which is controlled by genetic factors and external environment. Photoperiodic regulatory pathway is pivotal to control flowering in rice, in which florigen genes Hd3a and RTF1 are at the core and they are regulated by upstream Hd1-dependent, Ehd1-dependent, as well as both Hd1- and Ehd1-independent pathways. The three pathways bring a variety of light signal information together to Hd3a and RTF1 for further integration, and then transmit the signals in the form of florigen to the downstream flowering related genes. In this review, we summarize the research progress of photoperiod regulated genes on flowering time in rice, including the photoreceptors and circadian rhythm genes, the florigens, its upstream, downstream and interacting genes. We hope to provide a reference for in-depth study of rice flowering regulation.
27654112	Preclinical Research Most neuropsychiatric research, including that related to the circadian system, is performed using nocturnal animals, mainly laboratory mice and rats. Mood disorders are known to be associated with circadian rhythm abnormalities, but the mechanisms by which circadian rhythm disruptions interact with depression remain unclear. As the circadian system of diurnal and nocturnal mammals differs, we previously suggested that the utilization of diurnal animal models may be advantageous for understanding these relations. During the last 10 years, we and others established the validity of several diurnal rodent species as a model for the interactions between circadian rhythms and depression. Diurnal rodents respond to photoperiod manipulation in a similar way to humans, the behavioral outcome is directly related to the circadian system, and treatment that is effective in patients is also effective in the model. Moreover, less effective treatments in patients are also less effective in the model. We, therefore, suggest that using diurnal animal models to study circadian rhythms-related affective disorders, such as depression, will provide new insights that will hopefully lead to the development of more effective treatments. Drug Dev Res 77 : 347-356, 2016. © 2016 Wiley Periodicals, Inc.
27653034	Circadian disruption and obesity synergize to predispose to development of type 2 diabetes mellitus (T2DM), signifying that therapeutic targeting of both circadian and metabolic dysfunctions should be considered as a potential treatment approach. To address this hypothesis, we studied rats concomitantly exposed to circadian disruption and diet-induced obesity (CDO), a rat model recently shown to recapitulate phenotypical aspects of obese T2DM (eg, circadian disruption, obesity, insulin resistance, and islet failure). CDO rats were subsequently treated daily (for 12 wk) by timed oral gavage with vehicle, melatonin (a known chronobiotic), metformin, or combination treatment of both therapeutics. Melatonin treatment alone improved circadian activity rhythms, attenuated induction of β-cell failure, and enhanced glucose tolerance. Metformin alone did not modify circadian activity but enhanced insulin sensitivity and glucose tolerance. Importantly, the combination of melatonin and metformin had synergistic actions to modify progression of metabolic dysfunction in CDO rats through improved adiposity, circadian activity, insulin sensitivity, and islet cell failure. This study suggests that management of both circadian and metabolic dysfunctions should be considered as a potential preventative and therapeutic option for treatment of obesity and T2DM.
27651530	In contrast to daily rhythms that are common in the presence of the geophysical light-dark cycle, organisms at polar latitudes exhibit many diel activity patterns during natural periods of continuous solar light or darkness (polar day and night, respectively), from 24 h rhythms to arrhythmicity. In Arctic Greenland (73.7° N, 56.6° W) during polar day, we observed breeding-site attendance rhythms of thick-billed murres (Uria lomvia; n = 21 pairs), a charadriiform seabird, which provide biparental care at the colony. We found that U. lomvia egg-incubation and chick-brooding attendance is rhythmic and synchronized to the geophysical day (mean period length [rhythm duration] ± 95% confidence interval = 24.13 ± 0.52 h). Individual pair members had temporally segregated, sex-specific colony-attendance rhythms that were opposite (inverted) to each other, and these sex-specific rhythms were prominent at the population level. Our results provide a basis for investigating circadian systems at polar latitudes and sex-specific parental-care strategies. 
27651114	Several neuropsychiatric and neurological disorders have recently been characterized as dysfunctions arising from a 'final common pathway' of imbalanced excitation to inhibition within cortical networks. How the regulation of a cortical E/I ratio is affected by sleep and the circadian rhythm however, remains to be established. Here we addressed this issue through the analyses of TMS-evoked responses recorded over a 29 h sleep deprivation protocol conducted in young and healthy volunteers. Spectral analyses of TMS-evoked responses in frontal cortex revealed non-linear changes in gamma band evoked oscillations, compatible with an influence of circadian timing on inhibitory interneuron activity. In silico inferences of cell-to-cell excitatory and inhibitory connectivity and GABA/Glutamate receptor time constant based on neural mass modeling within the Dynamic causal modeling framework, further suggested excitation/inhibition balance was under a strong circadian influence. These results indicate that circadian changes in EEG spectral properties, in measure of excitatory/inhibitory connectivity and in GABA/glutamate receptor function could support the maintenance of cognitive performance during a normal waking day, but also during overnight wakefulness. More generally, these findings demonstrate a slow daily regulation of cortical excitation/inhibition balance, which depends on circadian-timing and prior sleep-wake history. 

27650461	The circadian master pacemaker in the suprachiasmatic nucleus (SCN) orchestrates peripheral clocks in various organs and synchronizes them with external time, including those in adipose tissue, which displays circadian oscillations in various metabolic and endocrine outputs. Because our knowledge about the instructive role of the SCN clock on peripheral tissue function is based mainly on SCN lesion studies, we here used an alternative strategy employing the Cre/ loxP system to functionally delete the SCN clock in mice. We performed whole-genome microarray hybridizations of murine epididymal white adipose tissue (eWAT) RNA preparations to characterize the role of the SCN clock in eWAT circadian transcriptome regulation. Most of the rhythmic transcripts in control animals were not rhythmic in SCN mutants, but a significant number of transcripts were rhythmic only in mutant eWAT. Core clock genes were rhythmic in both groups, but as was reported before for other tissues, rhythms were dampened and phase advanced in mutant animals. In SCN-mutant mice, eWAT lost the rhythm of metabolic pathway-related transcripts, while transcripts gaining rhythms in SCN-mutant mice were associated with various immune functions. These data reveal a complex interaction of SCN-derived and local circadian signals in the regulation of adipose transcriptome programs.
27649774	The purpose of this study was to examine the possible links between type 2 diabetes, daytime sleepiness, sleep quality and caffeine consumption.In this case-control field study, comparing type 2 diabetic ( n=134) and non-type 2 diabetic ( n=230) participants, subjects completed detailed and validated questionnaires to assess demographic status, health, daytime sleepiness, sleep quality and timing, diurnal preference, mistimed circadian rhythms and habitual caffeine intake. All participants gave saliva under standardised conditions for CYP1A2 genotyping and quantification of caffeine concentration. Hierarchical linear regression analyses examined whether type 2 diabetes status was associated with caffeine consumption.	Type 2 diabetic participants reported greater daytime sleepiness ( p=0.001), a higher prevalence of sleep apnoea ( p=0.005) and napping ( p=0.008), and greater habitual caffeine intake ( p<0.001), derived from the consumption of an extra cup of coffee each day. This finding was confirmed by higher saliva caffeine concentration at bedtime ( p=0.01). Multiple regression analyses revealed that type 2 diabetes status was associated with higher self-reported caffeine consumption ( p<0.02) and higher salivary caffeine ( p<0.02). Next to male sex, type 2 diabetes status was the strongest predictor of caffeine intake. Subjective sleep and circadian estimates were similar between case and control groups.	Type 2 diabetic patients may self-medicate with caffeine to alleviate daytime sleepiness. High caffeine intake reflects a lifestyle factor that may be considered when promoting type 2 diabetes management.	
27647678	Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization? 

27646174	Circadian rhythms in physiology and behavior are modulated by external factors such as light or temperature. We studied whether self-selected office lighting during the habitual waking period had a different impact on alertness, cognitive performance and hormonal secretion in extreme morning and evening chronotypes (N = 32), whose preferred bed- and wake-up times differed by several hours. The self-selected lighting condition was compared with constant bright light and a control condition in dim light. Saliva samples for hormonal analyses, subjective ratings of alertness, wellbeing, visual comfort and cognitive performance were regularly collected. Between the self-selected and the bright, but not the dim lighting condition, the onset of melatonin secretion in the evening (as marker for circadian phase) was significantly different for both chronotypes. Morning chronotypes reported a faster increase in sleepiness during the day than evening chronotypes, which was associated with higher cortisol secretion. Wellbeing, mood and performance in more difficult cognitive tasks were better in bright and self-selected lighting than in dim light for both chronotypes, whereas visual comfort was best in the self-selected lighting. To conclude, self-selection of lighting at work might positively influence biological and cognitive functions, and allow for inter-individual differences. 

27643448	Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4±0.6 vs. 2.3±1.5, p<0.001, respectively). An AM/PM cortisol ratio≥2.0 among patients with unsuppressed ACTH (>15 pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol≥1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia.
27642544	Disruptions in activity are core features of mood states in bipolar disorder (BD). This study sought to identify activity patterns that discriminate between mood states in BD. Locomotor activity was collected using actigraphy for six weeks in participants with inter-episode BD type I (n=37) or participants with no lifetime mood disorders (n=39). The 24-hour activity pattern of each participant-day was characterized and within-person differences in activity patterns were examined across mood states. Results show that among participants with BD, depressive days are distinguished from other mood states by an overall lower activity level, and a pattern of later activity onset, a midday elevation of activity, and low evening activity. No distinct within-person activity patterns were found for hypomanic/manic days. Since activity can be monitored non-invasively for extended time periods, activity pattern identification may be leveraged to detect mood states in BD, thereby providing more immediate delivery of care.

27638023	Several pathophysiologic factors, not harmful if taken alone, are capable of triggering unfavorable events when presenting together within the same temporal window (chronorisk), and the occurrence of many cardiovascular events is not evenly distributed in time. Both acute myocardial infarction and takotsubo syndrome seem to exhibit a temporal preference in their onset, characterized by variations according to time of day, day of the week, and month of the year, although with both analogies and differences. 
27637298	Automated verification of living organism models allows us to gain previously unknown knowledge about underlying biological processes. In this paper we show how parametric time model checking can be applied to define the time behavior of biological oscillatory systems more precisely. In particular, we focus on the resilience properties of such systems. This notion was introduced to understand the behavior of biological systems (e.g. the mammalian circadian rhythm) that are reactive and adaptive enough to endorse major changes in their environment (e.g. jet-lags, day-night alternating work-time). We formalize these properties through parametric TCTL and investigate the influence of environmental conditions changes on the resilience of living organisms under the uncertainty in parameters. In particular, we discuss the influence of various perturbations, e.g. artificial jet-lag or components knock-out on the parameters controlling the oscillatory behavior. This analysis is crucial when it comes to model elicitation for dynamic biological systems. We demonstrate the applicability of this technique using a simplified model of circadian clock and discuss its results with regard to other previous studies based on hybrid modeling.
27636900	Increasing evidence demonstrates that circadian clock proteins are important regulators of physiological functions including blood pressure. An established risk factor for developing cardiovascular disease is the absence of a blood pressure dip during the inactive period. The goal of the present study was to determine the effects of a high salt diet plus mineralocorticoid on PER1-mediated blood pressure regulation in a salt-resistant, normotensive mouse model, C57BL/6J.Blood pressure was measured using radiotelemetry. After control diet, wild-type (WT) and Per1 (KO) knockout mice were given a high salt diet (4% NaCl) and the long-acting mineralocorticoid deoxycorticosterone pivalate. Blood pressure and activity rhythms were analysed to evaluate changes over time.	Blood pressure in WT mice was not affected by a high salt diet plus mineralocorticoid. In contrast, Per1 KO mice exhibited significantly increased mean arterial pressure (MAP) in response to a high salt diet plus mineralocorticoid. The inactive/active phase ratio of MAP in WT mice was unchanged by high salt plus mineralocorticoid treatment. Importantly, this treatment caused Per1 KO mice to lose the expected decrease or 'dip' in blood pressure during the inactive compared to the active phase.	Loss of PER1 increased sensitivity to the high salt plus mineralocorticoid treatment. It also resulted in a non-dipper phenotype in this model of salt-sensitive hypertension and provides a unique model of non-dipping. Together, these data support an important role for the circadian clock protein PER1 in the modulation of blood pressure in a high salt/mineralocorticoid model of hypertension.	
27636197	Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax ≤ 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne-Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460-490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input. 
27635233	Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease . For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson's disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms. 
27634928	Occurrence of 24-h rhythms in species apparently lacking functional molecular clockwork indicates that strong circadian mechanisms are not essential prerequisites of robust timing, and that rhythmical patterns may arise instead as passive responses to periodically changing environmental stimuli. Thus, in a new synthesis of grazing in a ruminant (MINDY), crepuscular peaks of activity emerge from interactions between internal and external stimuli that influence motivation to feed, and the influence of the light/dark cycle is mediated through the effect of low nocturnal levels of food intake on gastric function. Drawing on risk allocation theory, we hypothesized that the timing of behavior in ruminants is influenced by the independent effects of light on motivation to feed and perceived risk of predation. We predicted that the antithetical relationship between these 2 drivers would vary with photoperiod, resulting in a systematic shift in the phase of activity relative to the solar cycle across the year. This prediction was formalized in a model in which phase of activity emerges from a photoperiod-dependent trade-off between food and safety. We tested this model using data on the temporal pattern of activity in reindeer/caribou Rangifer tarandus free-living at natural mountain pasture in sub-Arctic Norway. The resulting nonlinear relationship between the phasing of crepuscular activity and photoperiod, consistent with the model, suggests a mechanism for behavioral timing that is independent of the core circadian system. We anticipate that such timing depends on integration of metabolic feedback from the digestive system and the activity of the glucocorticoid axis which modulates the behavioral responses of the animal to environmental hazard. The hypothalamus is the obvious neural substrate to achieve this integration. 

27633015	In mammals, body temperature fluctuates diurnally around a mean value of 36°C-37°C. Despite the small differences between minimal and maximal values, body temperature rhythms can drive robust cycles in gene expression in cultured cells and, likely, animals. Here we studied the mechanisms responsible for the temperature-dependent expression of cold-inducible RNA-binding protein (CIRBP). In NIH3T3 fibroblasts exposed to simulated mouse body temperature cycles, Cirbp mRNA oscillates about threefold in abundance, as it does in mouse livers. This daily mRNA accumulation cycle is directly controlled by temperature oscillations and does not depend on the cells' circadian clocks. Here we show that the temperature-dependent accumulation of Cirbp mRNA is controlled primarily by the regulation of splicing efficiency, defined as the fraction of Cirbp pre-mRNA processed into mature mRNA. As revealed by genome-wide "approach to steady-state" kinetics, this post-transcriptional mechanism is widespread in the temperature-dependent control of gene expression. 
27631008	Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation. 
27630616	Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to "time" reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion. 
27630549	Under natural conditions diurnal rhythms of biological processes of the organism are synchronized with each other and to the environmental changes by means of the circadian system. Disturbances of the latter affect hormonal levels, sleep-wakefulness cycle and cognitive performance. To study mechanisms of such perturbations animal models subjected to artificial photoperiods are often used. The goal of current study was to understand the effects of circadian rhythm disruption, caused by a short light-dark cycle regime, on activity of the cerebral cortex in rodents.We used electroencephalogram to assess the distribution of vigilance states, perform spectral analysis, and estimate the homeostatic sleep drive. In addition, we analyzed spontaneous locomotion of C57BL/6J mice under symmetric, 22-, 21-, and 20-h-long light-dark cycles using video recording and tracking methods.	We found that shortening of photoperiod caused a significant increase of slow wave activity during non-rapid eye movement sleep suggesting an elevation of sleep pressure under such conditions. While the rhythm of spontaneous locomotion was completely entrained by all light-dark cycles tested, periodic changes in the power of the θ- and γ-frequency ranges during wakefulness gradually disappeared under 22- and 21-h-long light-dark cycles. This was associated with a significant increase in the θ-γ phase-amplitude coupling during wakefulness. Our results thus provide deeper understanding of the mechanisms underlying the impairment of learning and memory retention, which is associated with disturbed circadian regulation.	
27630067	To investigate whether the circadian rhythm disruption following the transition into and out of daylight saving time (DST) is associated with an increased risk of spontaneous delivery.We compared the number of spontaneous deliveries in the Swedish Medical Birth Register during the week after the change to and the week after the change from DST (exposure periods) with the average number of spontaneous deliveries in the control period, defined as the week before and the week after each exposure period.	Sweden, 1993-2006.	The primary outcomes were the weekly and the daily number of spontaneous deliveries in the exposure and the control periods. In secondary analyses we also compared the mean length of pregnancy of the women with spontaneous deliveries in the exposure and control periods.	The number of deliveries during the week after the transition into or out of DST was similar to that in the comparison period (18 519 observed vs 18 434 expected in case of the spring shift and 19 073 observed vs 19 122 expected in case of the autumn shift); the corresponding incidence ratio and 95% CIs were 1.005 (0.990 to 1.019) and 0.997 (0.983 to 1.012), respectively. There were no differences in the length of gestation of the deliveries in the exposure and the control periods.	Our results do not support the hypothesis that a minor circadian rhythm disruption is associated with an increased short-term risk of spontaneous delivery.	


27624757	The circadian clock allows plants to anticipate and respond to daily changes in ambient temperature. Mechanisms establishing the timing of circadian rhythms in Arabidopsis thaliana through temperature entrainment remain unclear. Also incompletely understood is the temperature compensation mechanism that maintains consistent period length within a range of ambient temperatures. A genetic screen for Arabidopsis mutants affecting temperature regulation of the PSEUDO-RESPONSE REGULATOR7 promoter yielded a novel allele of the SICKLE (SIC) gene. This mutant, sic-3, and the existing sic-1 mutant both exhibit low-amplitude or arrhythmic expression of core circadian clock genes under cool ambient temperature cycles, but not under light-dark entrainment. sic mutants also lengthen free running period in a manner consistent with impaired temperature compensation. sic mutant alleles accumulate LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED1 (CCA1) splice variants, among other alternatively spliced transcripts, which is exacerbated by cool temperatures. The cca1-1 lhy-20 double mutant is epistatic to sic-3, indicating the LHY and CCA1 splice variants are needed for sic-3 circadian clock phenotypes. It is not expected that SIC is directly involved in the circadian clock mechanism; instead, SIC likely contributes to pre-mRNA metabolism, and the splice variants that accumulate in sic mutants likely affect the circadian clock response to cool ambient temperature.
27624686	Fingolimod is an oral sphingosine-1-phospate (S1P) receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). In addition to therapeutic effects on lymphoid and neural tissue, fingolimod influences cardiovascular system by specific S1P-receptor modulation. The effects of S1P-receptor modulation on the endogenous circadian pattern of cardiac autonomic regulation (CAR), however, are not known. We examined the effects of fingolimod on the circadian pattern of CAR Ambulatory 24-h ECG recordings were undertaken in 27 RRMS patients before fingolimod (baseline), at the day of fingolimod initiation (1D) and after 3 months of fingolimod treatment (3M). The mean time between two consecutive R-peaks (RR-interval) and mean values for measures of heart rate variability (HRV) in time- and frequency domain were calculated from ECG recording at daytime and nighttime. The mean night:day-ratio of RR-interval was 1.23 ± 0.12 at baseline, decreased temporarily at 1D (1.16 ± 0.12; P < 0.01) and was higher at 3M (1.32 ± 0.11; P < 0.001) than at baseline. The night:day-ratio of HRV parameters reflecting parasympathetic cardiac regulation (pNN50, rMSSD, HFnu) decreased at 1D but recovered back to baseline at 3M (P < 0.05 for all). On the other hand, the night:day-ratio of TP, a parameter reflecting overall HRV gradually decreased and was lower at 3M than at baseline (P < 0.05). Our findings suggest that physiological relation between the circadian pattern of RR-interval and overall HRV as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment. In addition, fingolimod shifts the circadian equilibrium of CAR toward greater daytime dominance of overall HRV Accordingly, S1P-receptor modulation influences circadian pattern of CAR. 
27623842	In 2011 the U.S. Accreditation Council for Graduate Medical Education began limiting first year resident physicians (interns) to shifts of ≤16 consecutive hours. Controversy persists regarding the effectiveness of this policy for reducing errors and accidents while promoting education and patient care. Using a mathematical model of the effects of circadian rhythms and length of time awake on objective performance and subjective alertness, we quantitatively compared predictions for traditional intern schedules to those that limit work to ≤ 16 consecutive hours.We simulated two traditional schedules and three novel schedules using the mathematical model. The traditional schedules had extended duration work shifts (≥24 h) with overnight work shifts every second shift (including every third night, Q3) or every third shift (including every fourth night, Q4) night; the novel schedules had two different cross-cover (XC) night team schedules (XC-V1 and XC-V2) and a Rapid Cycle Rotation (RCR) schedule. Predicted objective performance and subjective alertness for each work shift were computed for each individual's schedule within a team and then combined for the team as a whole. Our primary outcome was the amount of time within a work shift during which a team's model-predicted objective performance and subjective alertness were lower than that expected after 16 or 24 h of continuous wake in an otherwise rested individual.	The model predicted fewer hours with poor performance and alertness, especially during night-time work hours, for all three novel schedules than for either the traditional Q3 or Q4 schedules.	Three proposed schedules that eliminate extended shifts may improve performance and alertness compared with traditional Q3 or Q4 schedules. Predicted times of worse performance and alertness were at night, which is also a time when supervision of trainees is lower. Mathematical modeling provides a quantitative comparison approach with potential to aid residency programs in schedule analysis and redesign.	
27622983	Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability). This ability requires that a circadian clock provide phase information (a time tag) to cognitive systems involved in linking representations of an event with spatial reference memory. To date, it is unclear which neuronal substrates are critical in this process, but one candidate structure is the hippocampus (HPC). The HPC is essential for normal performance on tasks that require allocentric spatial memory and exhibits circadian rhythms of gene expression that are sensitive to meal timing. Using a novel TPL training procedure and enriched, multidimensional environment, we trained rats to locate a food reward that varied between two locations relative to time of day. After rats acquired the task, they received either HPC or SHAM lesions and were re-tested. Rats with HPC lesions were initially impaired on the task relative to SHAM rats, but re-attained high scores with continued testing. Probe tests revealed that the rats were not using an alternation strategy or relying on light-dark transitions to locate the food reward. We hypothesize that transient disruption and recovery reflect a switch from HPC-dependent allocentric navigation (learning places) to dorsal striatum-dependent egocentric spatial navigation (learning routes to a location). Whatever the navigation strategy, these results demonstrate that the HPC is not required for rats to find food in different locations using circadian phase as a discriminative cue.
27622933	Genetic predisposition may contribute to the differences in drug-specific, class-specific or antidepressant-wide treatment resistance. Clinical studies with the genetic data are often limited in sample sizes. Drug response obtained from self-reports may offer an alternative approach to conduct a study with much larger sample size. Using the phenotype data collected from 23andMe 'Antidepressant Efficacy and Side Effects' survey and genotype data from 23andMe's research participants, we conducted genome-wide association study (GWAS) on subjects of European ancestry using four groups of phenotypes (a) non-treatment-resistant depression (n=7795) vs treatment-resistant depression (TRD, n=1311), (b) selective serotonin reuptake inhibitors (SSRI) responders (n=6348) vs non-responders (n=3340), (c) citalopram/escitalopram responders (n=2963) vs non-responders (n=2005), and (d) norepinephrine-dopamine reuptake inhibitor (NDRI, bupropion) responders (n=2675) vs non-responders (n=1861). Each of these subgroups was also compared with controls (n ~ 190 000). The most significant association was from bupropion responders vs non-responders analysis. Variant rs1908557 (P=2.6 × 10(-8), OR=1.35) passed the conventional genome-wide significance threshold (P=5 × 10(-8)) and was located within the intron of human spliced expressed sequence tags in chromosome 4. Gene sets associated with long-term depression, circadian rhythm and vascular endothelial growth factor (VEGF) pathway were enriched in the bupropion analysis. No single-nucleotide polymorphism passed genome-wide significance threshold in other analyses. The heritability estimates for each response group compared with controls were between 0.15 and 0.25, consistent with the known heritability for major depressive disorder. 
27622314	The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 ± 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP ≥10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.
27621470	This study quantifies sex differences in the diurnal and circadian variation of sleep and waking while controlling for menstrual cycle phase and hormonal contraceptive use. We compared the diurnal and circadian variation of sleep and alertness of 8 women studied during two phases of the menstrual cycle and 3 women studied during their midfollicular phase with that of 15 men. Participants underwent an ultradian sleep-wake cycle (USW) procedure consisting of 36 cycles of 60-min wake episodes alternating with 60-min nap opportunities. Core body temperature (CBT), salivary melatonin, subjective alertness, and polysomnographically recorded sleep were measured throughout this procedure. All analyzed measures showed a significant diurnal and circadian variation throughout the USW procedure. Compared with men, women demonstrated a significant phase advance of the CBT but not melatonin rhythms, as well as an advance in the diurnal and circadian variation of sleep measures and subjective alertness. Furthermore, women experienced an increased amplitude of the diurnal and circadian variation of alertness, mainly due to a larger decline in the nocturnal nadir. Our results indicate that women are likely initiating sleep at a later circadian phase than men, which may be one factor contributing to the increased susceptibility to sleep disturbances reported in women. Lower nighttime alertness is also observed, suggesting a physiological basis for a greater susceptibility to maladaptation to night shift work in women. 
27621181	Follistatin may affect lean and fat mass and be implicated in metabolic diseases. We aimed to elucidate physiological predictors of circulating follistatin variation in healthy young humans.This was an observational, cross-sectional study with two additional prospective observational arms (circadian, seasonal sub-studies) and one prospective interventional arm (mixed meal sub-study). Healthy, young individuals of both sexes (n=122) were subjected to anthropometric and body composition measurements and their eating and exercise behavior profiles were assessed by validated questionnaires. Sub-groups were subjected to standardized meal ingestion (n=36), day-night rhythm (n=20) and seasonal variation (n=20) studies. Main outcome of the study were circulating follistatin levels.	At baseline follistatin levels were correlated with creatinine (r=0.24; p=0.01), creatine phosphokinase (rs=0.22; p=0.02), and with lean body mass (rs=0.19; p=0.04) and were higher in males than females (p=0.004) after adjustment for leptin, which was its major predictor. Follistatin levels showed a circadian (p<0.001), but not a seasonal, variation, and were also affected by the phase of menstrual cycle in females (p=0.034). Follistatin levels were not affected by dietary or exercise habits but levels increased after a standardized meal ingestion (250kcal) (p=0.002).	In healthy young individuals circulating follistatin levels are correlated with muscle mass. Follistatin levels are associated with circulating leptin levels and display a day-night rhythm and a menstrual cycle, but not a seasonal, variation.	
27620461	Intertidal macroalgae are constantly subjected to high variations in the quality and quantity of incident irradiance that can eventually generate detrimental effect on the photosynthetic apparatus. The success of these organisms to colonize the stressful coastal habitat is mainly associated with the complexity of their morphological structures and the efficiency of the anti-stress mechanisms to minimize the physiological stress. Lessonia spicata (Phaeophyceae), a brown macroalga, that inhabits the intertidal zone in central-southern Chile was studied in regard to their physiological (quantum yield, electron transport rate, pigments) and biochemical (phlorotannins content, antioxidant metabolism, oxidative stress) responses during a daily light cycle under natural solar radiation. Major findings were that F v/F m, photosynthetic parameters (ETRmax, alpha, E k) and pigments in L. spicata showed an inverse relationship to the diurnal changes in solar radiation. Phlorotannins levels and antioxidant activity showed their highest values in treatment that included UV radiation. There was an increase in SOD and APX in relation at light stress, with a peak in activity between 5.2 and 10.1 W m-2 of biologically effective dose. The increase in peroxidative damage was proportional to light dose. These results indicated that different light doses can trigger a series of complementary mechanisms of acclimation in L. spicata based on: (i) down-regulation of photochemistry activity and decrease in concentration of photosynthetic pigments; (ii) induction of phenolic compounds with specific UV-screening functions; and (iii) reactive oxygen species (ROS) scavenging activity via complementary repair of the oxidative damage through increased activity of antioxidant enzymes and potentially increased amounts of phenolic compounds.
27618763	When food is restricted to a brief fixed period every day, animals show an increase in temperature, corticosterone concentration and locomotor activity for 2-3h before feeding time, termed food anticipatory activity. Mechanisms and neuroanatomical circuits responsible for food anticipatory activity remain unclear, and may involve both oscillators and networks related to temporal conditioning. Rabbit pups are nursed once-a-day so they represent a natural model of circadian food anticipatory activity. Food anticipatory behavior in pups may be associated with neural circuits that temporally anticipate feeding, while the nursing event may produce consummatory effects. Therefore, we used New Zealand white rabbit pups entrained to circadian feeding to investigate the hypothesis that structures related to reward expectation and conditioned emotional responses would show a metabolic rhythm anticipatory of the nursing event, different from that shown by structures related to reward delivery. Quantitative cytochrome oxidase histochemistry was used to measure regional brain metabolic activity at eight different times during the day. We found that neural metabolism peaked before nursing, during food anticipatory behavior, in nuclei of the extended amygdala (basolateral, medial and central nuclei, bed nucleus of the stria terminalis), lateral septum and accumbens core. After pups were fed, however, maximal metabolic activity was expressed in the accumbens shell, caudate, putamen and cortical amygdala. Neural and behavioral activation persisted when animals were fasted by two cycles, at the time of expected nursing. These findings suggest that metabolic activation of amygdala-septal-accumbens circuits involved in temporal conditioning may contribute to food anticipatory activity.
27618422	Synthetic corticosteroids may pose an environmental risk to fish. Here, we describe multiend point responses of adult zebrafish (8 months old) upon 21-day exposure to a commonly prescribed corticosteroid, fludrocortisone acetate (FLU), at concentrations between 0.006 and 42 μg/L. No remarkable reproductive impacts were observed, while physiological effects, including plasma glucose level and blood leukocyte numbers were significant altered even at 42 ng/L. Ovary parameters and transcriptional analysis of hypothalamic-pituitary-gonadal-liver axis revealed negligible effects. Significant alterations of the circadian rhythm network were observed in the zebrafish brain. Transcripts of several biomarker genes, including per1a and nr1d1, displayed strong transcriptional changes, which occurred at environmental relevant concentrations of 6 and 42 ng/L FLU. Importantly, the development and behavior of F1 embryos were significant changed. Heartbeat, hatching success and swimming behavior of F1 embryos were all increased even at 6 and 42 ng/L. All effects were further confirmed by exposure of eleuthero-embryos. Significant transcriptional changes of biomarker genes involved in gluconeogenesis, immune response and circadian rhythm in eleuthero-embryos confirmed the observations in adult fish. Hatching success, heartbeat, and swimming activity were increased at 81 ng/L and higher, as with F1 embryos. These results provide novel insights into the understanding of potential environmental risks of corticosteroids. 
27618415	The hypothesis that outdoor exposure might protect against myopia has generated much interest, although available data find only modest clinical efficacy. We tested the effect of outdoor rearing on form-deprivation myopia in chicks, a myopia model markedly inhibited by high-intensity indoor laboratory lighting.Unilaterally goggled cohorts of White Leghorn chicks were maintained in a species-appropriate, outdoor rural setting during daylight hours to the extent permitted by weather. Control chicks were reared indoors with incandescent lighting. Besides ocular refraction and ultrasound, we determined dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content in retina and vitreous and measured mRNA expression levels of selected clock and circadian rhythm-related genes in the retina/RPE.	Myopia developed in the goggled eyes of all cohorts. Whereas outdoor rearing lessened myopia by 44% at 4 days, a protective effect was no longer evident at 11 days. Outdoor rearing had no consistent effect on retinal or vitreous content of dopamine or DOPAC. Conforming to prior data on form-deprivation myopia, retina and vitreous levels of DOPAC were reduced in goggled eyes. Compared with contralateral eyes, the retinal expression of clock and circadian rhythm-related genes was modestly altered in myopic eyes of chicks reared indoors or outdoors.	Outdoor rearing of chicks induces only a partial decrease of goggle-induced myopia that is not maintained, without evidence that retinal dopamine metabolism accounts for the partial myopia inhibition under these outdoor conditions. Although modest, alterations in retinal gene expression suggest that studying circadian signals might be informative for understanding refractive mechanisms.	
27618116	Melanopsin-containing retinal ganglion cells play an important role in the non-image forming effects of light, through their direct projections on brain circuits involved in circadian rhythms, mood and alertness. Individual differences in the functionality of the melanopsin-signaling circuitry can be reliably quantified using the maximum post-illumination pupil response (PIPR) after blue light. Previous protocols for acquiring PIPR relied on the use of mydriatics to dilate the light-exposed eye. However, pharmacological pupil dilation is uncomfortable for the participants and requires ophthalmological expertise. Hence, we here investigated whether an individual's maximum PIPR can be validly obtained in a protocol that does not use mydriatics but rather increases the intensity of the light stimulus. In 18 participants (5 males, mean age ± SD: 34.6 ± 13.6 years) we evaluated the PIPR after exposure to intensified blue light (550 µW/cm²) provided to an undilated dynamic pupil. The test-retest reliability of the primary PIPR outcome parameter was very high, both between day-to-day assessments (Intraclass Correlation Coefficient (ICC) = 0.85), as well as between winter and summer assessments (ICC = 0.83). Compared to the PIPR obtained with the use of mydriatics and 160 µW/cm² blue light exposure, the method with intensified light without mydriatics showed almost zero bias according to Bland-Altman plots and had moderate to strong reliability (ICC = 0.67). In conclusion, for PIPR assessments, increasing the light intensity is a feasible and reliable alternative to pupil dilation to relieve the participant's burden and to allow for performance outside the ophthalmological clinic. 
27617515	Chronic telogen effluvium describes the clinical condition noted mostly in middle-aged women of increased, diffuse scalp hair shedding that is prolonged and often presents with a fluctuating course that may continue for years but does not lead to visible hair thinning. Despite its description almost 20 years ago, the underlying pathologic cause of CTE is yet to be identified. However the culmination of research in the field of hair biology and the burgeoning field of chronobiology may lead to exciting breakthroughs in our understanding of CTE. In this paper the current literature on CTE is reviewed and a hypothesis is put forth that CTE may be triggered by hormonal fluctuations and alterations in circadian control genes. 
27616682	Osteoarthritis (OA) is the most common joint disease but an effective pharmacological therapy has not been developed yet. To identify targets for treatment and ways to interfere with OA development and progression both spontaneous and induced OA models are still needed. In this narrative review it is discussed what variables can be identified that lead to variation in OA animal model studies.Literature was screened (Pubmed) with the following terms; OA animal models in combination with species, age, strain, gender/sex, housing, diet, fighting, circadian rhythm, transgenic. Relevant articles were selected and additional papers were searched for and read for specific subtopics.	Studies with OA models are subject to a multitude of variables, stimuli and conditions that can influence the outcome of an animal experiment. Outcome will depend on amongst others; the model used, species and strain, age, gender, diet, housing conditions, circadian rhythm, timing of intervention, stress levels and activity. Variations in these variables can account for discrepancies between OA model experiments, intervention studies and conclusions.	To improve OA animal model research, investigators should be aware of all the stimuli and conditions that can interfere with disease development and disease intervention and take these into account in their study design and execution.	

27614960	In mammals suprachiasmatic nucleus (SCN), acts as a light entrainable master clock and by generation of temporal oscillations regulates the peripheral organs acting as autonomous clocks resulting in overt behavioral and physiological rhythms. SCN also controls synthesis and release of melatonin (hormonal message for darkness) from pineal. Nitric Oxide (NO) acts as an important neurotransmitter in generating the phase shifts of circadian rhythms and participates in sleep-wake processes, maintenance of vascular tone as well as signalling and regulating inflammatory processes. Aging is associated with disruption of circadian timing system and decline in endogenous melatonin leading to several physiological disorders. Here we report the effect of aging on NO daily rhythms in various peripheral clocks such as kidney, intestine, liver, heart, lungs and testis. NO levels were measured at zeitgeber time (ZT) 0, 6, 12 and 18 in these tissues using Griess assay in male Wistar rats. Aging resulted in alteration of NO levels as well as phase of NO in both 12 and 24 months groups. Correlation analysis demonstrated loss of stoichiometric interaction between the various peripheral clocks with aging. Age induced alterations in NO daily rhythms were found to be most significant in liver and, interestingly least in lungs. Neurohormone melatonin, an endogenous synchroniser and an antiaging agent decreases with aging. We report further differential restoration with exogenous melatonin administration of age induced alterations in NO daily rhythms and mean levels in kidney, intestine and liver and the stoichiometric interactions between the various peripheral clocks.
27614897	Previous studies have shown that circadian genes might be involved in the development of polycystic ovarian syndrome (PCOS). Hyperandrogenism is a hallmark feature of PCOS. However, the effect of hyperandrogenism on circadian gene expression in human granulosa cells is unknown, and the general expression pattern of circadian genes in the human ovary is unclear.Expression of the circadian proteins CLOCK and PER2 in human ovaries was observed by immunohistochemistry. The mRNA expression patterns of the circadian genes CLOCK, PER2, and BMAL1, and the steroidogenesis-related genes STAR, CYP11A1, HSD3B2, and CYP19A1 in cultured human luteinized granulosa cells were analyzed over the course of 48 h after testosterone treatment by quantitative polymerase chain reaction.	Immunostaining of CLOCK and PER2 protein was detected in the granulosa cells of dominant antral follicles but was absent in the primordial, primary, or preantral follicles of human ovaries. After testosterone stimulation, expression of PER2 showed an oscillating pattern, with two peaks occurring at the 24th and 44th hours; expression of CLOCK increased significantly to the peak at the 24th hour, whereas expression of BMAL1 did not change significantly over time in human luteinized granulosa cells. Among the four steroidogenesis-related genes evaluated, only STAR displayed an oscillating expression pattern with two peaks occurring at the 24th and 40th hours after testosterone stimulation.	Circadian genes are expressed in the dominant antral follicles of the human ovary. Oscillating expression of the circadian gene PER2 can be induced by testosterone in human granulosa cells in vitro. Expression of STAR also displayed an oscillating pattern after testosterone stimulation. Our results indicate a potential relationship between the circadian clock and steroidogenesis in the human ovary, and demonstrate the effect of testosterone on circadian gene expression in granulosa cells.	

27612656	The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular underpinnings of depressive-like behaviours with an unbiased approach. The objective of the study is to integrate the results of these proteomic studies in depression models to shed light on the most relevant molecular pathways involved in the disease.Network analysis is performed integrating preexisting proteomic data from rodent models of depression. The IntAct mouse and the HRPD are used as reference protein-protein interaction databases. The functionality analyses of the networks are then performed by testing overrepresented GO biological process terms and pathways.	Functional enrichment analyses of the networks revealed an association with molecular processes related to depression in humans, such as those involved in the immune response. Pathways impacted by clinically effective antidepressants are modulated, including glutamatergic signaling and neurotrophic responses. Moreover, dysregulations of proteins regulating energy metabolism and circadian rhythms are implicated. The comparison with protein pathways modulated in depressive patients revealed significant overlapping.	This systems biology study supports the notion that animal models can contribute to the research into the biology and therapeutics of depression.	
27612057	Disturbed sleep is common in shift work. It is hypothesized that administration of exogenous melatonin could reduce the sleep latency and improve the sleep quality.To evaluate the efficacy of 3 mg melatonin taken 30 min before night time sleep on shift workers with difficulty falling asleep.	Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were applied to find out shift workers with difficulty falling asleep. A randomized, double-blind, placebo-controlled crossover study with periods of 3 night and washouts of 2 weeks comparing melatonin with placebo was performed. Night time sleep parameters obtained from somnowatch including total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE) and wakening after sleep onset (WASO) were analyzed.	Among 295 workers, 103 had difficulty falling asleep. Finally, from 50 randomly selected workers with difficulty falling asleep, 39 workers completed the study. Melatonin treatment significantly increased SE and decreased SOL in comparison with baseline and taking placebo. SE was increased from 82.1% at baseline to 85.5% after melatonin therapy. Also SOL was decreased from 0.27 h at baseline to 0.20 h after melatonin therapy. Effects of Melatonin administration on TST and WASO were not significant.	This study showed that melatonin therapy in shift workers with difficulty falling asleep significantly improved the sleep onset latency and sleep efficiency.	


27611726	Bruxism (BRX) is a condition of great interest for researchers and clinicians in dental and medical areas. BRX has two circadian manifestations; it can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, WB). However, it can be suffered together. Recent investigations suggest that central nervous system neurotransmitters and their genes could be involved in the genesis of BRX. Serotonin is responsible for the circadian rhythm, maintaining arousal, regulating stress response, muscle tone and breathing. Thus, serotonin could be associated with BRX pathogenesis. The aim of this work was to evaluate the frequency of genetic polymorphisms in the genes HTR1A (rs6295), HTR2A (rs1923884, rs4941573, rs6313, rs2770304), HTR2C (rs17260565) and SLC6A4 (rs63749047) in subjects undergoing BRX treatment. Patients included were classified according to their diagnosis in awake bruxism (61 patients), sleep bruxism (26 patients) and both (43 patients). The control group included 59 healthy patients with no signs of BRX. Data showed significant differences in allelic frequencies for the HTR2A rs2770304 polymorphism, where the C allele was associated with increased risk of SB (odds ratio = 2·13, 95% confidence interval: 1·08-4·21, P = 0·03). Our results suggest that polymorphisms in serotonergic pathways are involved in sleep bruxism. Further research is needed to clarify and increase the current understanding of BRX physiopathology.
27611469	The mechanisms of corneal epithelial lesions and delayed wound repair, as well as their association with diabetes mellitus, are critical issues for clinical ophthalmologists. To test whether the diabetic condition alters the circadian rhythm in a mouse cornea and whether insulin can synchronise the corneal clock, we studied the effects of streptozotocin-induced diabetes on the mitosis of epithelial cells, the recruitment of leukocytes to the cornea, and the expression of main core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the corneal epithelium. We also assessed the possible effect of insulin on these modifications. Diabetes downregulated Clock, Bmal1, and Per2 expression, upregulated Cry1 and Rev-erbα expression, reduced corneal epithelial mitosis, and increased leukocyte (neutrophils and γδ T-cells) recruitment to the cornea. Early treatments with insulin partially restored the altered rhythmicity in the diabetic cornea. In conclusion, insulin-dependent diabetes altered the normal rhythmicity of the cornea, and insulin administration had a beneficial effect on restoring normal rhythmicity in the diabetic cornea. 
27609640	Period circadian clock (Per) genes Per1 and Per2 have essential roles in circadian oscillation. In this study, we identified a new role of Per1-Per2 cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of Per1 and Per2 knockout mice depended on the copy number ratio of Per1:Per2. We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both Per1((-/-)) and Per2((-/-)) mice were entrained to a broader range of period length than wild-type mice. To analyse Per1-Per2 cooperative roles at the cell culture level, we established a Per2 knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the Per1 coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to "circa" 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium. 
27604658	Out-of-office blood pressure (BP) measured by home BP monitoring, or ambulatory BP monitoring, was demonstrated to be superior to office BP for the prediction of cardiovascular events. The J-HOP study of a nationwide Japanese cohort demonstrated that morning home BP is the best stroke predictor. In the prospective HONEST study of >21 000 hypertensives, on-treatment morning home BP was shown to be a strong predictor both of future coronary artery disease and stroke events. In subjects whose office BP was maintained at ⩾150 mm Hg, there was no increase in cardiovascular events when their morning systolic BP was well-controlled at <125 mm Hg. Since Asians show greater morning BP surges, it is particularly important for Asians to achieve 'perfect 24-hr BP control,' that is, the 24-h BP level, nocturnal BP dipping and BP variability including morning surge. The morning BP surge and the extremes of disrupted circadian rhythm (riser and extreme dipper patterns) are independent risks for stroke in hypertensives. A morning BP-guided approach is thus the first step toward perfect 24-h BP control, followed by the control of nocturnal hypertension. In the resonance hypothesis, the synergistic resonance of BP variability phenotypes would produce an extraordinary large 'dynamic BP surge' that can trigger a cardiovascular event, especially in high-risk patients with systemic hemodynamic atherothrombotic syndrome, a vicious cycle of exaggerated BP variability and vascular disease. In the future, information and communications technology and artificial intelligence technology with the innovation of wearable continuous surge BP monitoring will contribute to 'anticipation medicine' with the goal of zero cardiovascular events.
27602977	Exposure of the skin to ultraviolet (UV) irradiation causes many detrimental effects through mechanisms related to oxidative stress and DNA damage. Excessive oxidative stress can cause apoptosis and cellular dysfunction of epidermal cells leading to cellular senescence and connective tissue degradation. Direct and indirect damage to DNA predisposes the skin to cancer formation. Chronic UV exposure also leads to skin aging manifested as wrinkling, loss of skin tone, and decreased resilience. Fortunately, human skin has several natural mechanisms for combating UV-induced damage. The mechanisms operate on a diurnal rhythm, a cycle that repeats approximately every 24 hours. It is known that the circadian rhythm is involved in many skin physiologic processes, including water regulation and epidermal stem cell function. This study evaluated whether UV damage and the skin's natural mechanisms of inflammation and repair are also affected by circadian rhythm. We looked at UV-induced erythema on seven human subjects irradiated with simulated solar radiation in the morning (at 08:00 h) versus in the afternoon (at 16:00 h). Our data suggest that the same dose of UV radiation induces significantly more inflammation in the morning than in the afternoon. Changes in protein expression relevant to DNA damage, such as xeroderma pigmentosum, complementation group A (XPA), and cyclobutane pyrimidine dimers (CPD) from skin biopsies correlated with our clinical results. Both XPA and CPD levels were higher after the morning UV exposure compared with the afternoon exposure. <br /><br /> <em>J Drugs Dermatol.</em> 2016;15(9):1124-1130. 
27602274	The brain's biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. 

27601531	Several studies have indicated an increased risk of breast cancer (BC) among female flight attendants (FFAs); however, the results from epidemiological studies were not consistent. We thus conducted an updated meta-analysis to re-assess the risk of BC among FFAs, according to the MOOSE guideline.A systematical search of PubMed and Embase for relevant observational studies up to March 2016 was performed, supplemented by manual reviews of bibliographies in relevant studies. A random effect model was conducted to calculate the combined standard incidence ratio (SIR) and 95% confidence interval (95% CI) in BC risk.	Of the 719 citations retrieved, 10 were included, with more than 31 679 participants and 821 new cases. The combined SIR (95% CI) for BC in FFAs was 1.40 (95%CI 1.30-1.50), with no significant heterogeneity (P = 0.744; I(2 )=( )0.0%) or publication bias (Begg's test: z = 0.72, P = 0.474; Egger's test: t = 0.25, P = 0.805) among the included studies. The results were not significantly modified by publication year, geographic area, study quality or whether the fertility variables were adjusted.	Our meta-analysis suggests that FFAs have a higher risk of BC compared with the general population. More vigorous studies with larger sample sizes based on other populations, including the Chinese, are needed.	
27598047	Chronic lower limb oedema is one of the complications of superficial or deep chronic venous disorders. It is ranked as "C3"on the CEAP classification. In epidemiological studies, the recognition of oedema is mainly based on clinical signs, and oedema is more easily detected in the second part of the day when it becomes evident. We addressed the question whether oedema is already present in the morning in patients suffering of primary varicose veins without trophic changes.In total, 101 patients with primary varicose veins (C2 and/or C3 stage of the CEAP classification) and 122 controls were enrolled as they appeared in our centre. The consultation time was no later than 6 hours after the patient had woken up. Oedema was detected by pitting test and ultrasound.	The mean consultation time lapse was 3.7 ± 1.2 hours after waking-up. Oedema was more frequent in the group of primary varicose veins without trophic changes (36 % compared to 14 % in the control group; p < 0.01). Oedema was mainly detected by ultrasound and far less so by the pitting test.	Patients with varicose veins have morning oedema more frequently than patients without varicosis and at a higher rate than in epidemiological studies.	
27597764	In Caucasians and Native Americans living at altitude, hemoglobin mass is increased in spite of erythropoietin concentrations ([Epo]) not markedly differing from sea level values. We hypothesized that a nocturnal decrease of arterial oxygen saturation (SaO2) causes a temporary rise of [Epo] not detected by morning measurements. SaO2 (continuous, finger oximeter) and [Epo] (ELISA, every 4 h) were determined in young highlanders (altitude 2600 m) during 24 h of usual daily activity. In Series I (six male, nine female students), SaO2 fell during the night with the nadir occurring between 01:00 and 03:00; daily means (range 92.4-95.2%) were higher in females (+1.7%, P < 0.01). [Epo] showed opposite changes with zenith occurring at 04:00 without a sex difference. Mean daily values (22.9 ± 10.7SD U/L) were higher than values obtained at 08:00 (17.2 ± 9.5 U/L, P < 0.05). In Series II (seven females), only SaO2 was measured. During follicular and luteal phases, SaO2 variation was similar to Series I, but the rhythm was disturbed during menstruation. While daily [Epo] variations at sea level are not homogeneous, there is a diurnal variation at altitude following changes in SaO2 Larger hypoventilation-dependent decreases of alveolar PO2 decreases during the night probably cause a stronger reduction of SaO2 in highlanders compared to lowlanders. This variation might be enlarged by a diurnal fluctuation of Hb concentration. In spite of a lower [Hb], the higher SaO2 in women compared to men led to a similar arterial oxygen content, likely explaining the absence of differences in [Epo] between sexes. 


27593464	Intrinsic water use efficiency (Wi), the ratio of net CO2 assimilation (A) over stomatal conductance to water vapour (gs), is a complex trait used to assess plant performance. Improving Wi could lead in theory to higher productivity or reduced water usage by the plant, but the physiological traits for improvement and their combined effects on Wi have not been clearly identified. Under fluctuating light intensity, the temporal response of gs is an order of magnitude slower than A, which results in rapid variations in Wi. Compared to traditional approaches, our new model scales stoma behaviour at the leaf level to predict gs and A during a diurnal period, reproducing natural fluctuations of light intensity, in order to dissect Wi into traits of interest. The results confirmed the importance of stomatal density and photosynthetic capacity on Wi but also revealed the importance of incomplete stomatal closure under dark conditions as well as stomatal sensitivity to light intensity. The observed continuous decrease of A and gs over the diurnal period was successfully described by negative feedback of the accumulation of photosynthetic products. Investigation into the impact of leaf anatomy on temporal responses of A, gs and Wi revealed that a high density of stomata produces the most rapid response of gs but may result in lower Wi. 
27592828	Beta-cryptoxanthin [β-CRX, (3R)-β, β-caroten-3-ol] is a provitamin A and a potent antioxidant that is abundant in Satsuma mandarin orange (Citrus unshiu MARC.), which is the most popular fruit in Japan. The anti-stress effect of β-CRX on humans was evaluated in fifth-year university students during both routine daily life at the university and at pharmacy practice. The study design was a double-blind group comparison and participants (n=20; female 12, male 8) were randomly assigned to β-CRX-rich orange juice or placebo (β-CRX was removed from orange juice) groups. β-CRX or placebo juice (125 mL, once a day, after breakfast) were consumed from 10 d prior to the pharmacy practice and continued for 10 d into the practice period. To assess participants' anxiety, the state-trait anxiety inventory test was carried out before the pharmacy practice. Salivary α-amylase activity (sAA) was measured as a marker of sympathetic nervous system activity. In the placebo-group, sAA in the evening (post-practice sAA) tended to be higher than sAA in the morning (pre-practice sAA) during both routine daily life at the university and during pharmacy practice. In the β-CRX-group, the increase of post-practice sAA was suppressed in females. These results suggested that β-CRX has an anti-stress effect, at least, in females. 
27591963	Vagal afferent neurons (VANs) play an important role in the control of food intake by signaling nutrient type and quantity to the brain. Recent findings are broadening our view of how VANs impact not only food intake but also energy homeostasis. This review focuses exclusively on studies of the vagus nerve from the past 2 years that highlight major new advancements in the field. We firstly discuss evidence that VANs can directly sense nutrients, and we consider new insights into mechanisms affecting sensing of gastric distension and signaling by gastrointestinal hormones ghrelin and GLP1. We discuss evidence that disrupting vagal afferent signaling increases long-term control of food intake and body weight management, and the importance of this gut-brain pathway in mediating beneficial effects of bariatric surgery. We conclude by highlighting novel roles for vagal afferent neurons in circadian rhythm, thermogenesis, and reward that may provide insight into mechanisms by which VAN nutrient sensing controls long-term control of energy homeostasis.
27591429	The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long-term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic-pituitary-adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24-h light-dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression- and anxiety-related behaviour. Results showed that LL- and DD-raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL-raised mice showed increased corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL-raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD-raised mice. Taken together, these data suggest that altered postnatal light environments have long-term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood.

27589593	This paper focuses on the relationship between the circadian system and glucose metabolism. Research across the translational spectrum confirms the importance of the circadian system for glucose metabolism and offers promising clues as to when and why these systems go awry. In particular, basic research has started to clarify the molecular and genetic mechanisms through which the circadian system regulates metabolism. The study of human behavior, especially in the context of psychiatric disorders, such as bipolar disorder and major depression, forces us to see how inextricably linked mental health and metabolic health are. We also emphasize the remarkable opportunities for advancing circadian science through big data and advanced analytics. Advances in circadian research have translated into environmental and pharmacological interventions with tremendous therapeutic potential.
27589343	Primary aldosteronism (PA), the most common form of secondary hypertension, causes relevant morbidity. The value of salivary measurements of aldosterone in clinical routine in PA so far has not been assessed. First, we analyzed salivary and plasma aldosterone concentrations of 42 patients with PA and 37 hypertensive controls (HC) during a sodium infusion test prospectively. Second, morning salivary and plasma aldosterone concentrations as well as diurnal saliva aldosterone profiles were analyzed in 115 patients treated for PA (46 adrenalectomy, 56 spironolactone, 13 eplerenone). Salivary aldosterone was substantially elevated in PA patients compared to HC at baseline (106±119 vs. 40±21 ng/l, p=0.01), and after 4-h sodium infusion test (60±36 vs. 23±14, p=0.01). Positive correlation between salivary and plasma aldosterone levels was evident, with exception of concentrations in or below the lower normal range. Applying a salivary aldosterone cutoff of 51.2 ng/l, found by ROC curve analysis, rendered a sensitivity of 81% and a specificity of 73% for PA. The diurnal rhythm of aldosterone was preserved in untreated PA patients, but concentrations were higher in the context of PA, and normalized after surgery (118±57 vs. 31±18 ng/l, p<0.01). Taken together, salivary aldosterone measurements correlate with plasma levels, allowing simple and cost effective assessments of aldosterone secretion in an outpatient setting. Nevertheless, as this method alone cannot replace other plasma parameters, and as aldosterone profiling would not alter diagnostic or treatment strategies, salivary aldosterone measurements in routine practice are of limited clinical value.
27589258	Small, frequent meals (SFMs) are a dietary regimen characterized by multiple small eating episodes throughout the day. Clinical nutrition guidelines recommend SFMs (eg, 6-10 meals) to patients experiencing common symptoms (eg, early satiety) and gastrointestinal-related symptoms. However, whether the provision of SFMs palliatively improves morbidity of nutritionally at-risk individuals has yet to be elucidated. This narrative review summarizes current clinical guidelines recommending SFMs for the management of diseases in adult patients (≥18 years), with supporting experimental and epidemiologic evidence, and it provides suggestions pertaining to this recommendation by drawing on potential considerations from investigations in healthy adults. Limited studies suggest that SFMs may promote higher energy and fluid intakes, reduce gastrointestinal-related symptoms (including vomiting, bloating, and fullness), and prevent postprandial hypotension in patients with primary autonomic failure. Potential health complications related to SFMs include unwarranted weight gain, suboptimal nutrition quality, later meal times, sleep disturbances, limited intermittent fasting, and disordered eating that may exacerbate the underlying disease or related symptoms. Thus, it is prudent for health professionals to supplement SFM recommendations with additional guidance on meal size, frequency, and timing, with a strong emphasis on healthy meal quality. Future research should recognize a standardized definition for SFMs and utilize better methods to obtain reliable data on meal patterns.
27586294	The cardiac Na(+) channel (Nav1.5) conducts a depolarizing inward Na(+) current that is responsible for the generation of the upstroke Phase 0 of the action potential. In heart tissue, changes in Na(+) currents can affect conduction velocity and impulse propagation. The cardiac Nav1.5 is also involved in determination of the action potential duration, since some channels may reopen during the plateau phase, generating a persistent or late inward current. Mutations of cardiac Nav1.5 can induce gain or loss of channel function because of an increased late current or a decrease of peak current, respectively. Gain-of-function mutations cause Long QT syndrome type 3 and possibly atrial fibrillation, while loss-of-function channel mutations are associated with a wider variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, dilated cardiomyopathy, and sick sinus node syndrome. The penetrance and phenotypes resulting from Nav1.5 mutations also vary with age, gender, body temperature, circadian rhythm, and between regions of the heart. This phenotypic variability makes it difficult to correlate genotype-phenotype. We propose that mutations are only one contributor to the phenotype and additional modifications on Nav1.5 lead to the phenotypic variability. Possible modifiers include other genetic variations and alterations in the life cycle of Nav1.5 such as gene transcription, RNA processing, translation, posttranslational modifications, trafficking, complex assembly, and degradation. In this chapter, we summarize potential modifiers of cardiac Nav1.5 that could help explain the clinically observed phenotypic variability. Consideration of these modifiers could help improve genotype-phenotype correlations and lead to new therapeutic strategies. 
27585541	Circadian rhythm is an internal biological clock which initiates and monitors various physiological processes with a fixed time-related schedule. The master circadian pacemaker is located in the suprachiasmatic nucleus in the hypothalamus. The circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels. This cyclical physiological process, which is very complex and multifactorial, may be associated with metabolic alterations, atherosclerosis, impaired cognition, mood disturbances and even development of cancer. Sex differences do exist, and the well-known sleep disturbances associated with menopause are a good example. Circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis.
27585442	Robustness is considered to be an important feature of biological systems which may evolve when the functionality of a trait is associated with higher fitness across multiple environmental conditions. Thus, the ability to maintain stable biological phenotypes across environments is thought to be of adaptive value. Previously, we have reported higher intrinsic activity levels (activity levels of free-running rhythm in constant darkness) and power of rhythm (as assessed by amplitude of the periodogram) in Drosophila melanogaster populations (stocks) reared in constant darkness (DD stocks) as compared to those reared in constant light (LL stocks) and 12:12-h light-dark cycles (LD stocks) for over 19 years (∼330 generations). In the current study, we intended to examine whether the enhanced levels of activity observed in DD stocks persist under various environments such as photoperiods, ambient temperatures, non-24-h light-dark (LD) cycles, and semi-natural conditions (SN). We found that DD stocks largely retain their phenotype of enhanced activity levels across most of the above-mentioned environments suggesting the evolution of robust circadian clocks in DD stocks. Furthermore, we compared the peak activity levels of the three stocks across different environmental conditions relative to their peaks in constant darkness and found that the change in peak activity levels upon entrainment was not significantly different across the three stocks for any of the examined environmental conditions. This suggests that the enhancement of activity levels in DD stocks is not due to differential sensitivity to environment. Thus, these results suggest that rearing in constant darkness (DD) leads to evolution of robust circadian clocks suggesting a possible adaptive value of possessing such rhythms under constant dark environments. 
27584584	Depression has been linked to an imbalance in cortisol. Until recently, cortisol has been studied by measuring concentrations at single time points in blood or saliva samples. Cortisol concentrations vary with circadian rhythm and experiences, from time point to time point. The measurement of hair cortisol concentration (HCC) is a new method of accessing mean, long-term cortisol concentrations. Recent studies show positive associations between depression and HCC, and prenatal maternal cortisol is thought to influence the developing fetus. We therefore examined the association between HCC and self-reported symptoms of depression in second trimester pregnant women. Participants were 181 women, recruited between September 2011 and October 2013 to the Little-in-Norway (LiN)-study. These women answered the Edinburgh Postnatal Depression Rating Scale (EPDS) on self-reported symptoms of depression, and one cm maternal scalp hair was collected and analyzed for cortisol concentrations. Multiple regression analyses did not show depressive symptoms as a predictor for HCC in our selection of pregnant women, while gestational age was significantly related. In conclusion, our study indicated that symptoms of depression during pregnancy did not predict HCC, but further studies of clinically depressed, pregnant women using gestational age as an adjustment variable are warranted. 
27584008	The purpose of this review is to summarize recent developments linking disturbances of sleep and circadian rhythms to an increased risk for obesity, and to review novel research on potential countermeasures.Effective treatments for obesity are limited, with long-term adherence to lifestyle changes proving difficult to maintain. Identifying new preventive strategies based on modifiable risk factors is therefore imperative in the fight against obesity. Disturbances of sleep and circadian rhythms have an adverse impact on food choices, hunger and appetite, and have lifelong deleterious metabolic consequences when they occur during childhood and early adulthood. The upregulation of the endocannabinoid system and abnormalities in the temporal distribution of caloric intake were recently implicated in the link between sleep loss and obesity risk. In addition, alterations in circadian variation in the composition and functionality of the gut microbiome have been identified as potential contributors to metabolic dysfunction during jet lag and shift work. Insufficient sleep and circadian misalignment are thus new modifiable risk factors for obesity. Emerging evidence suggests that novel countermeasures, such as manipulations of the timing of food intake, may be effective strategies in the prevention of obesity.	Four important findings are briefly reviewed: disturbances of sleep and circadian rhythms in children and young adults are risk factors for the development of lifelong obesity; circadian misalignment, as occurs in shift work, has an adverse impact on energy balance and increases the risk of weight gain; the endocannabinoid system, an important regulator of hedonic feeding, could be a potential link between sleep, circadian rhythms, and feeding behavior; and disturbances of the circadian variation in composition of the gut microbiome may be involved in the increased risk of obesity associated with insufficient sleep and circadian misalignment.	
27582458	Cortisol has a distinct circadian rhythm with low concentrations at night, rising in the early hours of the morning, peaking on waking and declining over the day to low concentrations in the evening. Loss of this circadian rhythm, as seen in jetlag and shift work, is associated with fatigue in the short term and diabetes and obesity in the medium to long term. Patients with adrenal insufficiency on current glucocorticoid replacement with hydrocortisone have unphysiological cortisol concentrations being low on waking and high after each dose of hydrocortisone. Patients with adrenal insufficiency complain of fatigue, a poor quality of life and there is evidence of poor health outcomes including obesity potentially related to glucocorticoid replacement. New technologies are being developed that deliver more physiological glucocorticoid replacement including hydrocortisone by subcutaneous pump, Plenadren, a once-daily modified-release hydrocortisone and Chronocort, a delayed and sustained absorption hydrocortisone formulation that replicates the overnight profile of cortisol. In this review, we summarise the evidence regarding physiological glucocorticoid replacement with a focus on relevance to paediatrics.
27582096	Recent studies suggested a direct link between circadian rhythms and regulation of sodium excretion. Endothelin-1 (ET-1) regulates sodium balance by promoting natriuresis through the endothelin B receptor (ETB) in response to increased salt in the diet, but the effect that the time of day has on this natriuretic response is not known. Therefore, this study was designed to test the hypothesis that ETB receptor activation contributes to the diurnal control of sodium excretion and that sex differences contribute to this control as well. Twelve-hour urine collections were used to measure sodium excretion. On day 3 of the experiment, a NaCl load (900 μeq) was given by oral gavage either at Zeitgeber time [ZT] 0 (inactive period) or ZT12 (active period) to examine the natriuretic response to the acute salt load. Male and female ETB-deficient (ETB def) rats showed an impaired natriuretic response to a salt load at ZT0 compared with their respective transgenic controls (Tg cont). Male ETB def rats showed a delayed natriuretic response to a salt load given at ZT12 compared with male Tg cont, a contrast to the prompt response shown by female ETB def rats. Treatment with ABT-627, an ETA receptor antagonist, improved the natriuretic response seen within the first 12 h of a ZT0 salt load in both sexes. These findings demonstrate that diurnal excretion of an acute salt load 1) requires ET-1 and the ETB receptor, 2) is more evident in male vs. female rats, and 3) is opposed by the ETA receptor.
27581876	Task allocation among social insect workers is an ideal framework for studying the molecular mechanisms underlying behavioural plasticity because workers of similar genotype adopt different behavioural phenotypes. Elegant laboratory studies have pioneered this effort, but field studies involving the genetic regulation of task allocation are rare. Here, we investigate the expression of the foraging gene in harvester ant workers from five age- and task-related groups in a natural population, and we experimentally test how exposure to light affects foraging expression in brood workers and foragers. Results from our field study show that the regulation of the foraging gene in harvester ants occurs at two time scales: levels of foraging mRNA are associated with ontogenetic changes over weeks in worker age, location and task, and there are significant daily oscillations in foraging expression in foragers. The temporal dissection of foraging expression reveals that gene expression changes in foragers occur across a scale of hours and the level of expression is predicted by activity rhythms: foragers have high levels of foraging mRNA during daylight hours when they are most active outside the nests. In the experimental study, we find complex interactions in foraging expression between task behaviour and light exposure. Oscillations occur in foragers following experimental exposure to 13 L : 11 D (LD) conditions, but not in brood workers under similar conditions. No significant differences were seen in foraging expression over time in either task in 24 h dark (DD) conditions. Interestingly, the expression of foraging in both undisturbed field and experimentally treated foragers is also significantly correlated with the expression of the circadian clock gene, cycle Our results provide evidence that the regulation of this gene is context-dependent and associated with both ontogenetic and daily behavioural plasticity in field colonies of harvester ants. Our results underscore the importance of assaying temporal patterns in behavioural gene expression and suggest that gene regulation is an integral mechanism associated with behavioural plasticity in harvester ants. 
27581451	A sensitivity of the circadian clock to light/dark cycles ensures that biological rhythms maintain optimal phase relationships with the external day. In animals, the circadian clock neuron network (CCNN) driving sleep/activity rhythms receives light input from multiple photoreceptors, but how these photoreceptors modulate CCNN components is not well understood. Here we show that the Hofbauer-Buchner eyelets differentially modulate two classes of ventral lateral neurons (LNvs) within the Drosophila CCNN. The eyelets antagonize Cryptochrome (CRY)- and compound-eye-based photoreception in the large LNvs while synergizing CRY-mediated photoreception in the small LNvs. Furthermore, we show that the large LNvs interact with subsets of "evening cells" to adjust the timing of the evening peak of activity in a day length-dependent manner. Our work identifies a peptidergic connection between the large LNvs and a group of evening cells that is critical for the seasonal adjustment of circadian rhythms.In animals, circadian clocks have evolved to orchestrate the timing of behavior and metabolism. Consistent timing requires the entrainment these clocks to the solar day, a process that is critical for an organism's health. Light cycles are the most important external cue for the entrainment of circadian clocks, and the circadian system uses multiple photoreceptors to link timekeeping to the light/dark cycle. How light information from these photorecptors is integrated into the circadian clock neuron network to support entrainment is not understood. Our results establish that input from the HB eyelets differentially impacts the physiology of neuronal subgroups. This input pathway, together with input from the compound eyes, precisely times the activity of flies under long summer days. Our results provide a mechanistic model of light transduction and integration into the circadian system, identifying new and unexpected network motifs within the circadian clock neuron network.	
27581301	Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction.
27579611	School start time influences sleep parameters. Differences between circadian sleep parameters on weekends and weekdays have been associated with obesity, sleep, and psychiatric disorders. Moreover, circadian rhythm dysregulation affects the secretion of some hormones, such as melatonin and cortisol. In the current study, we investigate the effect of school start time on cortisol and melatonin levels in a community sample of Brazilian children and adolescents. This was a cross-sectional study of 454 students (mean age, 12.81 ± 2.56 years; 58.6% female). From this sample, 80 participants were randomly selected for saliva collection to measure melatonin and cortisol levels. Circadian sleep parameters were assessed by self-reported sleep and wake up schedules and the Morningness-Eveningness Questionnaire. The outcomes, salivary melatonin and cortisol levels, were measured in morning, afternoon and night saliva samples, and behavior problems were assessed using the Child Behavior Checklist (CBCL). The main results revealed that morning school start time decreased the secretion of melatonin. Morning melatonin levels were significantly positively correlated with the sleep midpoint on weekdays and on weekends. Afternoon melatonin levels were positively correlated with the sleep midpoint on weekends in the morning school students. Conversely, in the afternoon school students, night melatonin levels were negatively correlated with the sleep midpoint on weekdays. Cortisol secretion did not correlate with circadian sleep parameters in any of the school time groups. In conclusion, school start time influences melatonin secretion, which correlated with circadian sleep parameters. This correlation depends on the presence of psychiatric symptoms. Our findings emphasize the importance of drawing attention to the influence of school start time on the circadian rhythm of children and adolescents.
27577847	Although the prevailing paradigm has held that the polar night is a period of biological quiescence, recent studies have detected noticeable activity levels in marine organisms. In this study, we investigated the circadian rhythm of the scallop Chlamys islandica by continuously recording the animal's behaviour over 3 years in the Arctic (Svalbard). Our results showed that a circadian rhythm persists throughout the polar night and lasts for at least 4 months. Based on observations across three polar nights, we showed that the robustness and synchronicity of the rhythm depends on the angle of the sun below the horizon. The weakest rhythm occurred at the onset of the polar night during the nautical twilight. Surprisingly, the circadian behaviour began to recover during the darkest part of the polar night. Because active rhythms optimize the fitness of an organism, our study brings out that the scallops C. islandica remain active even during the polar night. 
27577611	Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. 
27576939	Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms. 
27575405	Circadian clocks control physiology and behavior of organisms in synchrony with external light dark cycles in changing photoperiods. The Madeira cockroach Rhyparobia maderae was the first model organism in which an endogenous circadian clock in the brain was identified. About 240 neurons constitute the cockroach circadian pacemaker network in the accessory medulla. The expression of high concentrations of neuropeptides, among them the most prominent circadian coupling factor pigment-dispersing factor, as well as their ability to generate endogenous ultradian and circadian rhythms in electrical activity and clock gene expression distinguish these pacemaker neurons. We assume that entrainment to light-dark cycles and the control of 24h rest-activity rhythms is achieved via peptidergic circuits forming autoreceptive labeled lines.
27573826	Well-established fine-scale urban mobility models today depend on detailed but cumbersome and expensive travel surveys for their calibration. Not much is known, however, about the set of mechanisms needed to generate complete mobility profiles if only using passive datasets with mostly sparse traces of individuals. In this study, we present a mechanistic modeling framework (TimeGeo) that effectively generates urban mobility patterns with resolution of 10 min and hundreds of meters. It ties together the inference of home and work activity locations from data, with the modeling of flexible activities (e.g., other) in space and time. The temporal choices are captured by only three features: the weekly home-based tour number, the dwell rate, and the burst rate. These combined generate for each individual: (i) stay duration of activities, (ii) number of visited locations per day, and (iii) daily mobility networks. These parameters capture how an individual deviates from the circadian rhythm of the population, and generate the wide spectrum of empirically observed mobility behaviors. The spatial choices of visited locations are modeled by a rank-based exploration and preferential return (r-EPR) mechanism that incorporates space in the EPR model. Finally, we show that a hierarchical multiplicative cascade method can measure the interaction between land use and generation of trips. In this way, urban structure is directly related to the observed distance of travels. This framework allows us to fully embrace the massive amount of individual data generated by information and communication technologies (ICTs) worldwide to comprehensively model urban mobility without travel surveys. 
27568888	Patients with circadian rhythm sleep disorders (CRSDs) often have coincidence of orthostatic dysregulation (OD). Both disorders have many common clinical features. However, the prevalence of OD in patients with CRSD has not been examined.Thirty-eight patients with CRSD with either delayed sleep phase disorder or free-running disorder were tested for OD using the new orthostatic test, which was originally established by Tanaka et al. (< 20 years) and the Schellong test, i.e., the active standing test (≥ 20 years).	The overall prevalence of OD in patients with CRSD was 57.9% (22/38), and prevalence of OD was 70% in patients under 20 years of age (14/20). These rates exceed the previously reported values in adolescents aged 14-15 years (15%), regarded as the age with highest OD prevalence. Prevalence was not significantly associated with CRSD severity and medications used.	We observed a high prevalence of OD in patients with CRSD, suggesting some relationship between CRSD and OD. Large-scale case-control studies are warranted to investigate the underlying mechanisms for this comorbidity.	
27568854	The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy. 
27568798	Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia.EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities (Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings.	Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia.	These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome.	
27568590	As the central pacemaker in mammals, the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is a heterogeneous structure consisting of multiple types of GABAergic neurons with distinct chemical identities [1, 2]. Although individual cells have a cellular clock driven by autoregulatory transcriptional/translational feedback loops of clock genes, interneuronal communication among SCN clock neurons is likely essential for the SCN to generate a highly robust, coherent circadian rhythm [1]. However, neuronal mechanisms that determine circadian period length remain unclear. The SCN is composed of two subdivisions: a ventral core region containing vasoactive intestinal peptide (VIP)-producing neurons and a dorsal shell region characterized by arginine vasopressin (AVP)-producing neurons. Here we examined whether AVP neurons act as pacemaker cells that regulate the circadian period of behavior rhythm in mice. The deletion of casein kinase 1 delta (CK1δ) specific to AVP neurons, which was expected to lengthen the period of cellular clocks [3-6], lengthened the free-running period of circadian behavior as well. Conversely, the overexpression of CK1δ specific to SCN AVP neurons shortened the free-running period. PER2::LUC imaging in slices confirmed that cellular circadian periods of the SCN shell were lengthened in mice without CK1δ in AVP neurons. Thus, AVP neurons may be an essential component of circadian pacemaker cells in the SCN. Remarkably, the alteration of the shell-core phase relationship in the SCN of these mice did not impair the generation per se of circadian behavior rhythm, thereby underscoring the robustness of the SCN network. 
27567825	We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.
27566781	We tested whether a sleep and circadian-based treatment shown to improve circadian adaptation to night shifts and attenuate negative effects on alertness, performance and sleep in young adults would also be effective in older adults.We assessed subjective alertness, sustained attention (psychomotor vigilance task, PVT), sleep duration (actigraphy) and circadian timing (salivary dim-light melatonin onset, DLMO) in 18 older adults (57.2±3.8 years; mean±SD) in a simulated shift work protocol. 4 day shifts were followed by 3 night shifts in the laboratory. Participants slept at home and were randomised to either the treatment group (scheduled evening sleep and enhanced lighting during the latter half of night shifts) or control group (ad-lib sleep and typical lighting during night shifts).	Compared with day shifts, alertness and sustained attention declined on the first night shift in both groups, and was worse in the latter half of the night shifts. Alertness and attention improved on nights 2 and 3 for the treatment group but remained lower for the control group. Sleep duration in the treatment group remained similar to baseline (6-7 hours) following night shifts, but was shorter (3-5 hours) following night shifts in the control group. Treatment group circadian timing advanced by 169.3±16.1 min (mean±SEM) but did not shift (-9.7±9.9 min) in the control group.	The combined treatment of scheduled evening sleep and enhanced lighting increased sleep duration and partially aligned circadian phase with sleep and work timing, resulting in improved night shift alertness and performance.	
27566064	Disruption of the maternal environment during pregnancy leads to behavioral changes and diseases in the adult offspring. To explore the influence of prenatal continuous light exposure (PCLE) on the adult offspring, we exposed pregnant Wistar rats to constant light during late gestation. Adult PCLE offspring showed an anxiety-like behavior and impairment of short-term memory in different tests. Measurements in the whole brain homogenates from newborn and adult offspring indicated decreased melatonin and serotonin levels and increased reactive oxygen species level in PCLE offspring. Further, we determined melatonin-, serotonin-, oxidative stress-, apoptosis-, and circadian system-related genes expression in different brain areas of adult offspring. The serotonin reuptaker Slc6a4 displayed a decreased expression in the prefrontal cortex of PCLE group. The circadian rhythm-related gene Rora was upregulated in the amygdala of PCLE offspring. Our results point to adverse behavioral effects of PCLE on adult offspring, involving serotonin and melatonin signaling dysregulation, increased chronic oxidative stress, and altered gene expression.
27562056	Shiftworkers run an increased risk of developing metabolic disorders, presumably as a result of disturbed circadian physiology. Eating at a time-of-day that is normally dedicated to resting and fasting, may contribute to this association. The hypothalamus is the key brain area that integrates different inputs, including environmental time information from the central biological clock in the suprachiasmatic nuclei, with peripheral information on energy status to maintain energy homeostasis. The orexin system within the lateral hypothalamus is an important output of the suprachiasmatic nuclei involved in the control of sleep/wake behavior and glucose homeostasis, among other functions. In this study, we tested the hypothesis that feeding during the rest period disturbs the orexin system as a possible underlying contributor to metabolic health problems. Male Wistar rats were exposed to an 8-week protocol in which food was available ad libitum for 24-h, for 12-h during the light phase (i.e., unnatural feeding time) or for 12-h during the dark phase (i.e., restricted feeding, but at the natural time-of-day). Animals forced to eat at an unnatural time, i.e., during the light period, showed no changes in orexin and orexin-receptor gene expression in the hypothalamus, but the rhythmic expression of clock genes in the lateral hypothalamus was absent in these animals. Light fed animals did show adverse changes in whole-body physiology and internal desynchronization of muscle and liver clock and metabolic gene expression. Eating at the 'wrong' time-of-day thus causes internal desynchronization at different levels, which in the long run may disrupt body physiology.
27560640	Micro RNAs (miRNAs) are small regulatory molecules of increasing biologists' interest. miRNAs, unlikely mRNA, do not encode proteins. It is a class of small double stranded RNA molecules that via their seed sequence interact with mRNA and inhibit its expression. It has been estimated that 30% of human gene expression is regulated by miRNAs. One miRNA usually targets several mRNAs and one mRNA can be regulated by several miRNAs. miRNA biogenesis is realized by key enzymes, Drosha and Dicer. miRNA/mRNA interaction depends on binding to RNA-induced silencing complex. Today, complete commercially available methodical proposals for miRNA investigation are available. There are techniques allowing the identification of new miRNAs and new miRNA targets, validation of predicted targets, measurement of miRNAs and their precursor levels, and validation of physiological role of miRNAs under in vitro and in vivo conditions. miRNAs have been shown to influence gene expression in several endocrine glands, including pancreas, ovary, testes, hypothalamus, and pituitary.
27560632	A disturbance of sensorimotor gating measured by prepulse inhibition of acoustic startle (PPI) is one of the best tests of the schizophrenia-like behavior. Vasopressin was implicated in the development of schizophrenia; therefore, the naturally occurring vasopressin-deficient Brattleboro rat has been suggested to be a reliable non-pharmacological animal model. However, previous studies focusing on PPI deficit did not use proper control and despite clear gender differences in the development of the disorder, the effect of gender has been mostly neglected.First, we compared the "noise" and "tone" type prepulse at 73-77-81 dB intensity during the light or dark phase using small (~150 g) or big (~500 g) Wistar rats. The test parameters were validated by a pharmacological schizophrenia model (30 mg/kg ketamine i.p.). Than male, female, and lactating vasopressin-deficient animals were compared with +/+ ones.	We established that the prepulse "noise" type is not optimal for PPI testing. The cycle of the day as well as the body weight had no effect on PPI. Even if we compared vasopressin-deficient animals with their closely related +/+ controls, the PPI deficiency was visible with more pronounced effect at 77 dB prepulse intensity similarly to pharmacological schizophrenia model. Despite our expectation, the gender as well as lactation had no effect on the vasopressin-deficiency induced PPI deficit.	The present data confirmed and extended our previous studies that vasopressin-deficient rat is a good model of schizophrenia. It seems that female as well as lactating Brattleboro rats are useful tools for testing putative novel antipsychotics in line with special attention required for schizophrenic women.	
27559298	The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. AhR binds a range of ligands, which prompts protein-protein interactions with other Per-Arnt-Sim (PAS)-domain-containing proteins and subsequent transcriptional activity. This review focuses on the reciprocal crosstalk between the activated AhR and the molecular circadian clock. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR activation influences the amplitude and phase of expression of circadian clock genes, hormones, and the behavioral responses of the clock system to changes in environmental illumination. Both the clock and AhR status and activation play significant and underappreciated roles in metabolic homeostasis. This review highlights the state of knowledge regarding how AhR may act together with the circadian clock to influence energy metabolism. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism. 
27559270	While many intertidal animals exhibit circatidal rhythms, the nature of the underlying endogenous clocks that control these rhythms has been controversial. In this study American horseshoe crabs, Limulus polyphemus, were used to test the circalunidian hypothesis by exposing them to four different tidal regimes. Overall, the results obtained support the circalunidian hypothesis: each of the twice-daily rhythms of activity appears to be controlled by a separate clock, each with an endogenous period of approximately 24.8h. First, spontaneous "skipping" of one of the daily bouts was observed under several different conditions. Second, the presence of two bouts of activity/day, with different periods, was observed. Lastly, we were able to separately synchronize bouts of activity to two artificial tidal regimes with different periods. These results, taken together, argue in favor of two separate circalunidian clocks in Limulus, each of which controls one of the two bouts of their daily tidal activity rhythms.
27558731	Circadian rhythms are endogenously generated daily oscillations in physiology that are found in all kingdoms of life. Experimental studies have shown that the fitness of Synechococcus elongatus, a photosynthetic microorganism, is severely affected in non-24-h environments. However, it has been difficult to study the effects of clock-environment mismatch on cellular physiology because such measurements require a precise determination of both clock state and growth rate in the same cell. Here, we designed a microscopy platform that allows us to expose cyanobacterial cells to pulses of light and dark while quantitatively measuring their growth, division rate, and circadian clock state over many days. Our measurements reveal that decreased fitness can result from a catastrophic growth arrest caused by unexpected darkness in a small subset of cells with incorrect clock times corresponding to the subjective morning. We find that the clock generates rhythms in the instantaneous growth rate of the cell, and that the time of darkness vulnerability coincides with the time of most rapid growth. Thus, the clock mediates a fundamental trade-off between growth and starvation tolerance in cycling environments. By measuring the response of the circadian rhythm to dark pulses of varying lengths, we constrain a mathematical model of a population's fitness under arbitrary light/dark schedules. This model predicts that the circadian clock is only advantageous in highly regular cycling environments with frequencies sufficiently close to the natural frequency of the clock. 
27558096	Temporally coordinated resorption and synthesis is the key to maintaining healthy bones. Articular cartilage is a highly specialized connective tissue within the joints that lines the surface of a long bone. Emerging evidence has suggested a critical role of the circadian system in controlling cartilage and bone biology. Articular cartilage is sparsely populated with chondrocytes, surrounded by abundant extracellular matrices that are synthesized and maintained solely by chondrocytes. Once damaged, the articular cartilage tissue has poor capacity for endogenous repair, leaving the joints prone to osteoarthritis, an age-related painful condition that affects millions of individuals worldwide. An important question is how articular cartilage has evolved its remarkable capacity to maintain homeostasis and withstand daily biomechanical challenges associated with resting/activity cycles. Equally important is how this avascular and aneural tissue senses time and uses this information to coordinate daily phases of metabolic activity and tissue remodeling/repair. Bone tissue derived from cartilage has similarly sparse populations of resident cells living in dense and largely mineralized matrices. We discuss recent progress on circadian clocks in these matrix-rich skeletal tissues and highlight avenues for future research. 
27557747	The term "adrenal fatigue" ("AF") has been used by some doctors, healthcare providers, and the general media to describe an alleged condition caused by chronic exposure to stressful situations. Despite this, "AF" has not been recognized by any Endocrinology society, who claim there is no hard evidence for the existence. The aim of this systematic review is to verify whether there is substantiation for "AF".A systematic search was performed at PUBMED, MEDLINE (Ebsco) and Cochrane databases, from the beginning of the data until April 22nd, 2016. Searched key words were: "adrenal" + "fatigue", "adrenal" + "burnout", "adrenal" + "exhaustion", "hypoadrenia", "burnout" + "cortisol", "fatigue" + "cortisol", "clinical" + "burnout", "cortisol" + "vitalility", "adrenal" + "vitality", and "cortisol" + "exhaustion". Eligibility criteria were: (1) articles written in English, (2) cortisol profile and fatigue or energy status as the primary outcome, (3) performed tests for evaluating the adrenal axis, (4) absence of influence of corticosteroid therapy, and (5) absence of confounding diseases. Type of questionnaire to distinct fatigued subjects, population studied, tests performed of selected studies were analyzed.	From 3,470 articles found, 58 studies fulfilled the criteria: 33 were carried in healthy individuals, and 25 in symptomatic patients. The most assessed exams were "Direct Awakening Cortisol" (n = 29), "Cortisol Awakening Response" (n = 27) and "Salivary Cortisol Rhythm" (n = 26).	We found an almost systematic finding of conflicting results derived from most of the studies methods utilized, regardless of the validation and the quality of performed tests. Some limitations of the review include: (1) heterogeneity of the study design; (2) the descriptive nature of most studies; (3) the poor quality assessment of fatigue; (4) the use of an unsubstantiated methodology in terms of cortisol assessment (not endorsed by endocrinologists); (5) false premises leading to an incorrect sequence of research direction; and, (6) inappropriate/invalid conclusions regarding causality and association between different information.	This systematic review proves that there is no substantiation that "adrenal fatigue" is an actual medical condition. Therefore, adrenal fatigue is still a myth.	
27556115	To collect data on treatment of behavioural sleep disorders in children and adolescents.A literature review based on the PUBMED database.	Based on the analysed materials three basic complementary procedures were identified - implementation of sleep hygiene, behavioural interventions and pharmacological treatment. The rules of sleep hygiene proven to be effective include: regular sleep schedule, adequately prepared place to sleep (a dark, quiet bedroom without multimedia), bedtime routine, avoiding caffeinated beverages. The following issues require further studies to confirm their effectiveness: falling asleep independently without parent's assistance, bedtime reading, physical activity, reducing daytime multimedia use, tryptophan rich breakfasts. Behavioural interventions and pharmacological treatment may in some cases be temporarily implemented to complement the sleep hygiene.	The implementation of sleep hygiene is a primary, fully acceptable to the child and parents, way to improve the baby sleep. In case of ineffectiveness of the proposed rules, those can be complemented with behavioural methods that are highly effective but some parents do not accept them or make mistakes in their introduction. Pharmacotherapy can be used as a temporary support for families with severe behavioural problems as an aid in the implementation of sleep hygiene and behavioural methods.	
27556114	Insomnia presents an increasing and significant health issue in paediatric population. As the problem had grown over past decade, it became recognised by the specialists dealing with children and adolescents. In a recent study American Academy of Child and Adolescent Psychiatry members were asked about their experience with patients complaining about sleep disturbances. Doctors reported that sleep was a problem for 1/3 of their patients out of which 1/4 required pharmacotherapy [1]. Multiple studies concerning adults confirmed significance of healthy sleep in optimal cognitive, emotional, social and biological functioning. Adequate sleep is important in prophylaxis of many chronic diseases such as obesity, diabetes, hypertension, myocardial infarction, stroke [2]. Due to increasing prevalence of insomnia in children and adolescents growing attention is paid to its short and long term consequences in this group. This review summarises available data on chronic insomnia prevalence and its consequences in population under 18 years old. 
27554418	Studies have demonstrated a pronounced dependence of memory formation on circadian time; however, the numerous mechanisms underlying this reliance are only beginning to be understood. While the 24-h cellular clock controls various aspects of hippocampal memory formation, its consolidation in particular (i.e., its conversion from short-term to long-term memory), appears to be heavily dependent on circadian activity in hippocampal neurons. Hippocampal memory consolidation requires phosphorylation of the cAMP Response Element-Binding protein, CREB, which upon phosphorylation promotes the transcription of genes necessary for long-term memory formation. Rhythmic cAMP/ERK-MAPK activity upstream of CREB is a necessary component. This Editorial highlights a study by Rawashdeh and coworkers, in which the authors establish the circadian clock gene Period1 (Per1) as a regulator of CREB phosphorylation in the mouse hippocampus, and thus reveal a functional link between circadian rhythms and learning efficiency. Read the highlighted article 'Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK' on page 731. 
27551048	Serum glucocorticoids play a critical role in synchronizing circadian rhythm in peripheral tissues, and multiple mechanisms regulate tissue sensitivity to glucocorticoids. In the skeleton, circadian rhythm helps coordinate bone formation and resorption. Circadian rhythm is regulated through transcriptional and post-transcriptional feedback loops that include microRNAs. How microRNAs regulate circadian rhythm in bone is unexplored. We show that in mouse calvaria, miR-433 displays robust circadian rhythm, peaking just after dark. In C3H/10T1/2 cells synchronized with a pulse of dexamethasone, inhibition of miR-433 using a tough decoy altered the period and amplitude of Per2 gene expression, suggesting that miR-433 regulates rhythm. Although miR-433 does not directly target the Per2 3'-UTR, it does target two rhythmically expressed genes in calvaria, Igf1 and Hif1α. miR-433 can target the glucocorticoid receptor; however, glucocorticoid receptor protein abundance was unaffected in miR-433 decoy cells. Rather, miR-433 inhibition dramatically enhanced glucocorticoid signaling due to increased nuclear receptor translocation, activating glucocorticoid receptor transcriptional targets. Last, in calvaria of transgenic mice expressing a miR-433 decoy in osteoblastic cells (Col3.6 promoter), the amplitude of Per2 and Bmal1 mRNA rhythm was increased, confirming that miR-433 regulates circadian rhythm. miR-433 was previously shown to target Runx2, and mRNA for Runx2 and its downstream target, osteocalcin, were also increased in miR-433 decoy mouse calvaria. We hypothesize that miR-433 helps maintain circadian rhythm in osteoblasts by regulating sensitivity to glucocorticoid receptor signaling.
27550400	Only implantable cardioverter defibrillators (ICD) have been proven to prevent sudden cardiac death (SCD) in patients with Brugada syndrome (BrS). However, ICD discharge, whether appropriate or inappropriate, leads to impaired quality of life and even increases rehospitalization. Quinidine might prevent the recurrence of ventricular arrhythmia (VA); however, the effect of low-dose quinidine for preventing spontaneous arrhythmias remains less clear.In our cardiology center, 10 confirmed patients with BrS (all men, mean age 38.7 ± 6.72 years) who underwent appropriate ICD shocks due to recurrent VAs were treated with quinidine (≤200 mg/day) and followed regularly.	All the patients underwent ICD shocks due to ventricular tachycardia (VT)/ventricular fibrillation (VF) before taking quinidine. A 24-hour distribution of VT/VF demonstrated that most of the events occurred in the sleeping time from 22:00 to 8:00. Quinidine prevented recurrence of VAs in nine patients. The other one patient took quinidine discontinuously because of anxiety suffered from less episodes of VA, and after psychological guidance, he took quinidine 200 mg/day and experienced no VA episodes from then on. In our series, only one patient suffered leukopenia related to quinidine. No other side effect was observed.	Quinidine with a very low dose (≤200 mg/day) well controlled VT/VF recurrence for a long-term period in Chinese patients with BrS. Administration (at 21:00) according to the circadian distribution of VT/VF episodes might increase the efficiency and improve the patient's tolerance.	
27549931	Shift work is often associated with sleepiness and sleep disorders. Person-directed, non-pharmacological interventions may positively influence the impact of shift work on sleep, thereby improving workers' well-being, safety, and health.To assess the effects of person-directed, non-pharmacological interventions for reducing sleepiness at work and improving the length and quality of sleep between shifts for shift workers.	We searched CENTRAL, MEDLINE Ovid, Embase, Web of Knowledge, ProQuest, PsycINFO, OpenGrey, and OSH-UPDATE from inception to August 2015. We also screened reference lists and conference proceedings and searched the World Health Organization (WHO) Trial register. We contacted experts to obtain unpublished data.	Randomised controlled trials (RCTs) (including cross-over designs) that investigated the effect of any person-directed, non-pharmacological intervention on sleepiness on-shift or sleep length and sleep quality off-shift in shift workers who also work nights.	At least two authors screened titles and abstracts for relevant studies, extracted data, and assessed risk of bias. We contacted authors to obtain missing information. We conducted meta-analyses when pooling of studies was possible.	We included 17 relevant trials (with 556 review-relevant participants) which we categorised into three types of interventions: (1) various exposures to bright light (n = 10); (2) various opportunities for napping (n = 4); and (3) other interventions, such as physical exercise or sleep education (n = 3). In most instances, the studies were too heterogeneous to pool. Most of the comparisons yielded low to very low quality evidence. Only one comparison provided moderate quality evidence. Overall, the included studies' results were inconclusive. We present the results regarding sleepiness below. Bright light Combining two comparable studies (with 184 participants altogether) that investigated the effect of bright light during the night on sleepiness during a shift, revealed a mean reduction 0.83 score points of sleepiness (measured via the Stanford Sleepiness Scale (SSS) (95% confidence interval (CI) -1.3 to -0.36, very low quality evidence). Another trial did not find a significant difference in overall sleepiness on another sleepiness scale (16 participants, low quality evidence).Bright light during the night plus sunglasses at dawn did not significantly influence sleepiness compared to normal light (1 study, 17 participants, assessment via reaction time, very low quality evidence).Bright light during the day shift did not significantly reduce sleepiness during the day compared to normal light (1 trial, 61 participants, subjective assessment, low quality evidence) or compared to normal light plus placebo capsule (1 trial, 12 participants, assessment via reaction time, very low quality evidence). Napping during the night shiftA meta-analysis on a single nap opportunity and the effect on the mean reaction time as a surrogate for sleepiness, resulted in a 11.87 ms reduction (95% CI 31.94 to -8.2, very low quality evidence). Two other studies also reported statistically non-significant decreases in reaction time (1 study seven participants; 1 study 49 participants, very low quality evidence).A two-nap opportunity resulted in a statistically non-significant increase of sleepiness (subjective assessment) in one study (mean difference (MD) 2.32, 95% CI -24.74 to 29.38, 1 study, 15 participants, low quality evidence). Other interventionsPhysical exercise and sleep education interventions showed promise, but sufficient data to draw conclusions are lacking.	Given the methodological diversity of the included studies, in terms of interventions, settings, and assessment tools, their limited reporting and the very low to low quality of the evidence they present, it is not possible to determine whether shift workers' sleepiness can be reduced or if their sleep length or quality can be improved with these interventions.We need better and adequately powered RCTs of the effect of bright light, and naps, either on their own or together and other non-pharmacological interventions that also consider shift workers' chronobiology on the investigated sleep parameters.	
27546572	Biological clocks allow organisms to anticipate daily environmental changes such as temperature fluctuations, abundance of daylight, and nutrient availability. Many circadian-controlled physiological states are coordinated by the release of systemically acting hormones, including steroids and insulin [1-7]. Thus, hormones relay circadian outputs to target tissues, and disrupting these endocrine rhythms impairs human health by affecting sleep patterns, energy homeostasis, and immune functions [8-10]. It is largely unclear, however, whether circadian circuits control hormone levels indirectly via central timekeeping neurons or whether peripheral endocrine clocks can modulate hormone synthesis directly. We show here that perturbing the circadian clock, specifically in the major steroid hormone-producing gland of Drosophila, the prothoracic gland (PG), unexpectedly blocks larval development due to an inability to produce sufficient steroids. This is surprising, because classic circadian null mutants are viable and result in arrhythmic adults [4, 11-14]. We found that Timeless and Period, both core components of the insect clock [15], are required for transcriptional upregulation of steroid hormone-producing enzymes. Timeless couples the circadian machinery directly to the two canonical pathways that regulate steroid synthesis in insects, insulin and PTTH signaling [16], respectively. Activating insulin signaling directly modulates Timeless function, suggesting that the local clock in the PG is normally synced with systemic insulin cues. Because both PTTH and systemic insulin signaling are themselves under circadian control, we conclude that de-synchronization of a local endocrine clock with external circadian cues is the primary cause for steroid production to fail. 
27546460	The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping. 
27545669	This study examined the link between circadian rhythm changes due to bright light exposure and subthreshold bipolarity. Molecular circadian rhythms, polysomnography, and actigraphy data were studied in 25 young, healthy male subjects, divided into high and low mood disorder questionnaire (MDQ) score groups. During the first 2 days of the study, the subjects were exposed to daily-living light (150 lux) for 4 hours before bedtime. Saliva and buccal cells were collected 5 times a day for 2 consecutive days. During the subsequent 5 days, the subjects were exposed to bright light (1,000 lux), and saliva and buccal cell samples were collected in the same way. Molecular circadian rhythms were analyzed using sine regression. Circadian rhythms of cortisol (F = 16.956, p < 0.001) and relative PER1/ARNTL gene expression (F = 122.1, p < 0.001) showed a delayed acrophase in both groups after bright light exposure. The high MDQ score group showed a significant delay in acrophase compared to the low MDQ score group only in salivary cortisol (F = 8.528, p = 0.008). The high MDQ score group showed hypersensitivity in cortisol rhythm shift after bright light exposure, suggesting characteristic molecular circadian rhythm changes in the high MDQ score group may be related to biological processes downstream from core circadian clock gene expression. 
27544998	Hericium erinaceus (HE), an edible mushroom, has been used as a herbal medicine in several Asian countries since ancient times. HE has potential as a medicine for the treatment and prevention of dementia, a disorder closely linked with circadian rhythm. This study investigated the effects of the intake of HE extracts on behavioral rhythm, photosensitivity of the circadian clock, and clock gene mRNA expression in the suprachiasmatic nucleus (SCN), a central clock, in mice. Although the HE ethanol extract only affected the offset time of activity, the HE water extract advanced the sleep-wake cycle without affecting the free-running period, photosensitivity, or the clock gene mRNA expression in SCN. In addition, both extracts decreased wakefulness around end of active phase. The findings of the present study suggest that HE may serve as a functional food in the prevention and treatment of Alzheimer's disease and delayed sleep phase syndrome. 
27544836	The brainstem is among the first regions affected in progressive supranuclear palsy (PSP) and is part of the sleep/circadian regulation network. In two small studies, blood pressure and core body temperature circadian patterns were disrupted in PSP; however, it is unclear if circadian activity rhythms are also affected. Our objective was to perform circadian analyses of the rest-activity rhythms in PSP and determine the association with increasing disease severity.Individuals with a clinical PSP diagnosis (n = 17; nine men) and healthy older adults (n = 17; nine men) were selected for this study. Participants wore actigraphy wristbands and completed sleep diaries for up to 14 consecutive days. Data were analyzed to assess circadian activity strength (amplitude, mesor, f-ratio), phase (acrophase), and circadian stability (intradaily variability, interdaily stability, relative amplitude). Analyses controlled for sleep fragmentation, cognition, and self-reported depression. The association between disease severity using the PSP rating scale and circadian activity rhythm disruption was assessed.	Individuals with PSP had significantly lower circadian activity mesor (p ≤ 0.001), amplitude (p ≤ 0.001), robustness (f-ratio, p <0.01), relative amplitude (p ≤ 0.001), and interdaily stability (p ≤ 0.01), with increased intradaily variability (p <0.05). CAR remained weaker in PSP after controlling for sleep fragmentation, and again when also controlling for cognitive impairment and depression. Weaker circadian activity (mesor, amplitude, f-ratio, and relative amplitude) was associated with increased disease severity.	Circadian activity rhythms are disrupted in individuals with PSP as compared to controls, and worsen with disease severity. This is the first study of its kind to describe circadian activity rhythms in PSP.	
27543154	Disturbances in circadian rhythms have been suggested as a possible cause of bipolar disorder (BD). Included in this study were 31 mood episodes of 26 BD patients, and 18 controls. Circadian rhythms of BD were evaluated at admission, at 2-week intervals during hospitalization, and at discharge. All participants wore wrist actigraphs during the studies. Saliva and buccal cells were obtained at 8:00, 11:00, 15:00, 19:00, and 23:00 for two consecutive days. Collected saliva and buccal cells were used for analysis of the cortisol and gene circadian rhythm, respectively. Circadian rhythms had different phases during acute mood episodes of BD compared to recovered states. In 23 acute manic episodes, circadian phases were ~7hour advanced (equivalent to ~17hour delayed). Phases of 21 out of these 23 cases returned to normal by ~7hour delay along with treatment, but two out of 23 cases returned to normal by ~17hour advance. In three cases of mixed manic episodes, the phases were ~6-7hour delayed. For five cases of depressive episodes, circadian rhythms phases were ~4-5hour delayed. After treatment, circadian phases resembled those of healthy controls. Circadian misalignment due to circadian rhythm phase shifts might be a pathophysiological mechanism of BD.
27542884	Delayed sleep-wake phase disorder (DSWPD) is commonly defined as an inability to fall asleep and wake at societal times resulting in excessive daytime sleepiness. Although the cause is multifaceted, delays in sleep time are largely driven by misalignment between the circadian pacemaker and the desired sleep-wake timing schedule. Current treatment approaches focus on correcting the circadian delay; however, there is a lack of data investigating combined therapies for treatment of DSWPD. 
27542830	Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period (dper), a core clock gene that encodes a critical component of the circadian oscillator, we showed that dper codon usage is important for circadian clock function. Codon optimization of dper resulted in conformational changes of the dPER protein, altered dPER phosphorylation profile and stability, and impaired dPER function in the circadian negative feedback loop, which manifests into changes in molecular rhythmicity and abnormal circadian behavioral output. This study provides an in vivo example that demonstrates the role of codon usage in determining protein structure and function in an animal system. These results suggest a universal mechanism in eukaryotes that uses a codon usage "code" within genetic codons to regulate cotranslational protein folding. 

27539946	To investigate the difference between nurses and the general population regarding seasonal variations in sleep disorders during 2004-2008. The effects of season and group interaction on sleep disorders with regard to different comorbidities were also examined.Studies on seasonal variations in sleep disorders were mainly conducted in Norway for the general population. Furthermore, whether different comorbidities cause seasonal variations in sleep disorders in nurses remains unknown.	A retrospective study.	Data from the Taiwan National Health Insurance Research Database were used in generalised estimating equation Poisson distribution models to investigate the differences in sleep disorders between nurses and the general population diagnosed with sleep disorders (each n = 7643) as well as the interaction effects of sleep disorders between the groups with respect to different seasons. Furthermore, the interaction effects between groups and seasons on sleep disorders in the subgroups of comorbid anxiety disorders and depressive disorders were studied.	Both the nurses and the general population had fewer outpatient visits for sleep disorders in winter than in other seasons. The nurses had fewer outpatient visits for sleep disorders than the general population did in each season. The nurses had more outpatient visits for sleep disorders in winter than in summer compared with the general population in the comorbid depressive disorder subgroup but not in the comorbid anxiety disorder subgroup.	Nurses and the general population exhibited similar seasonal patterns of sleep disorders, but nurses had fewer outpatient visits for sleep disorders than the general population did in each season. For nurses with comorbid depressive disorders, outpatient visits for sleep disorders were more numerous in winter than in summer, potentially because nurses with comorbid depressive disorders are affected by shorter daylight exposure during winter.	Depression and daylight exposure may be considered in mitigating sleep disorders in nurses.	
27538515	To evaluate the short-term reproducibility of diurnal intraocular pressure (IOP) and ocular perfusion pressure (OPP) measurements in normal volunteers, untreated normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) patients.Fifty-four healthy volunteers (control group), 67 NTG patients and 54 POAG patients were recruited. The IOPs of both eyes were measured with a Goldmann applanation tonometer at 3-h intervals over 2 consecutive days. Blood pressure (BP) measurements were collected at the same times. The mean IOP/OPP, peak IOP/OPP, trough IOP/OPP and IOP/OPP fluctuations on each day were also calculated. The intraclass correlation coefficients (ICCs) were used to evaluate the reproducibilities.	In the control group, the ICCs of mean IOP, peak IOP, trough IOP and IOP fluctuation were 0.921, 0.889, 0.888, and 0.661, respectively, and the ICCs of the mean OPP, peak OPP, trough OPP and OPP fluctuations were 0.962, 0.918, 0.953, and 0.680, respectively. In the NTG group, the ICCs of the mean IOP, peak IOP, trough IOP and IOP fluctuation were 0.862, 0.741, 0.798, and 0.290, respectively, and the ICCs of the mean OPP, peak OPP, trough OPP and OPP fluctuations were 0.947, 0.828, 0.927, and -0.008, respectively. In the POAG group, the ICCs of the mean IOP, peak IOP, trough IOP and IOP fluctuation were 0.857, 0.666, 0.808, and 0.546, respectively, and the ICCs of the mean OPP, peak OPP, trough OPP and OPP fluctuation were 0.934, 0.842, 0.910, and 0.093, respectively.	The IOP measurements within a single day were not highly reproducible in the short-term. The normal volunteers exhibited better IOP and OPP reproducibilities than the glaucoma patients. The IOP and OPP fluctuations could not be accurately evaluated based on the IOP or OPP measurements within a single day.	
27538446	Marine and freshwater zooplankton exhibit daily rhythmic patterns of behavior and physiology which may be regulated directly by the light:dark (LD) cycle and/or a molecular circadian clock. One of the best-studied zooplankton taxa, the freshwater crustacean Daphnia, has a 24 h diel vertical migration (DVM) behavior whereby the organism travels up and down through the water column daily. DVM plays a critical role in resource tracking and the behavioral avoidance of predators and damaging ultraviolet radiation. However, there is little information at the transcriptional level linking the expression patterns of genes to the rhythmic physiology/behavior of Daphnia.Here we analyzed genome-wide temporal transcriptional patterns from Daphnia pulex collected over a 44 h time period under a 12:12 LD cycle (diel) conditions using a cosine-fitting algorithm. We used a comprehensive network modeling and analysis approach to identify novel co-regulated rhythmic genes that have similar network topological properties and functional annotations as rhythmic genes identified by the cosine-fitting analyses. Furthermore, we used the network approach to predict with high accuracy novel gene-function associations, thus enhancing current functional annotations available for genes in this ecologically relevant model species. Our results reveal that genes in many functional groupings exhibit 24 h rhythms in their expression patterns under diel conditions. We highlight the rhythmic expression of immunity, oxidative detoxification, and sensory process genes. We discuss differences in the chronobiology of D. pulex from other well-characterized terrestrial arthropods.	This research adds to a growing body of literature suggesting the genetic mechanisms governing rhythmicity in crustaceans may be divergent from other arthropod lineages including insects. Lastly, these results highlight the power of using a network analysis approach to identify differential gene expression and provide novel functional annotation.	
27538100	Our current 24-h society and the weekday-weekend switch of our social clocks may affect young children's sleep and circadian rhythms. However, such evidence is scarce. We conducted a nationwide epidemiological study of sleep and health in preschool children aged 3-5 years attending kindergarten or childcare centers in Japan, using stratified one-stage cluster sampling. The target population was 2 969 627 individuals (as of 1 April 2013). The Children's ChronoType Questionnaire was used to measure chronotypes (morning (M)-type, neither (N)-type and evening (E)-type), and weekday and weekend sleep-wake parameters. Randomly sampled population estimates were obtained via respondents with a person-level weight, which accounted for survey responses and poststratification. Standard errors and 95% confidence intervals were adjusted for the complex survey design using jackknife estimation. A linear regression model of the correlation between chronotype and sleep-wake parameters and a multivariate logistic regression model for the links between chronotype and putative associated factors were used for statistical analyses. The estimated prevalence of M-, N- and E-types were 31.6%, 55.9% and 10.0%, respectively. The corresponding numbers of children were 937 910, 1 659 574 and 296 083. The remaining 2.5% was not specified. The proportions of children who woke up by themselves during the weekdays were 55.1%, 43.0% and 1.9% for M-, N- and E-types, respectively. Overall, bedtime, sleep onset time, wake-up time and get-up time during the weekdays were 21:04, 21:26, 6:55 and 6:59, respectively. Nocturnal sleep period, time in bed (TIB) and 24 h TIB (TIB and nap) during the weekdays were 9.49, 9.93 and 10.55 h, respectively. Sleep-wake timings were significantly and linearly delayed from M-, N-, to E-types (p < 0.001). The weekday 24 h TIB (10.47-10.66 h) and weekend nocturnal sleep period (9.58-9.76 h) did not differ significantly among chronotypes. For E-types, socially advanced weekdays rising times (approximately 1 h) caused nocturnal sleep deficit (0.57 h). Children's socially scheduled times (e.g. start and finish times, mealtimes and daytime nap) and their parents' diurnal preferences had significant adjusted odds ratios among E-types, while the significant unadjusted odds ratios for morning sunlight and multimedia exposure disappeared. These results suggest the importance of chronobiologically planned sleep discipline at home as well as assessment of socially scheduled times in children.
27537980	A delayed sleep-wake and circadian rhythm often occurs during puberty. While some individuals only develop a delayed sleep phase (DSP), others will fulfill the criteria for the diagnosis of delayed sleep phase disorder (DSPD). All previous studies have however not separated DSP from DSPD, and, as a result, the prevalence and associated factors are largely unknown for the two conditions individually. We estimated the prevalence of DSP and DSPD in a Swedish cohort of adolescents and young adults. We also investigated associated factors in the two conditions relative to each other and individuals with no DSP. A questionnaire regarding sleep patterns, demographics, substance use/abuse and symptoms of depression, anxiety, worry and rumination was sent to 1000 randomly selected participants (16-26 years of age) in Uppsala, Sweden (response rate = 68%). DSP was defined as a late sleep onset and a preferred late wake-up time. The DSPD diagnosis was further operationalized according to the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5) criteria including insomnia or excessive sleepiness, distress or dysfunction caused by the DSP and that the sleep problem had been evident for 3 months. DSP occurred at a frequency of 4.6% and DSPD at a frequency of 4% in the investigated cohort. DSP was more common in males and was associated with not attending educational activity or work, having shift work, nicotine and alcohol use and less rumination. DSPD was equally common in males and females and was associated with not attending educational activity or work and with elevated levels of anxiety. Both DSP and DSPD appear to be common in adolescents and young adults in this Swedish cohort. No educational activity or work was associated with both DSP and DSPD. However, there were also apparent differences between the two groups in shift work, substance use and mental health, relative to persons with no DSP. Thus, it seems reasonable to assess DSP and DSPD as distinct entities in future studies.
27537825	Daytime activity is largely regulated by the day/night pattern. Various physiological and cognitive functions display a variation during the diurnal period, where individuals manage their balance, spatial orientation and consequently their perception of the vertical. However, findings concerning daytime changes of postural control quality remain contradictory, mainly due to methodogical considerations. The aim of our study is to evaluate the effect of time of day on postural control and perception of the vertical. Fifteen male subjects underwent six test sessions over a 24-hour period. Each session involved a postural balance test (static/dynamic; eyes open/closed) and a subjective evaluation of sleepiness, fatigue and subjective visual vertical (SVV) (light stick tilted from 10 to 40°; eight trials). No time-of-day effect was observed on postural balance. However, perception of the vertical fluctuates during the day and is better at 10 a.m. than at 10 p.m. Despite the gradual perception of the vertical deterioration over the day, postural balance does not show any fluctuation. This postural balance consistency throughout the day may be the result of compensation mechanisms.
27535584	Circadian rhythms regulate a plethora of physiological processes. Perturbations of the rhythm can result in pathologies which are frequently studied in inbred mouse strains. We show that the genotype of mouse lines defines the circadian gene expression patterns. Expression of majority of core clock and output metabolic genes are phase delayed in the C56BL/6J line compared to 129S2 in the adrenal glands and the liver. Circadian amplitudes are generally higher in the 129S2 line. Experiments in dark - dark (DD) and light - dark conditions (LD), exome sequencing and data mining proposed that mouse lines differ in single nucleotide variants in the binding regions of clock related transcription factors in open chromatin regions. A possible mechanisms of differential circadian expression could be the entrainment and transmission of the light signal to peripheral organs. This is supported by the genotype effect in adrenal glands that is largest under LD, and by the high number of single nucleotide variants in the Receptor, Kinase and G-protein coupled receptor Panther molecular function categories. Different phenotypes of the two mouse lines and changed amino acid sequence of the Period 2 protein possibly contribute further to the observed differences in circadian gene expression. 
27535481	In women, progesterone suppresses luteinizing hormone (LH) (gonadotropin-releasing hormone) pulse frequency, but how rapidly this occurs is unknown. In estradiol-pretreated women in the late follicular phase, progesterone administration at 1800 did not slow sleep-associated LH pulse frequency. However, mechanisms controlling LH pulse frequency may differ according to sleep status; and we thus hypothesized that progesterone acutely suppresses waking LH pulse frequency. This was a randomized, double-blind, crossover study of LH secretory responses to progesterone versus placebo administered at 0600. We studied 12 normal women in the late follicular phase (cycle days 7-11), pretreated with 3 days of transdermal estradiol (0.2 mg/day). Subjects underwent a 24-h blood sampling protocol (starting at 2000) and received either 100 mg oral micronized progesterone or placebo at 0600. In a subsequent menstrual cycle, subjects underwent an identical protocol except that oral progesterone was exchanged for placebo or vice versa. Changes in 10-h LH pulse frequency were similar between progesterone and placebo. However, mean LH, LH pulse amplitude, and mean follicle-stimulating hormone exhibited significantly greater increases with progesterone. Compared to our previous study (progesterone administered at 1800), progesterone administration at 0600 was associated with a similar increase in mean LH, but a less pronounced increase in LH pulse amplitude. We conclude that, in estradiol-pretreated women in the late follicular phase, a single dose of progesterone does not suppress waking LH pulse frequency within 12 h, but it acutely amplifies mean LH and LH pulse amplitude - an effect that may be influenced by sleep status and/or time of day. 
27535380	The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. The neural and molecular mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals are unclear. Here we report that prokineticin 2, previously shown as a circadian clock output molecule, is expressed in the intrinsically photosensitive retinal ganglion cells, and the expression of prokineticin 2 in the intrinsically photosensitive retinal ganglion cells is oscillatory in a clock-dependent manner. We further show that the prokineticin 2 signaling is required for the activity and arousal suppression by light in the mouse. Between the nocturnal mouse and the diurnal monkey, a signaling receptor for prokineticin 2 is differentially expressed in the retinorecipient suprachiasmatic nucleus and the superior colliculus, brain projection targets of the intrinsically photosensitive retinal ganglion cells. Blockade with a selective antagonist reveals the respectively inhibitory and stimulatory effect of prokineticin 2 signaling on the arousal levels for the nocturnal mouse and the diurnal monkey. Thus, the mammalian diurnality or nocturnality is likely determined by the differential signaling of prokineticin 2 from the intrinsically photosensitive retinal ganglion cells onto their retinorecipient brain targets. 
27533392	Research from the University of Manchester has shown for the first time how spinal discs have 24-hour body clocks which can contribute to lower back pain when they malfunction. 
27530460	Sleep behavior is changing toward shorter sleep duration and a later chronotype. It results in a sleep debt that is acquitted on work-free days, inducing a small but recurrent sleep misalignment each week, referred to as "social jetlag". These sleep habits could affect health through misalignment with circadian rhythms.The primary objective is to address the impact of sleep behavior on glycemic control, assessed by HbA1c, in patients with type 1 diabetes, independently of other lifestyle or sleep-related factors. The secondary objective is to address whether circadian phase affects glycemic control.	In total, 80 adult patients with type 1 diabetes (46% female) were included in a clinical cohort study.	Sleep behavior was addressed objectively by a 7-day actimetry, lifestyle by questionnaires, sleep breathing disorders by nocturnal oximetry and circadian phase by dim light melatonin onset (DLMO).	Univariate analyses showed that chronotype (r = 0.23, P = 0.042) and social jetlag (r = 0.30, P = 0.008) were significantly associated with HbA1c. In multivariable analysis, social jetlag was the only sleep habit independently associated with HbA1c (β = 0.012 (0.006; 0.017), P < 0.001). HbA1c was lower in patients with a social jetlag below versus above the median (7.7% (7.1-8.7) and 8.7% (7.6-9.8), P = 0.011). DLMO was not associated with HbA1c. However, the later the DLMO, the worse the sleep efficiency (r = -0.41, P < 0.001) and fragmentation index (r = 0.35, P = 0.005).	Social jetlag, a small but recurrent circadian misalignment, is associated with worse glycemic control in type 1 diabetes, whereas circadian phase is not. Further intervention studies should address the potential improvement of glycemic control by correcting social jetlag.	
27530363	The rhythmic locomotor behavior of flies and mice provides a phenotype for the identification of clock genes, and the underlying molecular mechanism is well studied. However, interestingly, when examining locomotor rhythm in the wild, several key laboratory-based assumptions on circadian behavior are not supported in natural conditions. The rooster crowing 'cock-a-doodle-doo' is a symbol of the break of dawn in many countries. Previously, we used domestic inbred roosters and showed that the timing of roosters' crowing is regulated by the circadian clock under laboratory conditions. However, it is still unknown whether the regulation of crowing by circadian clock is observed under natural conditions. Therefore, here we used red jungle fowls and first confirmed that similar crowing rhythms with domesticated chickens are observed in red jungle fowls under the laboratory conditions. Red jungle fowls show predawn crowing before light onset under 12:12 light : dim light conditions and the free-running rhythm of crowing under total dim light conditions. We next examined the crowing rhythms under semi-wild conditions. Although the crowing of red jungle fowls changed seasonally under semi-wild conditions, predawn crowing was observed before sunrise in all seasons. This evidence suggests that seasonally changed crowing of red jungle fowls is under the control of a circadian clock.
27530303	Timing of circadian activities is controlled by rhythmic expression of clock genes in pacemaker neurons in the insect brain. Circadian behavior and clock gene expression can entrain to both thermoperiod and photoperiod but the availability of such cues, the organization of the brain, and the need for circadian behavior change dramatically during the course of insect metamorphosis. We asked whether photoperiod or thermoperiod entrains the clock during pupal and pharate adult stages by exposing flies to different combinations of thermoperiod and photoperiod and observing the effect on the timing of adult eclosion. This study used qRT-PCR to examine how entrainment and expression of circadian clock genes change during the course of development in the flesh fly, Sarcophaga crassipalpis. Thermoperiod entrains expression of period and controls the timing of adult eclosion, suggesting that the clock gene period may be upstream of the eclosion pathway. Rhythmic clock gene expression is evident in larvae, appears to cease during the early pharate adult stage, and resumes again by the time of adult eclosion. Our results indicate that both patterns of clock gene expression and the cues to which the clock entrains are dynamic and respond to different environmental signals at different developmental stages in S. crassipalpis.

27529973	The review establishes a link between a group of genes which are conserved in evolution and form a molecular oscillator responsible for generation of circadian rhythms and genetic determinants of aging including associated pathways of intracellular signaling. An analysis of mechanisms of development of age-dependent pathologies is conducted from the viewpoint of circadian genetics. Systematic data of circadian gene expression studies in animals demonstrating different rates of aging from accelerated to negligible are presented.
27529310	The suprachiasmatic nuclei (SCN) contain the major circadian clock responsible for generation of circadian rhythms in mammals. The time measured by the molecular circadian clock must eventually be translated into a neuronal firing rate pattern to transmit a meaningful signal to other tissues and organs in the animal. Previous observations suggest that circadian modulation of ryanodine receptors (RyR) is a key element of the output pathway from the molecular circadian clock. To directly test this hypothesis, we studied the effects of RyR activation and inhibition on real time expression of PERIOD2::LUCIFERASE, intracellular calcium levels and spontaneous firing frequency in mouse SCN neurons. Furthermore, we determined whether the RyR-2 mRNA is expressed with a daily variation in SCN neurons. We provide evidence that pharmacological manipulation of RyR in mice SCN neurons alters the free [Ca2+ ]i in the cytoplasm and the spontaneous firing without affecting the molecular clock mechanism. Our data also show a daily variation in RyR-2 mRNA from single mouse SCN neurons with highest levels during the day. Together, these results confirm the hypothesis that RyR-2 is a key element of the circadian clock output from SCN neurons.
27529127	Familial Advanced Sleep Phase (FASP) is a heritable human sleep phenotype characterized by very early sleep and wake times. We identified a missense mutation in the human Cryptochrome 2 (CRY2) gene that co-segregates with FASP in one family. The mutation leads to replacement of an alanine residue at position 260 with a threonine (A260T). In mice, the CRY2 mutation causes a shortened circadian period and reduced phase-shift to early-night light pulse associated with phase-advanced behavioral rhythms in the light-dark cycle. The A260T mutation is located in the phosphate loop of the flavin adenine dinucleotide (FAD) binding domain of CRY2. The mutation alters the conformation of CRY2, increasing its accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus promoting its degradation. These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior. 
27528682	Viruses are intracellular pathogens that hijack host cell machinery and resources to replicate. Rather than being constant, host physiology is rhythmic, undergoing circadian (∼24 h) oscillations in many virus-relevant pathways, but whether daily rhythms impact on viral replication is unknown. We find that the time of day of host infection regulates virus progression in live mice and individual cells. Furthermore, we demonstrate that herpes and influenza A virus infections are enhanced when host circadian rhythms are abolished by disrupting the key clock gene transcription factor Bmal1. Intracellular trafficking, biosynthetic processes, protein synthesis, and chromatin assembly all contribute to circadian regulation of virus infection. Moreover, herpesviruses differentially target components of the molecular circadian clockwork. Our work demonstrates that viruses exploit the clockwork for their own gain and that the clock represents a novel target for modulating viral replication that extends beyond any single family of these ubiquitous pathogens. 
27525420	In mammals, light exerts pervasive effects on physiology and behavior in two ways: indirectly through clock synchronization and the phase adjustment of circadian rhythms, and directly through the promotion of alertness and sleep, respectively, in diurnal and nocturnal species. A recent report by Pilorz and colleagues describes an even more complex role for the acute effects of light. In mice, blue light acutely causes behavioral arousal, whereas green wavelengths promote sleep. These opposing effects are mediated by melanopsin-based phototransduction through different neural pathways. These findings reconcile nocturnal and diurnal species through a common alerting response to blue light. One can hypothesize that the opposite responses to natural polychromatic light in night- or day-active animals may reflect higher sensitivity of nocturnal species to green, and diurnals to blue wavelengths, resulting in hypnogenic and alerting effects, respectively. Additional questions remain to be clarified. How do different light wavelengths affect other behaviors such as mood and cognition? How do those results apply to humans? How does light pose either a risk or benefit, depending on whether one needs to be asleep or alert? Indeed, in addition to timing, luminance levels, and light exposure duration, these findings stress the need to understand how best to adapt the color spectrum of light to our needs and to take this into account for the design of daily lighting concepts-a key challenge for today's society, especially with the emergence of LED light technology. 
27525110	Glaucoma is one of the leading causes of blindness worldwide. Recent studies suggest that intraocular pressure (IOP) fluctuations, peaks, and rhythm are important factors in disease advancement. Yet, current glaucoma management remains hinged on single IOP measurements during clinic hours. To overcome this limitation, 24-hour IOP monitoring devices have been employed and include self-tonometry, permanent IOP, and temporary IOP monitoring. This review discusses each IOP measuring strategy and focuses on the recently FDA-approved contact lens sensor (CLS). The CLS records IOP-related ocular patterns for 24 hours continuously. Using the CLS, IOP-related parameters have been found to be associated with the rate of visual field progression in primary open-angle glaucoma, disease progression in primary angle-closure glaucoma, and various clinical variables in ocular hypertension. The CLS has been used to quantify blink rate and limbal strain and measure the circadian rhythm in a variety of disease states including normal-tension glaucoma and thyroid eye disease. The effects of various IOP-lowering interventions were also characterized using the CLS. CLS provides a unique, safe, and well-tolerated way to study IOP-related patterns in a wide range of disease states. IOP-related patterns may help identify patients most at risk for disease progression and assist with the development of tailored treatments. 
27524253	Diel methane emission fluxes from a landfill that was covered by vegetation were investigated to reveal the methane emission mechanisms based on the interaction of vegetation characteristics and climate factors. The methane emissions showed large variation between daytime and nighttime, and the trend of methane emissions exhibited clear bimodal patterns from both Setaria viridis- and Neyraudia reynaudiana-covered areas. Plants play an important role in methane transportation as well as methane oxidation. The notable decrease in methane emissions after plants were cut suggests that methane transportation via plants is the primary way of methane emissions in the vegetated areas of landfill. Within plants, the methane emission fluxes were enhanced due to a convection mechanism. Given that the methane emission flux is highly correlated with the solar radiation during daytime, the convection mechanism could be attributed to the increase in solar radiation. Whereas the methane emission flux is affected by a combined impact of the wind speed and pedosphere characteristics during nighttime. An improved understanding of the methane emission mechanisms in vegetated landfills is expected to develop a reliable model for landfill methane emissions and to attenuate greenhouse gas emissions from landfills.
27524206	Despite a complex relationship between mood, sleep and rhythm, the impact of circadian disruptions on bipolar disorder (BD) has not been clarified. The purpose of this systematic review was to define current evidence regarding chronotype and circadian rhythm patterns in BD patients. 42 studies were included, involving 3432 BD patients. Disruption of the biological rhythm was identified, even in drug-naïve BD patients and independently of mood status. Daily profiles of melatonin levels and cortisol indicated a delayed phase. Depression was more frequently associated with circadian alterations than euthymia. Few studies evaluated mania, demonstrating irregular rhythms. Evening type was more common in BD adults. Studies about the influence of chronotype on depressive symptoms showed conflicting results. Only one investigation observed the influences of chronotype in mania, revealing no significant association. Effects of psychoeducation and lithium on rhythm in BD patients were poorly studied, demonstrating no improvement of rhythm parameters. Studies about genetics are incipient. In conclusion, disruption in circadian rhythm and eveningness are common in BD. Prospective research evaluating the impact of circadian disruption on mood symptoms, metabolism, seasonality, the influence of age and the effects of mood stabilizers are needed.
27520377	Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications. 
27516598	Human performance is modulated by circadian rhythmicity and homeostatic sleep pressure. Whether and how this interaction is represented at the regional brain level has not been established. We quantified changes in brain responses to a sustained-attention task during 13 functional magnetic resonance imaging sessions scheduled across the circadian cycle, during 42 hours of wakefulness and after recovery sleep, in 33 healthy participants. Cortical responses showed significant circadian rhythmicity, the phase of which varied across brain regions. Cortical responses also significantly decreased with accrued sleep debt. Subcortical areas exhibited primarily a circadian modulation that closely followed the melatonin profile. These findings expand our understanding of the mechanisms involved in maintaining cognition during the day and its deterioration during sleep deprivation and circadian misalignment. 
27516006	Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11. 
27515785	Melatonin exerts many physiological effects via melatonin receptors, among which the melatonin-2 receptor (MT2 ) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT2 was a critical target during the process. cAMP response element binding (CREB) is an essential transcription factor for memory formation and could be involved in MT2 signalling. Therefore, the present study was designed to investigate the effects of prophylactic melatonin on inhaled anaesthetic isoflurane-induced cognitive impairment, and to determine whether the protective effects of melatonin are dependent on MT2 and downstream CREB signalling in the hippocampus of aged rats. The results showed that prophylactic melatonin attenuated isoflurane-induced decreases in plasma/hippocampal melatonin levels and cognitive impairment in aged rats. Furthermore, 4P-PDOT, a selective MT2 antagonist, blocked the protective effects of melatonin on isoflurane-induced decreases in both hippocampal MT2 expression and downstream CREB phosphorylation. And 4P-PDOT blocked the attenuation of melatonin on isoflurane-induced memory impairment. Collectively, the results suggest that the protective effects of prophylactic melatonin are dependent on hippocampal MT2 -CREB signalling, which could be a potential therapeutic target for anaesthetic-induced cognitive impairment.
27515515	Delirium is a very common and distressing neuropsychiatric syndrome in palliative care. Increasing age, the presence of dementia and advanced cancer are well-known predisposing risk factors for delirium development. Sleep-wake cycle disturbance is frequently seen during delirium and melatonin has a pivotal role in the regulation of circadian rhythms. Current evidence across various settings suggests a potential preventative role for melatonin in patients at risk of delirium, but no studies are currently reported in patients with advanced cancer. The aim of this article is to describe the design of a feasibility study that is being conducted to inform a larger randomized, placebo-controlled, double-blind trial (RCT) to evaluate the role of exogenously administered melatonin in preventing delirium in patients with advanced cancer.Adult patients with a cancer diagnosis who are admitted to the palliative care unit will be randomized into a treatment or placebo group. The pharmacological intervention consists of a single daily dose of immediate-release melatonin (3 mg) at 21:00 ± 1 h, from day 1 to day 28 of admission. The primary objective of this initial study is to assess the feasibility of conducting the proposed RCT by testing recruitment and retention rates, appropriateness of study outcome measures, acceptability of study procedures and effectiveness of the blinding process. The primary outcome measure of the proposed larger RCT is time to first inpatient incident episode of delirium. We also plan to collect data on incident rates of delirium and patient-days of delirium, adjusting for length of admission.	The outcomes of this feasibility study will provide information on recruitment and retention rates, protocol violation frequency, effectiveness of the blinding process, acceptability of the study procedures, and safety of the proposed intervention. This will inform the design of a fully powered randomized controlled trial to evaluate the preventative role of melatonin administration in patients with advanced cancer.	
27515503	Bilateral lesions of the mesencephalic trigeminal sensory nucleus (Me5), which receives histaminergic neurons from the tuberomammillary nucleus (TMN), alter nocturnal feeding and related behaviors in mice, concomitant with a decrease in orexin mRNA level in the perifornical area (PFA) during the dark phase. Therefore, we investigated the neuronal input to the TMN from the Me5, as well as the effects of TMN lesions on the circadian profiles of feeding and related behaviors.We examined the presence of neurons projecting from the Me5 to the TMN by direct injection of a retrograde tracer, Fluorogold, into the TMN E2 sub-region (TMN-E2). We also assessed feeding, drinking, and locomotion for 24h using an automated feeding behavior measurement apparatus, and analyzed the hypothalamic orexin mRNA levels in both TMN-lesion and sham-operated mice.	The presence of neuronal projections from the Me5 to the TMN-E2 was confirmed. A decrease in food and water intake and locomotion during the latter half of the dark phase was delayed in TMN-lesion but not sham-operation mice. Further, orexin mRNA expression levels were higher in both the PFA and lateral hypothalamus area (LHA) in TMN-E2-lesion mice relative to control mice, during the early half of the dark phase compared with the light phase.	Our results suggest that histaminergic neurons in the TMN-E2 receive signals from the Me5 that modulate a switch from dark to light phase feeding and related behaviors, which in turn may be regulated by orexin neurons in the PFA and/or LHA.	
27512400	Although, the circadian clock is a universal biological system in plants and it orchestrates important role of plant production such as photosynthesis, floral induction and growth, there are few such studies on cultivated species. Lettuce is one major cultivated species for both open culture and plant factories and there is little information concerning its circadian clock system. In addition, most of the relevant genes have not been identified. In this study, we detected circadian oscillation in the lettuce transcriptome using time-course RNA sequencing (RNA-Seq) data. Constant light (LL) and light-dark (LD) conditions were used to detect circadian oscillation because the circadian clock has some basic properties: one is self-sustaining oscillation under constant light and another is entrainment to environmental cycles such as light and temperature. In the results, 215 contigs were detected as common oscillating contigs under both LL and LD conditions. The 215 common oscillating contigs included clock gene-like contigs CCA1 (CIRCADIAN CLOCK ASSOCIATED 1)-like, TOC1 (TIMING OF CAB EXPRESSION 1)-like and LHY (LATE ELONGATED HYPOCOTYL)-like, and their expression patterns were similar to those of Arabidopsis. Functional enrichment analysis by GO (gene ontology) Slim and GO Fat showed that the GO terms of response to light stimulus, response to stress, photosynthesis and circadian rhythms were enriched in the 215 common oscillating contigs and these terms were actually regulated by circadian clocks in plants. The 215 common oscillating contigs can be used to evaluate whether the gene expression pattern related to photosynthesis and optical response performs normally in lettuce. 
27512004	Previous studies indicate that there are at least a few regulatory systems involved in photoperiodic synchronisation of reproductive activity, which starts with the retina and ends at the gonadotropin-releasing hormone (GnRH) pulse generator. Recently we have shown indicated that the amount of carbon monoxide (CO) released from the eye into the ophthalmic venous blood depends on the intensity of sunlight. The aim of this study was to test whether changes in the concentration of carbon monoxide in the ophthalmic venous blood may modulate reproductive activity, as measured by changes in GnRH and GnRH receptor gene expression. The animal model used was mature male swine crossbred from wild boars and domestic sows (n = 48). We conducted in vivo experiments to determine the effect of increased CO concentrations in the cavernous sinus of the mammalian perihypophyseal vascular complex on gene expression of GnRH and GnRH receptors as well as serum luteinizing hormone (LH) levels. The experiments were performed during long photoperiod days near the summer solstice (second half of June) and short photoperiod days near the winter solstice (second half of December). These crossbred swine demonstrated a seasonally-dependent marked variation in GnRH and GnRH receptor gene expression and systemic LH levels in response to changes in CO concentration in ophthalmic venous blood. These results seem to confirm the hypothesis of humoral phototransduction as a mechanism for some of bright light's effects in animal chronobiology and the effect of CO on GnRH and GnRH receptor gene expression. 
27509741	Few estimates of migration rates or descriptions of behavior or survival exist for wild populations of out-migrating Pacific salmon smolts from natal freshwater rearing areas to the ocean. Using acoustic transmitters and fixed receiver arrays across four years (2010-2013), we tracked the migration of > 1850 wild sockeye salmon (Oncorhynchus nerka) smolts from Chilko Lake, British Columbia, to the coastal Pacific Ocean (> 1000 km distance). Cumulative survival to the ocean ranged 3-10% among years, although this may be slightly underestimated due to technical limitations at the final receiver array. Distinct spatial patterns in both behavior and survival were observed through all years. In small, clear, upper-river reaches, downstream migration largely occurred at night at speeds up to 50 km/d and coincided with poor survival. Among years, only 57-78% of smolts survived the first 80 km. Parallel laboratory experiments revealed excellent short-term survival and unhindered swimming performance of dummy-tagged smolts, suggesting that predators rather than tagging effects were responsible for the initial high mortality of acoustic-tagged smolts. Migration speeds increased in the Fraser River mainstem (~220 km/d in some years), diel movement patterns ceased, and smolt survival generally exceeded 90% in this segment. Marine movement rates and survival were variable across years, with among-year segment-specific survival being the most variable and lowest (19-61%) during the final (and longest, 240 km) marine migration segment. Osmoregulatory preparedness was not expected to influence marine survival, as smolts could maintain normal levels of plasma chloride when experimentally exposed to saltwater (30 ppt) immediately upon commencing their migration from Chilko Lake. Transportation of smolts downstream generally increased survival to the farthest marine array. The act of tagging may have affected smolts in the marine environment in some years as dummy-tagged fish had poorer survival than control fish when transitioned to saltwater in laboratory-based experiments. Current fisheries models for forecasting the number of adult sockeye returning to spawn have been inaccurate in recent years and generally do not incorporate juvenile or smolt survival information. Our results highlight significant potential for early migration conditions to influence adult recruitment.
27507933	The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation. 
27507854	The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator-activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.
27506892	Mammalian circadian rhythms regulate many metabolic processes. Recent studies suggest that brain and muscle Arnt-like 1 (BMAL1), an important component of mammalian circadian rhythm, is associated with insulin signaling. Several studies have shown that insulin is associated with bone metabolism; however, the relationship between BMAL1 and osteoblasts remains unclear.Expression of osteogenic markers and Bmal1 in MC3T3-E1 cells was measured by RT-PCR and Western blotting. Alizarin red S staining was performed to assess matrix mineralization in MC3T3-E1 cells.	mRNA levels of osteogenic genes and Bmal1 were up-regulated in MC3T3-E1 cells upon insulin treatment. In addition, Bmal1 overexpression increased the expression of osteogenic genes including inhibitor of DNA binding (Id1), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC). Interestingly, expression of Bone morphogenetic protein-2 (BMP2), an important upstream factor of Id1, Runx2, and OC, was markedly increased by Bmal1. Finally, we confirmed that insulin-induced BMP2 expression was attenuated in Bmal1 knockout (KO) cells. PCR analysis and alizarin red S staining showed that insulin-mediated increases gene expression and calcium deposition were reduced in Bmal1 KO cells compared to wild-type cells.	Taken together, these results demonstrate that Bmal1 promotes osteoblast differentiation by regulating BMP2 expression in MC3T3-E1 cells.	
27506798	The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. In Neurospora crassa, the circadian clock generates daily rhythms in the activation of conserved mitogen-activated protein kinase (MAPK) pathways when cells are grown in constant conditions, including rhythmic activation of the well-characterized p38 osmosensing (OS) MAPK pathway. Rhythmic phosphorylation of the MAPK OS-2 (P-OS-2) leads to temporal control of downstream targets of OS-2. We show that osmotic stress in N. crassa induced the phosphorylation of a eukaryotic elongation factor-2 (eEF-2) kinase, radiation sensitivity complementing kinase-2 (RCK-2), and that RCK-2 is necessary for high-level phosphorylation of eEF-2, a key regulator of translation elongation. The levels of phosphorylated RCK-2 and phosphorylated eEF-2 cycle in abundance in wild-type cells but not in cells deleted for OS-2 or the core clock component FREQUENCY (FRQ). Translation extracts from cells grown in constant conditions show decreased translational activity in the late subjective morning, coincident with the peak in eEF-2 phosphorylation, and rhythmic translation of glutathione S-transferase (GST-3) from constitutive mRNA levels in vivo is dependent on circadian regulation of eEF-2 activity. In contrast, rhythms in phosphorylated eEF-2 levels are not necessary for rhythms in accumulation of the clock protein FRQ, indicating that clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs. 
27504829	Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription. 
27503873	Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA. 
27503720	Several studies have examined changes in some haematochemical parameters as a function of the different physiological status (cyclic, pregnant and lactating) of goats, but no relevant literature has exhaustively investigated these variations from anestrous to estrous stages in cyclic goats. In this paper, we report nychthemeral and seasonal variations in ambient and body temperatures, and in some haematochemical parameters (glycemia, cholesterolemia, triglyceridemia, creatininemia and uremia) measured during summer, winter and spring, in seven (7) experimental cyclic female Bedouin goats (Capra hircus) living in the Béni-Abbès region (Algerian Sahara desert). Cosinor rhythmometry procedure was used to determine the rhythmic parameters of ambient temperature and haematochemical parameters. To determine the effect of time of day on the rhythmicity of the studied parameters, as well as their seasonality, repeated measure analysis of variance (ANOVA) was applied. The results showed that in spite of the nychthemeral profile presented by the ambient temperature for each season, the body temperature remained in a narrow range, thus indicating a successful thermoregulation. The rhythmometry analysis showed a circadian rhythmicity of ambient temperature and haematochemical parameters with diurnal acrophases. A statistically significant effect of the time of day was shown on all studied haematochemical parameters, except on creatininemia. It was also found that only uremia, cholesterolemia and triglyceridemia followed the seasonal sexual activity of the studied ruminant. This study demonstrated the good physiological adaptation developed by this breed in response to the harsh climatic conditions of its natural environment. 
27503352	The utility of any model species cannot be judged solely in terms of the tools and approaches it provides for genetic analysis. A fundamental consideration is also how its biology has been shaped by the environment and the ecological niche which it occupies. By comparing different species occupying very different habitats we can learn how molecular and cellular mechanisms change during evolution in order to optimally adapt to their environment. Such knowledge is as important as understanding how these mechanisms work. This is illustrated by the use of fish models for studying the function and evolution of the circadian clock. In this review we outline our current understanding of how fish clocks sense and respond to light and explain how this differs fundamentally from the situation with mammalian clocks. In addition, we present results from comparative studies involving two species of blind cavefish, Astyanax mexicanus and Phreatichthys andruzzii. This work reveals the consequences of evolution in perpetual darkness for the circadian clock and its regulation by light as well as for other mechanisms such as DNA repair, sleep, and metabolism which directly or indirectly are affected by regular exposure to sunlight. Major differences in the cave habitats inhabited by these two cavefish species have a clear impact on shaping the molecular and cellular adaptations to life in complete darkness. 
27503044	Flight attendants (FAs) may experience circadian disruption due to travel during normal sleep hours and through multiple time zones. This study investigated whether FAs are at higher risk for sleep disturbance compared to teachers, as assessed by questionnaire, diary, and activity monitors.Sleep/wake cycles of 45 FAs and 25 teachers were studied. For one menstrual cycle, participants wore an activity monitor and kept a daily diary. Sleep metrics included total sleep in the main sleep period (MSP), sleep efficiency (proportion of MSP spent sleeping), and nocturnal sleep fraction (proportion of sleep between 10 p.m. to 8 a.m. home time). Relationships between sleep metrics and occupation were analyzed with mixed and generalized linear models.	Both actigraph and diary data suggest that FAs sleep longer than teachers. However, several actigraph indices of sleep disturbance indicated that FAs incurred significant impairment of sleep compared to teachers. FAs were more likely than teachers to have poor sleep efficiency [adjusted odds ratio (OR) for lowest quartile of sleep efficiency = 1.9, 95% Confidence Interval (CI) 1.2 - 3.0] and to have a smaller proportion of their sleep between 10 p.m. and 8 a.m. home time (adjusted OR for lowest quartile of nocturnal sleep fraction = 3.1, CI 1.1 -9.0).	Study FAs experienced increased sleep disturbance compared to teachers, which may indicate circadian disruption. Grajewski B, Whelan EA, Nguyen MM, Kwan L, Cole RJ. Sleep disturbance in female flight attendants and teachers. Aerosp Med Hum Perform. 2016; 87(7)638-645.	
27500861	Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs. 
27500134	Circadian rhythms are 24-h oscillations present in most eukaryotes and many prokaryotes that synchronize activity to the day-night cycle. They are an essential feature of organismal and cell physiology that coordinate many of the metabolic, biosynthetic, and signal transduction pathways studied in biology. The molecular mechanism of circadian rhythm is controlled both by signal transduction and gene transcription as well as by metabolic feedback. The role of circadian rhythm in cancer cell development and survival is still not well understood, but as will be discussed in this Review, accumulated research suggests that circadian rhythm may be altered or disrupted in many human cancers downstream of common oncogenic alterations. Thus, a complete understanding of the genetic and metabolic alterations in cancer must take potential circadian rhythm perturbations into account, as this disruption itself will influence how gene expression and metabolism are altered in the cancer cell compared to its non-transformed neighbor. It will be important to better understand these circadian changes in both normal and cancer cell physiology to potentially design treatment modalities to exploit this insight. 
27500118	Many organisms have evolved an approximately 24-hour circadian rhythm that allows them to achieve internal physiological homeostasis with external environment. Suprachiasmatic nucleus (SCN) is the central pacemaker of circadian rhythm, and its activity is entrained to the external light-dark cycle. The SCN controls circadian rhythm through regulating the synthesis of melatonin by pineal gland via a multisynaptic pathway. Light, especially short-wavelength blue light, is the most potent environmental time cue in circadian photoentrainment. Recently, the discovery of a novel type of retinal photoreceptors, intrinsically photosensitive retinal ganglion cells, sheds light on the mechanism of circadian photoentrainment and raises concerns about the effect of ocular diseases on circadian system. With age, light transmittance is significantly decreased due to the aging of crystalline lens, thus possibly resulting in progressive loss of circadian photoreception. In the current review, we summarize the circadian physiology, highlight the important role of light in circadian rhythm regulation, discuss about the correlation between age-related cataract and sleep disorders, and compare the effect of blue light- filtering intraocular lenses (IOLs) and ultraviolet only filtering IOLs on circadian rhythm. 
27499509	Use of artificial light resulted in relative independence from the natural light-dark (LD) cycle, allowing human subjects to shift the timing of food intake and work to convenient times. However, the increase in artificial light exposure parallels the increase in obesity prevalence. Light is the dominant Zeitgeber for the central circadian clock, which resides within the hypothalamic suprachiasmatic nucleus, and coordinates daily rhythm in feeding behaviour and metabolism. Eating during inappropriate light conditions may result in metabolic disease via changes in the biological clock. In this review, we describe the physiological role of light in the circadian timing system and explore the interaction between the circadian timing system and metabolism. Furthermore, we discuss the acute and chronic effects of artificial light exposure on food intake and energy metabolism in animals and human subjects. We propose that living in synchrony with the natural daily LD cycle promotes metabolic health and increased exposure to artificial light at inappropriate times of day has adverse effects on metabolism, feeding behaviour and body weight regulation. Reducing the negative side effects of the extensive use of artificial light in human subjects might be useful in the prevention of metabolic disease.
27499228	Background Mobile phones are an important part of adolescents' life. In this study, the relationships among smartphone addiction, age, gender, and chronotype of German adolescents were examined. Materials and methods Two studies focused on two different measures of smartphone addiction. The Smartphone Addiction Proneness Scale (SAPS) was applied to 342 younger adolescents (13.39 ± 1.77; 176 boys, 165 girls, and 1 not indicated) in Study 1 and the Smartphone Addiction Scale was applied to 208 older adolescents (17.07 ± 4.28; 146 girls and 62 boys) in Study 2, both samples in southwest Germany. In addition, a demographic questionnaire and the Composite Scale of Morningness (CSM) and sleep measures were implemented. Results The most remarkable result of this study was that morningness-eveningness (as measured by CSM scores) is an important predictor for smartphone addiction; even stronger than sleep duration. Evening oriented adolescents scored higher on both smartphone addiction scales. In addition, gender is an important predictor for smartphone addiction and girls are more prone to become addicted. In addition, while sleep duration on weekdays negatively predicted SAPS, age, sleep duration on weekends, and midpoint of sleep on weekdays and weekends did not predicted smartphone addiction in both scales. The analysis of covariance revealed statistically significant effects of the covariates gender and age in both studies, as well as the main effect of chronotype. According to the t-test results, girls had higher scores than boys in smartphone addiction. Conclusion Evening types and girls are more prone to become smartphone addicted. 
27497909	Mitochondria produce hydrogen peroxide (H2O2) during energy metabolism in most mammalian cells as well as during the oxidation of cholesterol associated with the synthesis of steroid hormones in steroidogenic cells. Some of the H2O2 produced in mitochondria is released into the cytosol, where it serves as a key regulator of various signaling pathways. Given that mitochondria are equipped with several H2O2-eliminating enzymes, however, it had not been clear how mitochondrial H2O2 can escape destruction by these enzymes for such release. Peroxiredoxin III (PrxIII) is the most abundant and efficient H2O2-eliminating enzyme in mitochondria of most cell types. We found that PrxIII undergoes reversible inactivation through hyperoxidation of its catalytic cysteine residue to cysteine sulfinic acid, and that release of mitochondrial H2O2 likely occurs as a result of such PrxIII inactivation. The hyperoxidized form of PrxIII (PrxIII-SO2H) is reduced and reactivated by sulfiredoxin (Srx). We also found that the amounts of PrxIII-SO2H and Srx undergo antiphasic circadian oscillation in mitochondria of the adrenal gland, heart, and brown adipose tissue of mice maintained under normal conditions. Cytosolic Srx was found to be imported into mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is likely promoted by H2O2 released from mitochondria. The imported Srx was found to be degraded by Lon protease in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of Srx underlie Srx oscillation and consequent PrxIII-SO2H oscillation in mitochondria. The rhythmic change in the amount of PrxIII-SO2H suggests that mitochondrial release of H2O2 is also likely a circadian event that conveys temporal information on steroidogenesis in the adrenal gland and on energy metabolism in heart and brown adipose tissue to cytosolic signaling pathways.
27495157	Pancreatic islet failure is a characteristic feature of impaired glucose control in diabetes mellitus. Circadian control of islet function is essential for maintaining proper glucose homeostasis. Circadian variations in transcriptional pathways have been described in diverse cell types and shown to be critical for optimization of cellular function in vivo. In the current study, we utilized Short Time Series Expression Miner (STEM) analysis to identify diurnally expressed transcripts and biological pathways from mouse islets isolated at 4 h intervals throughout the 24 h light-dark cycle. STEM analysis identified 19 distinct chronological model profiles, and genes belonging to each profile were subsequently annotated to significantly enriched Kyoto Encyclopedia of Genes and Genomes biological pathways. Several transcriptional pathways essential for proper islet function (e.g., insulin secretion, oxidative phosphorylation), cell survival (e.g., insulin signaling, apoptosis) and cell proliferation (DNA replication, homologous recombination) demonstrated significant time-dependent variations. Notably, KEGG pathway analysis revealed "protein processing in endoplasmic reticulum - mmu04141" as one of the most enriched time-dependent pathways in islets. This study provides unique data set on time-dependent diurnal profiles of islet gene expression and biological pathways, and suggests that diurnal variation of the islet transcriptome is an important feature of islet homeostasis, which should be taken into consideration for optimal experimental design and interpretation of future islet studies. 
27494874	Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.
27494321	Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans. 
27494182	A 24-hour light and dark cycle-dependent rhythmicity pervades physiological processes in virtually all living organisms including humans. These regular oscillations are caused by external cues to endogenous, independent biological time-keeping systems (clocks). The rhythm is reflected by gene expression that varies in a circadian and specific fashion in different organs and tissues and is regulated largely by dynamic epigenetic and post-transcriptional mechanisms. This leads to well-documented oscillations of specific electrolytes, hormones, metabolites, and plasma proteins in blood samples. An emerging, important class of gene regulators is short single-stranded RNA (micro-RNA, miRNA) that interferes post-transcriptionally with gene expression and thus may play a role in the circadian variation of gene expression. MiRNAs are promising biomarkers by virtue of their disease-specific tissue expression and because of their presence as stable entities in the circulation. However, no studies have addressed the putative circadian rhythmicity of circulating, cell-free miRNAs. This question is important both for using miRNAs as biological markers and for clues to miRNA function in the regulation of circadian gene expression. Here, we investigate 92 miRNAs in plasma samples from 24 young male, healthy volunteers repeatedly sampled 9 times during a 24-hour stay in a regulated environment. We demonstrate that a third (26/79) of the measurable plasma miRNAs (using RT-qPCR on a microfluidic system) exhibit a rhythmic behavior and are distributed in two main phase patterns. Some of these miRNAs weakly target known clock genes and many have strong targets in intracellular MAPK signaling pathways. These novel findings highlight the importance of considering bio-oscillations in miRNA biomarker studies and suggest the further study of a set of specific circulating miRNAs in the regulation and functioning of biological clocks. 
27494172	Rhythmic incremental growth lines and the presence of melatonin receptors were discovered in tooth enamel, suggesting possible role of circadian rhythm. We therefore hypothesized that circadian rhythm may regulate enamel formation through melatonin receptors. To test this hypothesis, we examined expression of melatonin receptors (MTs) and amelogenin (AMELX), a maker of enamel formation, during tooth germ development in mouse. Using qRT-PCR and immunocytochemistry, we found that mRNA and protein levels of both MTs and AMELX in normal mandibular first molar tooth germs increased gradually after birth, peaked at 3 or 4 day postnatal, and then decreased. Expression of MTs and AMELX by immunocytochemistry was significantly delayed in neonatal mice raised in all-dark or all-light environment as well as the enamel development. Furthermore, development of tooth enamel was also delayed showing significant immature histology in those animals, especially for newborn mice raised in all daylight condition. Interestingly, disruption in circadian rhythm in pregnant mice also resulted in delayed enamel development in their babies. Treatment with melatonin receptor antagonist 4P-PDOT in pregnant mice caused underexpression of MTs and AMELX associated with long-lasting deficiency in baby enamel tissue. Electromicroscopic evidence demonstrated increased necrosis and poor enamel mineralization in ameloblasts. The above results suggest that circadian rhythm is important for normal enamel development at both pre- and postnatal stages. Melatonin receptors were partly responsible for the regulation. 
27493185	Young sunflower plants track the Sun from east to west during the day and then reorient during the night to face east in anticipation of dawn. In contrast, mature plants cease movement with their flower heads facing east. We show that circadian regulation of directional growth pathways accounts for both phenomena and leads to increased vegetative biomass and enhanced pollinator visits to flowers. Solar tracking movements are driven by antiphasic patterns of elongation on the east and west sides of the stem. Genes implicated in control of phototropic growth, but not clock genes, are differentially expressed on the opposite sides of solar tracking stems. Thus, interactions between environmental response pathways and the internal circadian oscillator coordinate physiological processes with predictable changes in the environment to influence growth and reproduction. 
27492700	In a control population, we filed the 24-hour urinary calcium to set normal values, based on weight, BMI and menopause. By assessing calcium intake, 25OHD, PTH, CTX, GFR, we wanted to study how these could influence calcium excretion. A total of 317 subjects of 55.82 ± 12.6 years were studied: 249 women (210 were postmenopausal) and 66 men. Mean urinary calcium 24h was 4.07 ± 2.53 mmol: 3.99 ± 2.89 in men, 3.54 ± 2.44 in premenopausal women, 4.18 ± 2.42 in postmenopausal women. 24-hour urine calcium was lower in overweight subjects whether they are men or women. It was positively correlated to 25OHD, CTX, GFR, serum calcium and negatively to PTH, BMI and weight. In conclusion, urinary calcium was lower in overweight subjects, it increases after menopause. Dietary calcium intake seems little involved in explaining variations in urinary calcium which depends essentially on bone remodeling (CTX), GFR, levels of vitamin D and PTH. 
27492458	The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis.
27492405	Blood levels of glucose and immunoreactive insulin were assessed in women with android and gynoid types of obesity or normal body weight (control group) in the dynamics of oral glucose tolerance test in the morning and in the evening. In the control group, the mean concentrations of glucose and immunoreactive insulin were significantly higher in the evening at all test terms (0, 60 and 120 min), which is indicative of physiological insulin resistance in the evening. In the group of women with gynoid obesity, no difference in the levels of glucose and immunoreactive insulin was revealed in the morning and evening tests, but in the evening tests, glucose (60 and 120 min) and immunoreactive insulin (120 min) levels were lower than in the control group. In the group of women with android obesity, the evening glucose level on minutes 60 and 120 of the test was higher than in the morning, but immunoreactive insulin did not vary throughout the day and on minutes 60 and 120 it surpassed the corresponding parameter in the control group by 2-4 times. In case of gynoid obesity, glucose load was followed by hyperinsulinemia and hypoglycemia; in android obesity, it was followed by hyperinsulinemia, hyperglycemia, and insulin resistance irrespective of the time of the day. 
27492302	陽光照射對老人健康之影響.適度的陽光照射不僅有助於人體維生素D的生成，對改善骨骼健康、情緒認知有正面的影響外，更可調節褪黑激素的分泌而調控人體生理時鐘，有益於改善老人的睡眠品質，增加身體活動和社交的參與度。但長時間曝露在陽光下，對人體皮膚、眼睛及免疫系統的傷害也是不可忽視的。不過因許多研究均顯示，老人接觸陽光的時間普遍不足，特別是機構老人的活動型態多以室內為主，清醒時間多是坐著發呆或是坐在電視前打瞌睡。再加上健康因素、環境設計、個人喜好與機構活動設計，都會使得機構老人接觸陽光的時間少於一般可自我照顧的長者。因此建議除了從飲食及營養補充品中適當補充維生素D外，也可以在做好適當的防曬措施下，讓老人每週進行戶外活動至少五次，每天20–30分鐘。長期照護機構在硬體設備亦建議能增加老人接觸陽光的方便性與可近性外，也可將部分的活動設計在戶外舉行，讓機構的老人有適當接觸陽光的機會。.	Appropriate exposure to sunlight not only contributes to the production of vitamin D, which has been associated with enhanced bone health, mood, and cognitive functions, but also regulates the secretion of melatonin, which has been associated with the mediation of circadian rhythms, improved sleep quality, and optimized physical and social activity in the elderly. However, damage to the skin, eyes, and immune system has also been widely associated with long-term exposure to sunlight. Several studies have shown that many elderly, especially those that reside in institutions, do not receive sufficient sunlight exposure. Institutionalized elderly tend to participate in indoor activities and spend significant periods of time alone and asleep in front of the television. Furthermore, factors such as poor health, environmental design, indoor/outdoor preference, and activity design may impact the access of institutionalized elderly to sunlight more than their non-institutionalized peers. Therefore, we suggest that in addition to obtaining sufficient levels of vitamin D from their diet and from supplements, the elderly should perform outdoor activities for 20-30 minutes a day for five days each week. Furthermore, we suggest that the environment of the care facility should be made be more accessible and that some activities should be held outdoors. 	
27491166	The aim of this study was to investigate the influence of antihypertensive therapy with adding of gamma-amino-beta-phenylbutyric acid hydrochloride on the autonornic regulation of tcardiovascular system and the psychoemotional status in young men with hypertension. The study included 58 male with hypertension, aged 18-39 years (mean age 31.7 yearst 2.3 years), of them 28 patients (group I) administered beta-blocker and the other received a complex therapy which included beta-blocker and gamma-amino-beta-phenylbutyric acid hydrochiotide--Noofen ("OlainFarm", Latvia) 250 mg 3 times a day for 4 weeks. The control group consisted of 20 healthy indi&iduals aged 18-39 years (mean age 31.5 years +/- 2.5 years). The examination included of standard clinical; biochemical and instrumental investigatIons. We conducted a clinical measurement of blorid pressure, ambulatory blood pressure monitoring (ABPM), Doppler echocardiography, heart rate variability, autononlic symptoms questionnaire and Spielberger--Hanina Anxiety Scale. Analysis of circadian blbod pressure profile arid autonomic nervous system state in young men with hypertension, in spite of the short disenle history demonstratnl violations of the blood pressure circadian rhythm associated with the violation of the autonomic regulation of cardiovascular system as indreased sympathetic activity and decreased parasympathetic activity heart tate. In hypertensive patients with autonomic dysfunction we noted a reduction of level of mental health, which was reflected in an increase in'the number of people with high and moderate levels of reactive and personal anxiety It has been demonstratedthat the use of combination therapy with adding Noofen in young hypertensive men and autonomic dysfunction helped significantly improve the HRV parameters and restore autonomic balance on time parameters of heart rate variability reduced the level of reactive anxiety and imprdved the psychoemotional state.
27491145	In 106 patients with essential hypertension stage II losartan effectively lowers systolic and diastolic blood pressure during the day, thus contributing to the normalization of the circadian blood pressure profile in patients with initial breach, and does not affect the normal circadian rhythm. Long losartan promotes regression remodeling processes of cardiac muscle and reduce preload and afterload.
27489346	Circadian clocks are composed of transcriptional/translational feedback loops (TTFLs) at the cellular level. In Drosophila TTFLs, the transcription factor dCLOCK (dCLK)/CYCLE (CYC) activates clock target gene expression, which is repressed by the physical interaction with PERIOD (PER). Here, we show that amino acids (AA) 657-707 of dCLK, a region that is homologous to the mouse Clock exon 19-encoded region, is crucial for PER binding and E-box-dependent transactivation in S2 cells. Consistently, in transgenic flies expressing dCLK with an AA657-707 deletion in the Clock (Clk(out)) genetic background (p{dClk-Δ};Clk(out)), oscillation of core clock genes' mRNAs displayed diminished amplitude compared with control flies, and the highly abundant dCLKΔ657-707 showed significantly decreased binding to PER. Behaviorally, the p{dClk-Δ};Clk(out) flies exhibited arrhythmic locomotor behavior in the photic entrainment condition but showed anticipatory activities of temperature transition and improved free-running rhythms in the temperature entrainment condition. Surprisingly, p{dClk-Δ};Clk(out) flies showed pacemaker-neuron-dependent alterations in molecular rhythms; the abundance of dCLK target clock proteins was reduced in ventral lateral neurons (LNvs) but not in dorsal neurons (DNs) in both entrainment conditions. In p{dClk-Δ};Clk(out) flies, however, strong but delayed molecular oscillations in temperature cycle-sensitive pacemaker neurons, such as DN1s and DN2s, were correlated with delayed anticipatory activities of temperature transition. Taken together, our study reveals that the LNv molecular clockwork is more sensitive than the clockwork of DNs to dysregulation of dCLK by AA657-707 deletion. Therefore, we propose that the dCLK/CYC-controlled TTFL operates differently in subsets of pacemaker neurons, which may contribute to their specific functions. 
27489225	The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration.Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1.	Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs.	We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.	
27487452	Rhythmic changes in light and temperature conditions form the primary environmental cues that synchronize the molecular circadian clock of most species with the external cycles of day and night. Previous studies established a role for the CREB-binding protein (CBP) in molecular clock function by coactivation of circadian transcription. Here, we report that moderately increased levels of CBP strongly dampen circadian behavioural rhythms without affecting molecular oscillations of circadian transcription. Interestingly, light-dark cycles as well as high temperature facilitated a circadian control of behavioural activity. Based on these observations we propose that in addition to its coactivator function for circadian transcription, CBP is involved in the regulation of circadian behaviour down-stream of the circadian clock. 
27486508	Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 (-/-) mouse (iMSBmal1 (-/-)).Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 (-/-) mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 (-/-) muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 (-/-) muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle.	These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism.	
27485946	Sleep disorders appear to be frequent comorbidities in patients with frontotemporal dementia (FTD). Insomnia and excessive daytime sleepiness commonly occur in patients with FTD and significantly contribute to caregiver burden and burnout. Sleep is severely fragmented in FTD patients, likely secondary to behavioral disturbances, other primary sleep disorders such as sleep disordered breathing and restless leg syndrome, and neurodegeneration of nuclei involved in sleep and wakefulness. Treatment of primary sleep disorders may improve excessive daytime sleepiness and sleep quality and may improve daytime cognitive functioning. Rapid eye movement (REM) sleep behavior disorder is rare in FTD and may be confused with excessive nocturnal activity due to disturbed circadian rhythm. The relationship between FTD, sleep quality, and sleep disorders requires further study to better understand the contribution of disturbed sleep to daytime neurocognitive functioning and quality of life in FTD. Further, future studies should focus on comparing sleep disturbances between different FTD syndromes, especially behavioral variant FTD and primary progressive aphasia. Comorbid sleep disorders should be promptly sought and treated in patients with FTD to improve patient and caregiver quality of life. 
27485147	Previous studies consistently reported a diurnal variation in the occurrence of intracerebral hemorrhage (ICH), with a morning peak. However, limited knowledge exists on the circadian pattern of ICH severity and outcome. This study aimed to determine possible associations between ICH onset time and admission severity and 90-day outcomes using the combined data set of the pilot and main-phase Intensive blood pressure (BP) reduction in an acute cerebral hemorrhage trial (INTERACT). The ICH onset time was categorized into three groups (1: 00:00-07:59; 2: 08:00-15:59; and 3: 16:00-23:59). We found an association between onset time and low Glasgow Coma Scale score: aOR (time 1: 1.72, 95% CI 1.12-2.66; time 3: 1.95, 95% CI 1.31-2.89, p = 0.003; in comparison to time 2). There was no association between onset time and volume of ICH (adjusted p = 0.354) or 90-day outcomes of death or major disability, and death and major disability separately (all adjusted p > 0.4). The results showed that more severe cases of ICH patients, defined by a reduced level of consciousness, had late afternoon to early morning stroke onset, but this was unrelated to baseline hematoma volume or location. There was no circadian influence on ICH clinical outcome.
27485028	The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end-effector of the hypothalamus-pituitary-adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery.
27484793	Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.
27484676	Night-shift work may cause severe disturbances in the worker's circadian rhythm, which has been associated with the onset of health problems and diseases. As a substantial part of the workforce is exposed to night-shift work, harmful aspects of night-shift work should not be overlooked. The aim of the Klokwerk + study is to study the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects. First, we will study the relation between night-shift work exposure and body weight and between night-shift work exposure and infection susceptibility. Second, we will examine the mechanisms linking night-shift work exposure to body weight and infection susceptibility, with a specific focus on sleep, physical activity, diet, light exposure, vitamin D level, and immunological factors. Lastly, we will focus on the identification of biomarkers for chronic circadian disturbance associated with night-shift work.The design of this study is a prospective observational cohort study consisting of 1,960 health care workers aged 18-65 years. The study population will consist of a group of night-shift workers and an equally sized group of non-night-shift workers. During the study, there will be two measurement periods. As one of the main outcomes of this study is infection susceptibility, the measurement periods will take place at approximately the first (September/October) (T0) and the last month (April/May) (T1, after 6 months) of the flu season. The measurements will consist of questionnaires, anthropometric measurements, a smartphone application to determine infection susceptibility, food diaries, actigraphy, light sensors, and blood sample analyses.	The Klokwerk + study will contribute to the current need for high-quality data on the health effects of night-shift work and its underlying behavioral and physiological mechanisms. The findings can be the starting point for the development of interventions that prevent negative health effects caused by night-shift work. In addition, the identification of biomarkers indicative of loss of homeostasis due to circadian disturbance may be an important asset in monitoring the effects of such interventions.	

27484135	Large-scale storage of CO2 within sub-sea geological formations is a viable option for reducing the volume of this greenhouse gas released directly to the atmosphere from anthropogenic activities. Risks to benthic marine life following possible leakage of gas through the seabed from this carbon capture and storage (CCS) initiative are not yet well established. This study examined behavior (activity patterns) in brown shrimp (Crangon crangon), exposed to a range of reduced seawater pH conditions (7.6, 7, or 6.5) simulating leakage scenarios of varying scales. Brown shrimp have an endogenous rhythmicity associated with their activity, which dictates they are most active during hours of darkness, presumably as protection against vision-dependent predators. This endogenous rhythm in activity continues to be expressed when shrimp are held under constant low-light conditions in the lab and provides an ecologically relevant endpoint to measure when examining the influence of reduced pH on the behavior of these animals. No marked differences in activity pattern were observed between control shrimp maintained at pH 8.1 and those at pH 7.6. However, changes in activity were evident at pH 7 and pH 6.5, where significant shifts in timing and intensity of activity occurred. There was an unexpected increase in activity within periods of expected light, probably signaling efforts by shrimp to migrate away from reduced seawater pH conditions. The loss of this important member of the benthic community due to migration may have important consequences for many of the resilient species that remain. 
27482157	The main aim of this study is to investigate the occurrence and severity of FSD in women working in tertiary hospitals.The study sample was drawn from health care women between the ages of 20 and 65 years, working in two hospitals in Greece. This descriptive study used a structured Greek questionnaire and sexual function screener and quality of life sectors were consisted of rated scale questions. Eighty eight questionnaires were returned properly completed. The statistical analysis used the SPSS statistical program.	Female sexual dysfunction is a highly prevalent health issue whose exact incidence is not well defined. Factors that can contribute to female sexual dysfunction may be psychogenic, physical, mixed or unknown. Each of these factors consists of individual components that influence the sexual response; however their precise impact in FSD development and progression is unknown. Moreover, the role of circadian rhythm disorders (especially that of shift work sleep disorder) to the development and progression of FSD has been poorly investigated.	Working environment and patterns of work schedules may play a role in FSD however it has been difficult to specify in what extent they contribute to FSD development.	
27481310	Symptom-based criteria to diagnose irritable bowel syndrome (IBS) positively perform only modestly. Our aim was to assess whether including other items from the clinical history and limited diagnostic evaluation improves their performance.We collected complete symptom, colonoscopy, and histology data from 318 consecutive, unselected adult patients with lower gastrointestinal (GI) symptoms in secondary care. All participants underwent colonoscopy, with relevant organic findings recorded. The reference standard used to define the presence of true IBS was patient-reported lower abdominal pain or discomfort associated with a change in bowel habit, in the absence of organic GI disease. Sensitivity, specificity, and positive and negative likelihood ratios (LRs), with 95% confidence intervals, were calculated for Rome III criteria, as well as for modifications, incorporating nocturnal stools, results of simple blood tests (hemoglobin and C-reactive protein (CRP)), measures of somatization, and/or affective disorders (hospital anxiety or depression scale (HADS) score).	The sensitivity and specificity of the Rome III criteria for identifying IBS was 69.6%, and 82.0%, respectively, with positive and negative LRs of 3.87 and 0.37, respectively. Clinically useful enhancements in positive LRs were provided by combining Rome III criteria with: (a) high level of somatization (7.27); (b) normal hemoglobin and CRP with HADS score of ≥8 (5.04); (c) normal hemoglobin and CRP with a high level of somatization (7.56); or (d) no nocturnal passage of stool with a high level of somatization (17.3). Specificity was ≥95% with each of these modifications.	Incorporating nocturnal stools, somatization, and affective disorders from the clinical history, and hemoglobin and CRP measurements, enhances the positive LR and specificity of symptom-based Rome III criteria for IBS.	
27480652	To investigate sleep architecture and blood pressure dynamic change in patients with Sleep apnea syndrome by electrocardiogram-based cardiopulmonary coupling analysis system.Seventy-nine sleep disorder participants (PSQI≥8) were enrolled. Electrocardiogram-based cardiopulmonary coupling analysis device and ambulatory blood pressure monitoring were synchronously used to evaluate sleep architecture and blood pressure circadian rhythm. The patients were divided into SAS group (47 participants) and non-SAS group (32 participants) according to the Apnea Hypopnea Index (AHI) that calculated by CPC device. The data of sleep architecture and blood pressure variability were compared between two groups.	Compared with non-SAS group, SAS group have less proportion of deep sleep, more proportion of light sleep, higher mean blood pressure in 24 hours and daytime, lower nocturnal blood pressure dipping, faster mean heart rate in night time (P<0.05). AHI has moderate inverse correlation with deep sleep time, wake/dream time (-0.6≤r<-0.3), moderate positive correlation with light sleep time (0.3<r≤0.6), high inverse correlation with nocturnal blood pressure dipping (r=-0.785, P=0.000), moderate positive correlation with mean diastolic blood pressure (r=0.425, P=0.019).	Our study shows that less proportion of deep sleep, more proportion of light sleep, 24 hours mean blood pressure and nocturnal blood pressure increase in the patients with Sleep Apnea Syndrome. The severity of Sleep Apnea Syndrome has a positive correlation with the severity of abnormal sleep architecture and the degree of blood pressure elevation.	

27479324	Little is known about the ability of Drosophila circadian neurons to promote sleep. Here we show, using optogenetic manipulation and video recording, that a subset of dorsal clock neurons (DN1s) are potent sleep-promoting cells that release glutamate to directly inhibit key pacemaker neurons. The pacemakers promote morning arousal by activating these DN1s, implying that a late-day feedback circuit drives midday siesta and night-time sleep. To investigate more plastic aspects of the sleep program, we used a calcium assay to monitor and compare the real-time activity of DN1 neurons in freely behaving males and females. Our results revealed that DN1 neurons were more active in males than in females, consistent with the finding that male flies sleep more during the day. DN1 activity is also enhanced by elevated temperature, consistent with the ability of higher temperatures to increase sleep. These new approaches indicate that DN1s have a major effect on the fly sleep-wake profile and integrate environmental information with the circadian molecular program.
27478138	Disruption of the cyclic feature of the day-night environment can cause negative effects on daily activity and advanced brain functions such as learning, memory and decision-making behaviour. These functions in songbirds, including corvids, involve the hippocampus, pallium and midbrain, as revealed by ZENK (a neuronal activation marker) and tyrosine hydroxylase (TH) expressions. TH is rate-limiting marker enzyme of the biosynthesis of dopamine, widely implicated in learning and memory. Here, we measured ZENK and TH immunoreactivity in the hippocampal, pallial and midbrain regions in response to cognitive performance (learning-memory retrieval) tests in Indian house crows (Corvus splendens) exposed to constant light environment (LL) with controls on 12h light:12h darkness. Along with the decay of circadian rhythm in activity behaviour, LL caused a significant decline in the cognitive performance. There was also a decrease under LL in the activity of neurons in the hippocampus, medial and central caudal nidopallium, and hyperpallium apicale, which are widely distributed with TH-immunoreactive fibres. Further, under LL, TH- immunoreactive neurons were reduced in number in midbrain dopamine synthesis sites, the venteral tegmental area (VTA) and substantia nigra (SN), with a negative correlation of co-localized ZENK/TH- immunoreactive cells on errors during the association tasks. These results show decreased activity of learning and memory neural systems, and underscore the role of dopamine in reduced cognitive performance of diurnal corvids with disrupted circadian rhythms under an abrupt light environment. 
27478137	Lithium has been used for the treatment of bipolar disorder (BD). However, the mechanisms how lithium exerts its mood stabilizing effects remain to be studied. The disorder in circadian pacemaking has been suggested as an underlying mechanism of the characteristic mood instability of the BD. Lithium is also known to lengthen the circadian periods. We recently proposed that chronic methamphetamine treatment induced circadian oscillation as a complex oscillator including multiple dopaminergic brain areas, and the complex oscillator regulates behavior rhythm independent from the central circadian oscillator in the suprachiasmatic nucleus (SCN). Sleep-wake pattern of rapid cycling BD exhibits similar rhythm disorganization to methamphetamine treated animals. Therefore, we hypothesized that the dysregulated circadian rhythm in BD patients is caused by desynchronization of sleep-wake rhythms from the central clock in the SCN, and that mood stabilizing effect of lithium is achieved through their resynchronization. In the present experiment, we examined how lithium affects the circadian rhythms of brain areas involved in the complex oscillator as well as the SCN. Here we report that lithium lengthens the circadian periods in the SCN, olfactory bulb, median eminence and substantia nigra with dose and area specific manner. The effective lithium dose was much higher than the plasma levels that are required for lengthening the circadian behavior rhythms as well for therapeutic use. Low dose of lithium did not lengthen the period but enhanced the amplitude of circadian rhythms, which may exert therapeutic effects on BD. 
27477112	Intraocular pressure (IOP) is not a fixed value and varies over both the short term and periods lasting several months or years. In particular, IOP is known to vary throughout the 24-h period of a day, defined as a nyctohemeral rhythm in humans. In clinical practice, it is crucial to evaluate the changes in IOP over 24 h in several situations, including the diagnosis of ocular hypertension and glaucoma (IOP is often higher at night) and to optimize the therapeutic management of glaucoma. Until recently, all evaluations of 24-h IOP rhythm were performed using repeated IOP measurements, requiring individuals to be awakened for nocturnal measurements. This method may be imperfect, because it is not physiologic and disturbs the sleep architecture, and also because it provides a limited number of time point measurements not sufficient to finely asses IOP changes. These limitations may have biased previous descriptions of physiological IOP rhythm. Recently, extraocular and intraocular devices integrating a pressure sensor for continuous IOP monitoring have been developed and are available for use in humans. The objective of this article is to present the contributions of these new 24-h monitoring devices for the study of the nyctohemeral rhythms. In healthy subjects and untreated glaucoma subjects, a nyctohemeral rhythm is consistently found and frequently characterized by a mean diurnal IOP lower than the mean nocturnal IOP, with a diurnal bathyphase - usually in the middle or at the end of the afternoon - and a nocturnal acrophase, usually in the middle or at the end of the night.
27477077	The circadian clock is an endogenous biological mechanism that generates autonomous daily cycles in physiological activities. The phosphorylation levels of KaiC oscillated with a period of 24 h in an ATP-dependent clock oscillator reconstituted in vitro from KaiA, KaiB and KaiC. We examined the complex formations of KaiA and KaiB with KaiC in the KaiABC clock oscillator by fluorescence correlation spectrometry (FCS) analysis. The formation of KaiB-containing protein complex(es) oscillated in a circadian manner, with a single peak at 12 h and single trough at 24 h in the circadian cycle, whereas that of KaiA-containing protein complex(es) oscillated with two peaks at 12 and 24 h. FCS and surface plasmon resonance analyses showed that the binding affinity of KaiA for a mutant KaiC with Ala substitutions at the two phosphorylation sites considered to mimic the nonphosphorylated form of KaiC (np-KaiC) was higher than that for a mutant KaiC with Asp substitutions at the two phosphorylation sites considered to mimic the completely phosphorylated form of KaiC (cp-KaiC). The results from the study suggest that a KaiA-KaiB-cp-KaiC ternary complex and a KaiA-np-KaiC complex were formed at 12 and 24 h, respectively. 
27476975	Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. 
27476471	Night-time changes in bioluminescence intensity in the coastal area of the Black Sea were recorded. It was noted that the biomass of luminous organisms is closely correlated with the biomass of plankton and other pelagic organisms, including commercial pelagic fish. The parameters of plankton communities' basic biological rhythms were determined using the discrete Fourier transform method. These rhythms were manifest as spatial and temporal changes in the bioluminescence intensity. It was shown that changes in the bioluminescence intensity over a 14.0-h period were due to the duration of the light/dark cycles. By contrast, changes in bioluminescence intensity with periods of 4.7 and 2.8 h were due to the endogenous rhythms of the plankton community (feeding and cell division). An original method for evaluating of errors in the calculated periods of the biological rhythms was proposed. A strong correlation (r = 0.906) was observed between the measured and calculated values for the bioluminescence intensity, which provided support for the assumptions made.
27474266	What is the topic of this review? This review highlights temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. What advances does it highlight? Advances include: 1) cardiac glucose utilization peaks during the active period to meet increased energetic demands at this time; 2) synthesis of glycogen and triglyceride peak in the heart during the latter half of the active period, likely in anticipation of the upcoming sleep/fasting period; and 3) protein turnover increases in the heart at the beginning of the sleep phase, probably to promote growth and repair at this time. Cell-autonomous circadian clocks have emerged as crucial mediators of 24 h rhythms in cellular processes. In doing so, these molecular timekeepers confer the selective advantage of anticipation, allowing cells and organs to prepare for stimuli and stresses before their onset. The heart is subjected to dramatic fluctuations in energetic demand and nutrient supply in association with sleep-wake and fasting-feeding cycles. Recent studies suggest that the cardiomyocyte circadian clock orchestrates daily rhythms in both oxidative and non-oxidative glucose and fatty acid metabolism, as well as protein turnover. Here, I review this evidence and discuss whether disruption of these rhythms can contribute to cardiovascular disease.
27474264	What is the topic of this review? This brief symposium report is focused on the molecular and physiological evidence that supports a key role for the circadian clock in the regulation of kidney function. What advances does it highlight? Progress in understanding the molecular mechanism of the kidney clock is reviewed here, including new results from global 'omics' studies and candidate gene approaches. The molecular kidney clock is a master regulator of gene expression that affects renal electrolyte and drug handling as well as blood pressure. In this brief review, an overview of the molecular and physiological evidence for the kidney clock and the implications for the regulation of renal physiology and pathophysiology are presented. Accumulating evidence suggests that the molecular circadian clock acts as a master regulator of gene expression in the kidney. Global transcriptomic approaches have revealed the important finding that there are thousands of genes in the kidney subject to regulation by the molecular clock. Candidate gene approaches have also yielded information regarding regulation of renal sodium transport genes by the molecular clock. To date, the evidence linking the molecular kidney clock to rhythmic renal function provides strong support for the concept that circadian control of gene expression underlies rhythms in physiological function.
27474192	While previous studies have demonstrated short-wavelength sensitivity to the acute alerting effects of light during the biological night, fewer studies have assessed the alerting effect of light during the daytime. This study assessed the wavelength-dependent sensitivity of the acute alerting effects of daytime light exposure following chronic sleep restriction in 60 young adults (29 men, 31 women; 22.5 ± 3.1 mean ± SD years). Participants were restricted to 5 h time in bed the night before laboratory admission and 3 h time in bed in the laboratory, aligned by wake time. Participants were randomized for exposure to 3 h total of either narrowband blue (λmax 458-480 nm, n = 23) or green light (λmax 551-555 nm, n = 25) of equal photon densities (2.8-8.4 × 10(13) photons/cm(2)/sec), beginning 3.25 h after waking, and compared with a darkness control (0 lux, n = 12). Subjective sleepiness (Karolinska Sleepiness Scale), sustained attention (auditory Psychomotor Vigilance Task), mood (Profile of Mood States Bi-Polar form), working memory (2-back task), selective attention (Stroop task), and polysomnographic and ocular sleepiness measures (Optalert) were assessed prior to, during, and after light exposure. We found no significant effect of light wavelength on these measures, with the exception of a single mood subscale. Further research is needed to optimize the characteristics of lighting systems to induce alerting effects during the daytime, taking into account potential interactions between homeostatic sleep pressure, circadian phase, and light responsiveness. 
27474007	Camels are well adapted to hot arid environments and can contribute significantly to the economy of developing countries in arid regions of the world. Full understanding of the physiology of camels requires understanding of the internal temporal order of the body, as reflected in daily or circadian rhythms. In the current study, we investigated the daily rhythmicity of 20 physiological variables in camels exposed to natural oscillations of ambient temperature in a desert environment and compared the daily temporal courses of the variables. We also studied the rhythm of core body temperature under experimental conditions with constant ambient temperature in the presence and absence of a light-dark cycle. The obtained results indicated that different physiological variables exhibit different degrees of daily rhythmicity and reach their daily peaks at different times of the day, starting with plasma cholesterol, which peaks 24min after midnight, and ending with plasma calcium, which peaks 3h before midnight. Furthermore, the rhythm of core body temperature persisted in the absence of environmental rhythmicity, thus confirming its endogenous nature. The observed delay in the acrophase of core body temperature rhythm under constant conditions suggests that the circadian period is longer than 24h. Further studies with more refined experimental manipulation of different variables are needed to fully elucidate the causal network of circadian rhythms in dromedary camels. 
27473633	To test the feasibility, acceptability, and effects of a home-based morning versus evening bright light treatment on function and pain sensitivity in women with fibromyalgia.A single blind randomized study with two treatment arms: 6 days of a 1 hour morning light treatment or 6 days of a 1 hour evening light treatment. Function, pain sensitivity, and circadian timing were assessed before and after treatment.	Participants slept at home, except for two nights in Sleep Center.	Ten women meeting the American College of Rheumatology's diagnostic criteria for fibromyalgia, including normal blood test results.	Self-reported function was assessed with the Fibromyalgia Impact Questionnaire (FIQ). Pain sensitivity was assessed using a heat stimulus that gave measures of threshold and tolerance. Circadian timing was assessed with the dim light melatonin onset.	Both morning and evening light treatments led to improvements in function and pain sensitivity. However, only the morning light treatment led to a clinically meaningful improvement in function (>14% reduction from baseline FIQ) and morning light significantly increased pain threshold more than evening light ( P  < 0.05). Phase advances in circadian timing were associated with an increase in pain tolerance (r = 0.67, P  < 0.05).	Bright light treatment appears to be a feasible and acceptable adjunctive treatment to women with fibromyalgia. Those who undergo morning light treatment may show improvements in function and pain sensitivity. Advances in circadian timing may be one mechanism by which morning light improves pain sensitivity. Findings can inform the design of a randomized controlled trial.	
27472375	Oscillations in circadian metabolism are crucial to the well being of organism. Our understanding of metabolic rhythms has been greatly enhanced by recent advances in high-throughput systems biology experimental techniques and data analysis. In an in vitro setting, metabolite rhythms can be measured by time-dependent sampling over an experimental period spanning one or more days at sufficent resolution to elucidate rhythms. We hypothesized that cellular metabolic effects over such a time course would be influenced by both oscillatory and circadian-independent cell metabolic effects. Here we use nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling of mammalian cell culture media of synchronized U2 OS cells containing an intact transcriptional clock. The experiment was conducted over 48 h, typical for circadian biology studies, and samples collected at 2 h resolution to unravel such non-oscillatory effects. Our data suggest specific metabolic activities exist that change continuously over time in this settting and we demonstrate that the non-oscillatory effects are generally monotonic and possible to model with multivariate regression. Deconvolution of such non-circadian persistent changes are of paramount importance to consider while studying circadian metabolic oscillations. 
27472211	PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.
27470330	Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep-i.e. 'why' sleep evolved-remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or 'nest'. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and defending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans. 
27468954	Crustacean hyperglycemic hormone (CHH) has been extensively studied in decapod crustaceans where it is known to exert pleiotropic effects, including regulation of blood glucose levels. Hyperglycemia in decapods seems to be temporally gated to coincide with periods of activity, under circadian clock control. Here, we used gene cloning, in situ hybridization and immunohistochemistry to describe the characterization and localization of CHH in two peracarid crustaceans, Eurydice pulchra and Talitrus saltator. We also exploited the robust behavioral rhythmicity of these species to test the hypothesis that CHH mRNA expression would resonate with their circatidal (12.4h) and circadian (24h) behavioral phenotypes. We show that both species express a single CHH transcript in the cerebral ganglia, encoding peptides featuring all expected, conserved characteristics of other CHHs. E. pulchra preproCHH is an amidated 73 amino acid peptide N-terminally flanked by a short, 18 amino acid precursor related peptide (CPRP) whilst the T. saltator prohormone is also amidated but 72 amino acids in length and has a 56 residue CPRP. The localization of both was mapped by immunohistochemistry to the protocerebrum with axon tracts leading to the sinus gland and into the tritocerebrum, with striking similarities to terrestrial isopod species. We substantiated the cellular position of CHH immunoreactive cells by in situ hybridization. Although both species showed robust activity rhythms, neither exhibited rhythmic transcriptional activity indicating that CHH transcription is not likely to be under clock control. These data make a contribution to the inventory of CHHs that is currently lacking for non-decapod species.
27468160	High-fat diet (HFD) induces overeating and obesity. Green tea (-)-epigallocatechin-3-gallate (EGCG) reduces HFD-induced body weight and body fat gain mainly through increased lipid metabolism and fat oxidation. However, little is known about its effect on HFD-induced alterations in feeding behavior.Three diet groups of wildtype C57B/6j male mice at 5 months old were fed on normal chow diet, 1 week of HFD (60% of energy) and 3 months of HFD (diet-induced obesity (DIO)) prior to EGCG supplement in respective diet. EGCG had no effect on feeding behavior in normal chow diet group. Increased daytime feeding induced by HFD was selectively corrected by EGCG treatment in HFD groups, including reversed food intake, feeding frequency and meal size in HFD + EGCG group, and reduced food intake and feeding frequency in DIO + EGCG group. Moreover, EGCG treatment altered diurnally oscillating expression pattern of key appetite-regulating genes, including AGRP, POMC, and CART, and key circadian genes Clock and Bmal1 in hypothalamus of DIO mice, indicating its central effect on feeding regulation.	Our study demonstrates that EGCG supplement specifically counteracts daytime overeating induced by HFD in mice, suggesting its central role in regulating feeding behavior and energy homeostasis.	
27467757	Heterosis has been widely used in agriculture, but the molecular mechanism for this remains largely elusive. In Arabidopsis hybrids and allopolyploids, increased photosynthetic and metabolic activities are linked to altered expression of circadian clock regulators, including CIRCADIAN CLOCK ASSOCIATED1 (CCA1). It is unknown whether a similar mechanism mediates heterosis in maize hybrids. Here we report that higher levels of carbon fixation and starch accumulation in the maize hybrids are associated with altered temporal gene expression. Two maize CCA1 homologs, ZmCCA1a and ZmCCA1b, are diurnally up-regulated in the hybrids. Expressing ZmCCA1 complements the cca1 mutant phenotype in Arabidopsis, and overexpressing ZmCCA1b disrupts circadian rhythms and biomass heterosis. Furthermore, overexpressing ZmCCA1b in maize reduced chlorophyll content and plant height. Reduced height stems from reduced node elongation but not total node number in both greenhouse and field conditions. Phenotypes are less severe in the field than in the greenhouse, suggesting that enhanced light and/or metabolic activities in the field can compensate for altered circadian regulation in growth vigor. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals a temporal shift of ZmCCA1-binding targets to the early morning in the hybrids, suggesting that activation of morning-phased genes in the hybrids promotes photosynthesis and growth vigor. This temporal shift of ZmCCA1-binding targets correlated with nonadditive and additive gene expression in early and late stages of seedling development. These results could guide breeding better hybrid crops to meet the growing demand in food and bioenergy.
27466289	Poor breast cancer-related quality of life is associated with flattened cortisol rhythms and inflammation in breast cancer survivors and women with advanced disease. We explored the associations of cancer-specific distress (Impact of Events Scale), mood (Profile of Mood States), activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient) and cortisol (diurnal slope) circadian rhythms, and inflammation (interleukin-6) with quality of life (Functional Assessment of Cancer Therapy-Breast) among patients awaiting breast cancer surgery ( N = 57). Models were adjusted for differences in age and cancer stage. Distress and mood disturbance were significantly correlated with lower quality of life. Ethnic differences in the relationship between distress and mood disturbance with global quality of life and subscales of quality of life were observed. Actigraphic measures showed that in comparison with non-Hispanic patients, African Americans had significantly poorer activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient). Circadian disruption and inflammation were not associated with quality of life. Physiological dysregulation and associated comorbidities may take time to develop over the course of disease and treatment.
27465732	In humans, numbers of circulating T cells show a circadian rhythm with peak counts during the night and a steep decline in the morning. Sleep per se appears to counter this rhythm by acutely reducing the total number of T cells. The T-cell population, however, is rather heterogeneous, comprising various subpopulations with different features and functions and also different circadian rhythms. Therefore, we examined here whether sleep likewise differentially affects these subsets. We measured eight different T-cell subsets (naïve, central memory, effector memory, and effector CD4+ and CD8+ T cells) over a 24-h period under conditions of sustained wakefulness compared with a regular sleep-wake cycle in 14 healthy young men. Sleep reduced the number of all T-cell subsets during nighttime with this effect reaching the P < 0.05 level of significance in all but one subpopulation, i.e., effector CD4+ T cells, where it only approached significance. Furthermore, sleep was associated with an increase in growth hormone, prolactin, and aldosterone levels, whereas concentrations of catecholamines tended to be lower than during nocturnal wakefulness. The effect of sleep uniformly decreasing the different T-cell subsets is surprising considering their differential function and circadian rhythms, and even more so, since the sleep-induced decreases in these subsets are probably conveyed by different hormonal mediators. Although the reductions in cell numbers are rather small, they are comparable to changes seen, for example, after vaccination and are, therefore, likely to be of physiological relevance.
27465723	Circadian rhythms control aspects of physiological events, including lipid metabolism, showing rhythmic fluctuation over 24 h. Therefore, it is not sufficient to evaluate thoroughly how dietary components regulate lipid metabolism with a single time-point assay. In the present study, a time-course study was performed to analyze the effect of sea cucumber saponin echinoside A (EA) on lipid metabolism over 24 h. Results showed that EA lowered the levels of TC and TG in both serum and liver at most time-points during the 24 h. Activities of hepatic lipogenic enzymes and lipolytic enzymes were inhibited and elevated respectively by EA to varied degrees at different time-points. Meanwhile, parallel variation trends of gene expression involved in fatty acid synthesis and β-oxidation were observed accordingly. The interaction between EA and lipid metabolism showed a time-dependent effect. Overall, EA impaired fatty acid synthesis and enhanced mitochondrial fatty acid β-oxidation in ad libitum feeding over 24 h. 
27465521	Melatonin is an endogenous indoleamine with a wide range of biological functions. In addition to modulating circadian rhythms, it plays important roles in the health as an antioxidant. Melatonin has also the ability to induce apoptosis in cancer cells and to enhance the antitumoral activity of chemotherapeutic agents. In this study, the effect of melatonin on hyperthermia-induced apoptosis was explored using human leukemia cells. The results demonstrate that melatonin greatly improved the cytotoxicity of hyperthermia in U937 cells. The potentiation of cell death was achieved with 1 mmol/L concentrations of the indoleamine but not with concentrations close to physiological levels in blood (1 nmol/L). This effect was associated to an enhancement of the apoptotic response, revealed by an increase in cells with hypodiploid DNA content and activation of multiple caspases (caspase-2, caspase-3, caspase-8, and caspase-9). Melatonin also increased hyperthermia-induced Bid activation as well as translocation of Bax from the cytosol to mitochondria and cytochrome c release. Hyperthermia-provoked apoptosis and potentiation by melatonin were abrogated by a broad-spectrum caspase inhibitor (z-VAD-fmk) as well as by specific inhibitors against caspase-8 or caspase-3. In contrast, blocking of the mitochondrial pathway of apoptosis either with a caspase-9 inhibitor or overexpressing the anti-apoptotic protein Bcl-2 (U937/Bcl-2) reduced the number of apoptotic cells in response to hyperthermia but it was unable to suppress melatonin enhancement. Melatonin appears to modulate the apoptotic response triggered by hyperthermia in a cell type-specific manner as similar results were observed in HL-60 but not in K562 or MOLT-3 cells. 
27465361	The purpose of this study was to evaluate invasive and metastatic potential of urothelial cancer by investigating differential expression of various clock genes/proteins participating in the 24 h circadian rhythms and to compare these gene expressions with transcription of other cancer-associated genes.Twenty seven paired samples of tumour and benign tissue collected from patients who underwent cystectomy were analysed and compared to 15 samples of normal bladder tissue taken from patients who underwent cystoscopy for benign prostate hyperplasia (unrelated donors). Immunohistochemical analyses were made for clock and clock-related proteins. In addition, the gene-expression levels of 22 genes (clock genes, casein kinases, oncogenes, tumour suppressor genes and cytokeratins) were analysed by real-time quantitative PCR (qPCR).	Considerable up- or down-regulation and altered cellular distribution of different clock proteins, a reduction of casein kinase1A1 (CSNK1A1) and increase of casein kinase alpha 1 E (CSNK1E) were found. The pattern was significantly correlated with simultaneous up-regulation of stimulatory tumour markers, and a down-regulation of several suppressor genes. The pattern was mainly seen in aneuploid high-grade cancers. Considerable alterations were also found in the neighbouring bladder mucosa.	The close correlation between altered expression of various clock genes and common tumour markers in urothelial cancer indicates that disturbed function in the cellular clock work may be an important additional mechanism contributing to cancer progression and malignant behaviour.	
27463559	Animal studies demonstrate that circadian rhythm disruption during pregnancy can be deleterious to reproductive capacity and the long-term health of the progeny. Our previous studies in rats have shown that exposure of pregnant dams to an environment that significantly disrupts maternal circadian rhythms programs increased adiposity and poor glucose metabolism in offspring. In this study, we used mice with a ClockΔ19 mutation to determine whether foetal development within a genetically disrupted circadian environment affects pregnancy outcomes and alters the metabolic health of offspring. Ten female ClockΔ19+MEL mutant mice were mated with 10 wildtype males, and 10 wildtype females were mated with 10 ClockΔ19+MEL mutant males. While genetically identical, the heterozygote foetuses were exposed to either a normal (wildtype dams) or disrupted (ClockΔ19+MEL mutant dams) circadian environment during gestation. Pregnancy outcomes including time to mate, gestation length, litter size and birth weight were assessed. One male and one female offspring from each litter were assessed for postnatal growth, body composition, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test at 3 and 12 months of age. There was no effect of maternal genotype on pregnancy outcomes, with days to plug, gestation length, litter size and perinatal mortality not significantly different between wildtype and ClockΔ19+MEL mutant dams. Similarly, there was no effect of maternal genotype on weight of the offspring at birth or at any stage of postnatal growth. While there was an effect of sex on various tissue weights at 3 and 12 months of age, there were minimal effects of maternal genotype. Relative adrenal weight was significantly reduced (-32%) in offspring from ClockΔ19+MEL mutant dams, whereas gastrocnemius muscle was significantly increased (+16%) at 3 months of age only. Intraperitoneal glucose tolerance tests at 3 months of age revealed female offspring from ClockΔ19+MEL mutant dams had significantly reduced area under the curve following glucose administration (-25%), although no differences were found at 12 months of age. There was no effect of maternal genotype on intraperitoneal insulin tolerance at 3 or 12 months of age for either sex. These results demonstrate that foetal growth within a genetically disrupted circadian environment during gestation has no effect on pregnancy success, and only marginal impacts upon the long-term metabolic health of offspring. These results do not support the hypothesis that circadian rhythm disruption during pregnancy programs poor metabolic homeostasis in offspring. However, when maintained on a 12L:12D photoperiod, the ClockΔ19+MEL mutant dams display relatively normal patterns of activity and melatonin secretion, which may have reduced the impact of the mutation upon foetal metabolic programming.
27463411	The circadian time structure of an organism can be desynchronized in a large number of instances, including the intake of specific drugs. We have previously found that propofol, which is a general anesthetic, induces a desynchronization of the circadian time structure in rats, with a 60-80 min significant phase advance of body temperature circadian rhythm. We thus deemed it worthwhile to examine whether this phase shift of body temperature was related to a modification of the circadian period Tau. Propofol was administered at three different Zeitgeber Times (ZTs): ZT6 (middle of the rest period), ZT10 (2 h prior to the beginning of activity period), ZT16 (4 h after the beginning of the activity period), with ZT0 being the beginning of the rest period (light onset) and ZT12 being the beginning of the activity period (light offset). Control rats (n = 20) were injected at the same ZTs with 10% intralipid, which is a control lipidic solution. Whereas no modification of the circadian period of body temperature was observed in the control rats, propofol administration resulted in a significant shortening of the period by 96 and 180 min at ZT6 and ZT10, respectively. By contrast, the period was significantly lengthened by 90 min at ZT16. We also found differences in the time it took for the rats to readjust their body temperature to the original 24-h rhythm. At ZT16, the speed of readjustment was more rapid than at the two other ZTs that we investigated. This study hence shows (i) the disruptive effects of the anesthetic propofol on the body temperature circadian rhythm, and it points out that (ii) the period Tau for body temperature responds to this anesthetic drug according to a Tau-response curve. By sustaining postoperative sleep-wake disorders, the disruptive effects of propofol on circadian time structure might have important implications for the use of this drug in humans.
27463133	The cryptochrome/photolyase protein family possesses a conserved triad of tryptophans that may act as a molecular wire to transport electrons from the protein surface to the FAD cofactor for activation and/or signaling-state formation. Members from the animal (and animal-like) cryptochrome subclade use this process in a light-induced fashion in a number of exciting responses, such as the (re-)setting of circadian rhythms or magnetoreception; however, electron-transfer pathways have not been explored in detail yet. Therefore, we present an in-depth time-resolved optical and electron-paramagnetic resonance spectroscopic study of two cryptochromes from Chlamydomonas reinhardtii and Drosophila melanogaster. The results do not only reveal the existence of a fourth, more distant aromatic amino acid that serves as a terminal electron donor in both proteins, but also show that a tyrosine is able to fulfill this very role in Chlamydomonas reinhardtii cryptochrome. Additionally, exchange of the respective fourth aromatic amino acid to redox-inactive phenylalanines still leads to light-induced radical pair formation; however, the lifetimes of these species are drastically reduced from the ms- to the μs-range. The results presented in this study open up a new chapter, to our knowledge, in the diversity of electron-transfer pathways in cryptochromes. Moreover, they could explain unique functions of animal cryptochromes, in particular their potential roles in magnetoreception because magnetic-field effects of light-induced radical pairs strongly depend on distance and orientation parameters. 

27462335	Clock-generated biological rhythms provide an adaptive advantage to an organism, resulting in increased fitness and survival. To better elucidate the plant response to the circadian system, we surveyed protein oscillations in Arabidopsis seedlings under constant light. Using large-scale two-dimensional difference in gel electrophoresis (2D-DIGE) the abundance of more than 1000 proteins spots was reproducibly resolved quantified and profiled across a circadian time series. A comparison between phenol-extracted samples and RuBisCO-depleted extracts identified 71 and 40 rhythmically-expressed proteins, respectively, and between 30 and 40% of these derive from non-rhythmic transcripts. These included proteins influencing transcriptional regulation, translation, metabolism, photosynthesis, protein chaperones, and stress-mediated responses. The phasing of maximum expression for the cyclic proteins was similar for both datasets, with a nearly even distribution of peak phases across the time series. STRING clustering analysis identified two interaction networks with a notable number of oscillating proteins: plastid-based and cytosolic chaperones and 10 proteins involved in photosynthesis. The oscillation of the ABA receptor, PYR1/RCAR11, with peak expression near dusk adds to a growing body of evidence that intimately ties ABA signaling to the circadian system. Taken together, this study provides new insights into the importance of post-transcriptional circadian control of plant physiology and metabolism. 
27461005	Modern lifestyles prolong daily activities into the nighttime, disrupting circadian rhythms, which may cause sleep disturbances. Sleep disturbances have been implicated in the dysregulation of blood glucose levels and reported to increase the risk of type 2 diabetes (T2D) and diabetic complications. Sleep disorders are treated using anti-insomnia drugs that target ionotropic and G protein-coupled receptors (GPCRs), including γ-aminobutyric acid (GABA) agonists, melatonin agonists, and orexin receptor antagonists. A deeper understanding of the effects of these medications on glucose metabolism and their underlying mechanisms of action is crucial for the treatment of diabetic patients with sleep disorders. In this review we focus on the beneficial impact of sleep on glucose metabolism and suggest a possible strategy for therapeutic intervention against sleep-related metabolic disorders. 
27459238	Circadian rhythms are highly important not only for the synchronization of animals and humans with their periodic environment but also for their fitness. Accordingly, the disruption of the circadian system may have adverse consequences. A certain number of animals in our breeding stock of Djungarian hamsters are episodically active throughout the day. Also body temperature and melatonin lack 24-h rhythms. Obviously in these animals, the suprachiasmatic nuclei (SCN) as the central pacemaker do not generate a circadian signal. Moreover, these so-called arrhythmic (AR) hamsters have cognitive deficits. Since motor activity is believed to stabilize circadian rhythms, we investigated the effect of voluntary wheel running. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14 L/10 D lighting regimen. AR animals were selected according to their activity pattern obtained by means of passive infrared motion detectors. In a first step, the daily activity behavior was investigated for 3 weeks each without and with running wheels. To estimate putative photic masking effects, hamsters were exposed to light (LPs) and DPs and also released into constant darkness for a minimum of 3 weeks. A novel object recognition (NOR) test was performed to evaluate cognitive abilities both before and after 3 weeks of wheel availability. The activity patterns of hamsters with low wheel activity were still AR. With more intense running, daily patterns with higher values in the dark time were obtained. Obviously, this was due to masking as LPs did suppress and DPs induced motor activity. When transferred to constant darkness, in some animals the daily rhythm disappeared. In other hamsters, namely those which used the wheels most actively, the rhythm was preserved and free-ran, what can be taken as indication of a reconstitution of circadian rhythmicity. Also, animals showing a 24-h activity pattern after 3 weeks of extensive wheel running were able to recognize the novel object in the NOR test but not so before. The results show that voluntary exercise may reestablish circadian rhythmicity and improve cognitive performance.
27459195	Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a β-adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell-autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+. 
27459109	Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period, blood pressure (BP) was monitored weekly, and daily rhythms of melatonin, corticosterone, leptin and testosterone were evaluated at the end of the experiment. In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase-delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects.
27458911	A new study shows that nocturnal light exposure rapidly disrupts the central circadian clock as well as reduces motor performance and bone health. These findings provide a striking example of the costs of living in a disrupted light/dark cycle. 
27457257	To compare the diurnal and nocturnal effects of latanoprostene bunod 0.024% solution with timolol maleate 0.5% solution on intraocular pressure (IOP) and ocular perfusion pressure.Prospective, open-label randomized crossover trial.	Twenty-five patients (aged 43-82 years) with ocular hypertension or early primary open-angle glaucoma were enrolled. Baseline IOP and blood pressure were measured in a sleep laboratory every 2 hours in the sitting and supine positions during the 16-hour diurnal/wake period and in the supine position during the 8-hour nocturnal/sleep period. Subjects were randomly assigned to bilateral treatments of latanoprostene bunod at 8 PM or timolol at 8 AM and 8 PM. The second laboratory recording occurred after the 4-week treatment. Subjects were crossed over to the comparator treatment for 4 weeks before the third laboratory recording. Mean IOP and calculated ocular perfusion pressure were compared for the diurnal and nocturnal periods.	Twenty-one subjects completed the study. Both treatments reduced diurnal sitting and supine IOP compared to baseline by 2.3-3.9 mm Hg (all P < .001) with no statistically significant difference between the 2 treatments. Nocturnal IOP under latanoprostene bunod treatment was 2.5 ± 3.1 mm Hg (mean ± SD) less than baseline (P = .002) and 2.3 ± 3.0 mm Hg less than timolol treatment (P = .004). Latanoprostene bunod treatment resulted in greater diurnal sitting and supine ocular perfusion pressures compared with baseline (P ≤ .006) and greater nocturnal ocular perfusion pressure compared with timolol treatment (P = .010).	During the nocturnal period, latanoprostene bunod caused more IOP reduction and more increase of ocular perfusion pressure than timolol.	
27456060	Aldehyde-oxidase-4 (AOX4) is one of the mouse aldehyde oxidase isoenzymes and its physiological function is unknown. The major source of AOX4 is the Harderian-gland, where the enzyme is characterized by daily rhythmic fluctuations. Deletion of the Aox4 gene causes perturbations in the expression of the circadian-rhythms gene pathway, as indicated by transcriptomic analysis. AOX4 inactivation alters the diurnal oscillations in the expression of master clock-genes. Similar effects are observed in other organs devoid of AOX4, such as white adipose tissue, liver and hypothalamus indicating a systemic action. While perturbations of clock-genes is sex-independent in the Harderian-gland and hypothalamus, sex influences this trait in liver and white-adipose-tissue which are characterized by the presence of AOX isoforms other than AOX4. In knock-out animals, perturbations in clock-gene expression are accompanied by reduced locomotor activity, resistance to diet induced obesity and to hepatic steatosis. All these effects are observed in female and male animals. Resistance to obesity is due to diminished fat accumulation resulting from increased energy dissipation, as white-adipocytes undergo trans-differentiation towards brown-adipocytes. Metabolomics and enzymatic data indicate that 5-hydroxyindolacetic acid and tryptophan are novel endogenous AOX4 substrates, potentially involved in AOX4 systemic actions. 
27453946	Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system.
27453716	We recently have reported the 24-hour glucose, insulin and glucagon responses to a 72-hour fast compared to a 72-hour macronutrient-sufficient, carbohydrate-free diet in men with type 2 diabetes. The 72-hour time period was used because it is the time required for the major metabolic adjustments to a lack of food to be instituted. As part of that study, ghrelin and leptin responses were monitored.Twenty-four-hour total ghrelin and overnight fasting leptin concentrations were determined in males with type 2 diabetes when ingesting a standard, mixed meal diet (control), followed by a carbohydrate-free diet for 72 h or were starved for 72 h, using a crossover design.	A rise in ghrelin concentration before and a decrease after meals was present when the standard diet was ingested. However, in contrast to literature reports in normal subjects, a circadian variation was not apparent. Meal related changes were absent with starvation. A carbohydrate-free diet resulted in a daylong decrease in ghrelin. It also resulted in a 19 % decrease in the overnight fasting leptin concentration. Leptin was decreased 54 % with total starvation.	Ingestion of a typical mixed-meal diet results in meal-related changes in ghrelin similar to those reported in normal subjects, although the circadian rhythm was not apparent. Except for the lack of meal-related changes, starvation did not change the concentration. A carbohydrate-free, high fat diet resulted in a daylong suppression of ghrelin. The leptin concentration was decreased by both the carbohydrate-free diet and starvation.	
27453687	The influence of light and maternal activity on early infant activity rhythm were studied in 43 healthy, maternal-infant pairs. Aims included description of infant and maternal circadian rhythm of environmental light, assessing relations among of activity and light circadian rhythm parameters, and exploring the influence of light on infant activity independent of maternal activity. Three-day light and activity records were obtained using actigraphy monitors at infant ages 4, 8, and 12 weeks. Circadian rhythm timing, amplitude, 24-hour fit, rhythm center, and regularity were determined using cosinor and nonparametric circadian rhythm analyses (NPCRA). All maternal and infant circadian parameters for light were highly correlated. When maternal activity was controlled, the partial correlations between infant activity and light rhythm timing, amplitude, 24-hour fit, and rhythm center demonstrated significant relation (r = .338 to .662) at infant age 12 weeks, suggesting entrainment. In contrast, when maternal light was controlled there was significant relation between maternal and infant activity rhythm (r = 0.470, 0.500, and 0.638 at 4, 8 and 12 weeks, respectively) suggesting the influence of maternal-infant interaction independent of photo entrainment of cycle timing over the first 12 weeks of life. Both light and maternal activity may offer avenues for shaping infant activity rhythm during early infancy.
27452327	Aim Red cell distribution width (RDW), an index of erythrocyte size, is associated with high risk for cardiovascular disease. Nondipping hypertension (HT) is lack of nocturnal fall in blood pressure(BP). The association between RDW and non-dipping BP in normotensive and hypertensive patients was investigated. Methods A total of 170 patients were categorized into 4 groups: Normotensive-Dipper (NT-D), Normotensive-Non-dipper (NTND), Hypertensive-Dipper (HT-D) and Hypertensive-Non-dipper(HT-ND). RDW and hs-CRP levels were measured. Results Hypertensive patients had higher RDW and hs-CRP levels(14.5 ± 0.87 vs.12.7 ± 0.66, p<0.001 for RDW; 0.99 ± 0.52 vs.0.63 ± 0.43, p<0.001 for hs-CRP). Besides, the RDW levels were higher in non-dippers (13.0 ± 0.63 vs.12.4 ± 0.55, p<0.001 for NT-ND and NT-D; 14.9 ± 0.78 vs.14.2 ± 0.82, p<0.001 for HT-ND and HT-D) Conclusion RDW is elevated in non-dipping BP both in normotensive and hypertensive subjects, which may be related with increased inflammatory state. 
27451986	Traits related to flower advertisement and reward sometimes vary in a circadian way, reflecting phenotypic specialization. However, specialized flowers are not necessarily restricted to specialized pollinators. This is the case of most Silene species, typically associated with diurnal or nocturnal syndromes of pollination but usually showing complex suites of pollinators.A Silene species with mixed floral features between diurnal and nocturnal syndromes was used to test how petal opening, nectar production, scent emission and pollination success correlate in a circadian rhythm, and whether this is influenced by environmental conditions. The effect of diurnal and nocturnal visitation rates on plant reproductive success is also explored in three populations, including the effect of the pollinating seed predator Hadena sancta KEY RESULTS: The result showed that repeated petal opening at dusk was correlated with nectar secretion and higher scent production during the night. However, depending on environmental conditions, petals remain opened for a while in the morning, when nectar and pollen still were available. Pollen deposition was similarly effective at night and in the morning, but less effective in the afternoon. These results were consistent with field studies.	The circadian rhythm regulating floral attractiveness and reward in S. colorata is predominantly adapted to nocturnal flower visitors. However, favourable environmental conditions lengthen the optimal daily period of flower attraction and pollination towards morning. This allows the complementarity of day and night pollination. Diurnal pollination may help to compensate the plant reproductive success when nocturnal pollinators are scarce and when the net outcome of H. sancta shifts from mutualism to parasitism. These results suggest a functional mechanism explaining why the supposed nocturnal syndrome of many Silene species does not successfully predict their pollinator guilds.	
27451315	There is limited research on hot flushes and night sweats in women with a hysterectomy with ovarian conservation. We aimed to describe the patterns of these symptoms in a cohort of Australian women and to investigate the relationship between distinct symptom patterns and hysterectomy status.Repeated-measures latent class analysis (LCA) was used to identify hot flushes and night sweats symptom patterns across seven surveys (over 17 years) in the mid-cohort of the Australian Longitudinal Study on Women's Health. Multinomial logistic regression was used to assess the associations of the symptom patterns in women with a hysterectomy with ovarian conservation (n=1129) versus women without a hysterectomy (n=4977).	A higher proportion of women with a hysterectomy than of those without experienced a constant pattern of hot flushes (15% versus 30%) and night sweats (9% versus 19%). Women with a hysterectomy had higher odds of constant hot flushes versus minimal hot flushes (OR=1.97, 95% CI: 1.64, 2.35) and constant versus minimal night sweats (OR=2.09, 95% CI: 1.70, 2.55). Smoking, a 'lower level of education to non-professional occupation' pathway and body mass index (BMI) patterns of 'always obese' and 'increasingly obese' were also associated with a higher risk of constant symptoms.	Women who have a hysterectomy (with ovarian conservation) have a higher risk of hot flushes and night sweats that persist over an extended period.	
27449477	The pineal gland produces the hormone melatonin, and its volume may influence melatonin levels. We describe an innovative method for estimating pineal volume in humans and present the association of pineal parenchyma volume with levels of the primary melatonin metabolite, 6-sulfatoxymelatonin. We selected a random sample of 122 older Icelandic men nested within the AGES-Reykjavik cohort and measured their total pineal volume, their parenchyma volume, and the extent of calcification and cysts. For volume estimations we used manual segmentation of magnetic resonance images in the axial plane with simultaneous side-by-side view of the sagittal and coronal plane. We used multivariable adjusted linear regression models to estimate the association of pineal parenchyma volume and baseline characteristics, including 6-sulfatoxymelatonin levels. We used logistic regression to test for differences in first morning urinary 6-sulfatoxymelatonin levels among men with or without cystic or calcified glands. The pineal glands varied in volume, shape, and composition. Cysts were present in 59% of the glands and calcifications in 21%. The mean total pineal volume measured 207 mm(3) (range 65-536 mm(3)) and parenchyma volume 178 mm(3) (range 65-503 mm(3)). In multivariable-adjusted models, pineal parenchyma volume was positively correlated with 6-sulfatoxymelatonin levels (β = 0.52, p < 0.001). Levels of 6-sulfatoxymelatonin did not differ significantly by presence of cysts or calcification. By using an innovative method for pineal assessment, we found pineal parenchyma volume to be positively correlated with 6-sulfatoxymelatonin levels, in line with other recent studies. 
27449476	Many people in our modern civilized society sleep later on free days compared to work days. This discrepancy in sleep timing will lead to so-called 'social jetlag' on work days with negative consequences for performance and health. Light therapy in the morning is often proposed as the most effective method to advance the circadian rhythm and sleep phase. However, most studies focus on direct effects on the circadian system and not on posttreatment effects on sleep phase and sleep integrity. In this placebo-controlled home study we investigated if blue light, rather than amber light therapy, can phase shift the sleep phase along with the circadian rhythm with preservation of sleep integrity and performance. We selected 42 participants who suffered from 'social jetlag' on workdays. Participants were randomly assigned to either high-intensity blue light exposure or amber light exposure (placebo) with similar photopic illuminance. The protocol consisted of 14 baseline days without sleep restrictions, 9 treatment days with either 30-min blue light pulses or 30-min amber light pulses in the morning along with a sleep advancing scheme and 7 posttreatment days without sleep restrictions. Melatonin samples were taken at days 1, 7, 14 (baseline), day 23 (effect treatment), and day 30 (posttreatment). Light exposure was recorded continuously. Sleep was monitored through actigraphy. Performance was measured with a reaction time task. As expected, the phase advance of the melatonin rhythm from day 14 to day 23 was significantly larger in the blue light exposure group, compared to the amber light group (84 min ± 51 (SD) and 48 min ± 47 (SD) respectively; t36 = 2.23, p < 0.05). Wake-up time during the posttreatment days was slightly earlier compared to baseline in the blue light group compared to slightly later in the amber light group (-21 min ± 33 (SD) and +12 min ± 33 (SD) respectively; F1,35 = 9.20, p < 0.01). The number of sleep bouts was significantly higher in the amber light group compared to the blue light group during sleep in the treatment period (F1,32 = 4.40, p < 0.05). Performance was significantly worse compared to baseline at all times during (F1,13 = 10.1, p < 0.01) and after amber light treatment (F1,13 = 17.1, p < 0.01), while only in the morning during posttreatment in the blue light condition (F1,10 = 9.8, p < 0.05). The data support the conclusion that blue light was able to compensate for the sleep integrity reduction and to a large extent for the performance decrement that was observed in the amber light condition, both probably as a consequence of the advancing sleep schedule. This study shows that blue light therapy in the morning, applied in a home setting, supports a sleep advancing protocol by phase advancing the circadian rhythm as well as sleep timing. 
27449361	Mood disorders constitute a high burden for both patients and society. Notwithstanding the large arsenal of available treatment options, a considerable group of patients does not remit on current antidepressant treatment. There is an urgent need to develop alternative treatment strategies. Recently, low-strength transcranial pulsed electromagnetic field (tPEMF) stimulation has been purported as a promising strategy for such treatment-resistant depression (TRD). The mode of action of this new technique is however largely unknown.We searched PubMed for literature reports on the effects of tPEMF and for information regarding its working mechanism and biological substrate.	Most studies more or less connect with the major hypotheses of depression and concern the effects of tPEMF on brain metabolism, neuronal connectivity, brain plasticity, and the immune system. Relatively few studies paid attention to the possible chronobiologic effects of electromagnetic fields.	We reviewed the literature of a new and still developing field. Some of the reports involved translational studies, which inevitably limits the reach of the conclusions.	Weak magnetic fields influence divergent neurobiological processes. The antidepressant effect of tPEMF may be specifically attributable to its effects on local brain activity and connectivity.	
27449058	Neurospora crassa is a model organism for the study of circadian clocks, molecular machineries that confer ∼24-hr rhythms to different processes at the cellular and organismal levels. The FREQUENCY (FRQ) protein is a central component of the Neurospora core clock, a transcription/translation negative feedback loop that controls genome-wide rhythmic gene expression. A genetic screen aimed at determining new components involved in the latter process identified regulation of conidiation 1 (rco-1), the ortholog of the Saccharomyces cerevisiae Tup1 corepressor, as affecting period length. By employing bioluminescent transcriptional and translational fusion reporters, we evaluated frq and FRQ expression levels in the rco-1 mutant background observing that, in contrast to prior reports, frq and FRQ expression are robustly rhythmic in the absence of RCO-1, although both amplitude and period length of the core clock are affected. Moreover, we detected a defect in metabolic compensation, such that high-glucose concentrations in the medium result in a significant decrease in period when RCO-1 is absent. Proteins physically interacting with RCO-1 were identified through co-immunoprecipitation and mass spectrometry; these include several components involved in chromatin remodeling and transcription, some of which, when absent, lead to a slight change in period. In the aggregate, these results indicate a dual role for RCO-1: although it is not essential for core-clock function, it regulates proper period and amplitude of core-clock dynamics and is also required for the rhythmic regulation of several clock-controlled genes. 
27448524	Diurnal salivary cortisol profiles are valuable indicators of adrenocortical functioning in epidemiological research and clinical practice. However, normative reference values derived from a large number of participants and across a wide age range are still missing. To fill this gap, data were compiled from 15 independently conducted field studies with a total of 104,623 salivary cortisol samples obtained from 18,698 unselected individuals (mean age: 48.3 years, age range: 0.5-98.5 years, 39% females). Besides providing a descriptive analysis of the complete dataset, we also performed mixed-effects growth curve modeling of diurnal salivary cortisol (i.e., 1-16h after awakening). Cortisol decreased significantly across the day and was influenced by both, age and sex. Intriguingly, we also found a pronounced impact of sampling season with elevated diurnal cortisol in spring and decreased levels in autumn. However, the majority of variance was accounted for by between-participant and between-study variance components. Based on these analyses, reference ranges (LC/MS-MS calibrated) for cortisol concentrations in saliva were derived for different times across the day, with more specific reference ranges generated for males and females in different age categories. This integrative summary provides important reference values on salivary cortisol to aid basic scientists and clinicians in interpreting deviations from the normal diurnal cycle.
27448057	Low levels of physical activity and the presence of obesity are associated with mitochondrial dysfunction. In addition, mitochondrial dysfunction has been associated with the development of insulin resistance and type 2 diabetes mellitus (T2DM). Although the evidence for a causal relationship between mitochondrial function and insulin resistance is still weak, emerging evidence indicates that boosting mitochondrial function might be beneficial to patient health. Exercise training is probably the most recognized promoter of mitochondrial function and insulin sensitivity and hence is still regarded as the best strategy to prevent and treat T2DM. Animal data, however, have revealed several new insights into the regulation of mitochondrial metabolism, and novel targets for interventions to boost mitochondrial function have emerged. Importantly, many of these targets seem to be regulated by factors such as nutrition, ambient temperature and circadian rhythms, which provides a basis for nonpharmacological strategies to prevent or treat T2DM in humans. Here, we will review the current evidence that mitochondrial function can be targeted therapeutically to improve insulin sensitivity and to prevent T2DM, focusing mainly on human intervention studies.
27447698	High temperature causes negative effects on grain yield and quality of rice (Oryza sativa L.). In this study, the effects of short-term high temperature (SHT) on grain quality and starch granules were investigated in two rice cultivars Nanjing 41 (NJ41, heat-sensitive) and Wuxiangjing 14 (WJ14, heat-tolerant) at post-anthesis stage (anthesis and early grain-filling stage). The results of rice quality analysis showed that chalky rate and chalkiness increased while brown rice rate, milled rice rate, and head rice rate decreased in two rice cultivars with the increase of high temperature and prolonged duration. Moreover, SHT stress reduced the accumulation of amylose as well as starch accumulation. The starch accumulation and eating quality were more sensitive to SHT than the appearance and milling quality. The starch structure data observed by scanning electron microscope further showed that the starch granules are arranged loosely and more single starch granules appeared after SHT treatment. The extent of change in rice quality and starch traits of WJ14 under SHT was lower than that of NJ41. The effects of SHT at anthesis stage were greater than that at grain-filling stage. Taken together, the results could help further understand the physiological and biochemical processes governing rice quality under high-temperature conditions.
27445984	The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoid production, yet it is unclear how the clock responds to acute stress. We hypothesized that stress-induced ACTH provides a signal that phase shifts the adrenal clock. To assess whether acute stress phase shifts the adrenal clock in vivo in a phase-dependent manner, mPER2:LUC mice on a 12:12-h light:dark cycle underwent restraint stress for 15 min or no stress at zeitgeber time (ZT) 2 (early subjective day) or at ZT16 (early subjective night). Adrenal explants from mice stressed at ZT2 showed mPER2:LUC rhythms that were phase-advanced by ~2 h, whereas adrenals from mice stressed at ZT16 showed rhythms that were phase-delayed by ~2 h. The biphasic response was also observed in mice injected subcutaneously either with saline or with ACTH at ZT2 or ZT16. Blockade of the ACTH response with the glucocorticoid, dexamethasone, prevented restraint stress-induced phase shifts in the mPER2:LUC rhythm both at ZT2 and at ZT16. The finding that acute stress results in a phase-dependent shift in the adrenal mPER2:LUC rhythm that can be blocked by dexamethasone indicates that stress-induced effectors, including ACTH, act to phase shift the adrenal clock rhythm. 
27445838	Sexual activity before competition has been considered as a possible cause for reduced performance since ancient Greece and Rome. Recently, the hypothesis that optimal sport performance could be influenced by a variety of factors including sexual activity before competition has been investigated. However, few scientific data are available, with the exception of anecdotal reports of individual experiences. The present systematic review focused on the current scientific evidence on the effects of sexual activity on sport performance regardless of sport type. Data were obtained following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, using PubMed/MEDLINE, ISI/Web of Science, the Cochrane Collaboration Database, Cochrane Library, Evidence Database (PEDro), Evidence Based Medicine (EBM) Search review, National Guidelines, ProQuest, and Scopus, all searched from inception further, to broaden the search, no time filter nor language restriction have been applied. Also, the gray literature was mined using Google Scholar. Only relevant scientific articles reporting outcomes of athletic performance after sexual activity were considered. The impact of sexual activity before a sport competition is still unclear, but most studies generally seem to exclude a direct impact of sexual activity on athletic aerobic and strength performance. The most important aspect seems to be the interval from the time of the sports competition that affects negatively the performance if it is shorter than 2 h. There are possible negative effects from some possible concurrent wrong behaviors such as smoking or alcohol abuse. There are no investigations about the effect of masturbation in this context. There is a need to clarify the effects of sexual activity on competition performance. The present evidence suggests that sexual activity the day before competition does not exert any negative impact on performance, even though high-quality, randomized controlled studies are urgently needed. 
27445242	Sleep disorders are common in neurology practice, but are often undiagnosed and untreated. Specific patient cohorts, such as older adults, patients residing in nursing homes, and patients with underlying chronic neurologic and psychiatric disorders, are at particular risk. If these sleep problems are not properly evaluated and managed the patient may experience exacerbation of the underlying neurologic disorder. This article highlights some of the key sleep disorders relevant to practicing neurologists, emphasizing hypersomnolence, insomnia, and sleep-related movement disorders in the setting of neurologic disorders to enhance the tools available for evaluation, and discusses management strategies. 
27444022	Circadian (∼24 h) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptional-translational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, the author discusses how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modelling of transcriptional repression mechanisms in molecular circadian clocks. 
27443484	Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the culture medium is enriched with growth factors, and the absence of such acceleration in confluent cells. In order to explain these observations, we study a possible entrainment of the circadian clock by the cell cycle through a regulation of clock genes around the mitosis phase. We develop a computational model and a formal specification of the observed behavior to investigate the conditions of entrainment in period and phase. We show that either the selective activation of RevErb-α or the selective inhibition of Bmal1 transcription during the mitosis phase, allow us to fit the experimental data on both period and phase, while a uniform inhibition of transcription during mitosis seems incompatible with the phase data. We conclude on the arguments favoring the RevErb-α up-regulation hypothesis and on some further predictions of the model.
27442503	Recent studies have suggested that there are certain pathophysiological relationships between bipolar disorder (BD) and circadian rhythm dysfunction. However, apparently no studies have clarified the prevalence of circadian rhythm sleep-wake disorders (CRSWD) in patients with BD. This study was set out to investigate the prevalence of CRSWD and associated factors in patients with BD. One hundred four euthymic BD outpatients participated in this study. The subjects were asked to answer questionnaires including demographic variables, clinical course of BD, and family history of psychiatric disorders and suicide. Severity of BD was assessed by the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. CRSWD was diagnosed by clinical interview, together with sleep logs, according to the International Classification of Sleep Disorders, third edition (ICSD-3). Thirty-five subjects (32.4%) met the criteria for CRSWD. The age at the time of investigation and that at the onset of BD were both lower in the CRSWD group than in the non-CRSWD group. The rates of family history of psychiatric disorders and suicide in the CRSWD group were higher than those in the non-CRSWD group. Multiple logistic regression analysis revealed that the presence of CRSWD was significantly associated with younger onset age of BD and family history of suicide. The prevalence of CRSWD could be quite high in BD patients. Younger onset age of BD and family history of suicide were associated with presence of CRSWD in BD patients. 
27441544	The aim of the research was to study the state of melatonin-positive-labeled cells (MPLC) of GM in desynchronosis in rats of different age and gender. 780 sections of the pyloric part of the gastric mucosa were studied in rats of both genders at the age of 9, 15 and 20 months. Animals were divided into intact control groups and the groups of the animals kept under the conditions of continuous light for 14 days - desynchronosis. The study was performed by the method of immunohistochemical staining with the primary antibodies to melatonin (Biorbyt, UK) and the secondary Alexa Fluor 488-conjugated antibody (Abcam, UK). In the course of the research it was found that MPLC in all experimental groups were mainly located in the basal and middle segments of the tubular glands of gastric mucosa and were represented by three types of cells. In desynchronosis the number of melatonin-positive-labeled cells significantly reduced in almost every age group, with the exception of females at the age of 20 months. Thus in elderly males and females the number of melatonin-positive-labeled cells of type III increases, whereas in young and mature males it decreases, and cells of type I predominate. 
27441387	Paraspeckles are nuclear bodies form around the long non-coding RNA, Neat1, and RNA-binding proteins. While their role is not fully understood, they are believed to control gene expression at a post-transcriptional level by means of the nuclear retention of mRNA containing in their 3'-UTR inverted repeats of Alu sequences (IRAlu). In this study, we found that, in pituitary cells, all components of paraspeckles including four major proteins and Neat1 displayed a circadian expression pattern. Furthermore the insertion of IRAlu at the 3'-UTR of the EGFP cDNA led to a rhythmic circadian nuclear retention of the egfp mRNA that was lost when paraspeckles were disrupted whereas insertion of a single antisense Alu had only a weak effect. Using real-time video-microscopy, these IRAlu were further shown to drive a circadian expression of EGFP protein. This study shows that paraspeckles, thanks to their circadian expression, control circadian gene expression at a post-transcriptional level. 
27441028	Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Daily scheduled restricted feeding (RF), in which the food available time is restricted for several hours each day, elicits anticipatory activity. This food-anticipatory activity (FAA) is controlled by a food-entrainable oscillator (FEO) that is distinct from the suprachiasmatic nucleus (SCN), the master pacemaker in mammals. In an earlier report, we described generation of transgenic (Tg) mice ubiquitously overexpressing cysteine414-alanine mutant mCRY1. The Tg mice displayed long locomotor free-running periods (approximately 28 h) with rhythm splitting. Furthermore, their locomotor activity immediately re-adjusted to the advance of light-dark cycles (LD), suggesting some disorder in the coupling of SCN neurons. The present study examined the restricted feeding cycle (RF)-induced entrainment of locomotor activity in Tg mice in various light conditions. In LD, wild-type controls showed both FAA and LD-entrained activities. In Tg mice, almost all activity was eventually consolidated to a single bout before the feeding time. The result suggests a possibility that in Tg mice the feeding cycle dominates the LD cycle as an entrainment agent. In constant darkness (DD), wild-type mice exhibited robust free-run activity and FAA during RF. For Tg mice, only the rhythm entrained to RF was observed in DD. Furthermore, after returning to free feeding, the free-run started from the RF-entrained phase. These results suggest that the SCN of Tg mice is entrainable to RF and that the mCRY1 mutation alters the sensitivity of SCN to the cycle of nonphotic zeitgebers.
27440914	The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease. 
27440219	The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3'UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1. 
27439492	With the current societal norm of shiftwork and long working hours, maintaining a stable daily life is becoming very difficult. An irregular lifestyle disrupts circadian rhythms, resulting in the malfunction of body physiology and ultimately leading to lifestyle-related diseases, including hypertension. By analyzing completely arrhythmic Cry1/Cry2 double-knockout (Cry-null) mice, we found salt-sensitive hypertension accompanied by hyperaldosteronism. On the basis of a DNA microarray analysis of the adrenal gland and subsequent biochemical analyses, we discovered that Hsd3b6/HSD3B1, a subtype of 3β-HSD, is markedly overexpressed in aldosterone-producing cells in the Cry-null adrenal cortex. In addition, we found that Hsd3b6/HSD3B1, which converts pregnenolone to progesterone, is a clock-controlled gene and might also be a key enzyme for the regulation of aldosterone biosynthesis, in addition to the previously established CYP11B2, which synthesizes aldosterone from deoxycorticosterone. Importantly, angiotensin II induces HSD3B1 via the transcription factor NGFIB in human adrenocortical H295R cells, similarly to CYP11B2. As HSD3B1 levels are abnormally high in the adrenal aldosterone-producing cells of idiopathic hyperaldosteronism (IHA), the temporal component of this system in the pathophysiology of IHA is a promising area for future research.
27436770	To improve the welfare of caged laying hens, a pecking device made of stones was introduced on the cage floor. Twenty-four White Leghorn hens aged 15 months were divided into four groups: single-housed hens with device, single-housed control hens, pair-housed hens with device and pair-housed control hens. Hens housed with the device pecked at various pecking objects less often than control hens. Agonistic behavior was also lower in hens with the device than in hens without the device, implied a possibility of improvement in quality of pecking stimuli with the device. Not only time spent pecking, but also quality of pecking might be important to fill their need for stimulation. Both single- and pair-housed hens more often pecked at the device in the evening. Response to various pecking objects also showed that pecking behaviors were most frequently expressed in the evening. Increased foraging at dusk is a well-known habit; therefore, the increase in pecking behavior in the evening might reflect the hens' general circadian rhythm. These results indicate that the device made of stones could promote some instinctive behavior. Enhancement of behavioral repertories and reduced agonistic behavior with the pecking device might improve the welfare of caged laying hens. 
27435153	Seasonal variations in physiology and behavior have frequently been reported. Light is the major zeitgeber for synchronizing internal circadian rhythms with the external solar day. Non-image forming effects of light radiation, for example, phase resetting of the circadian rhythms, melatonin suppression, and acute alerting effects, depend on several characteristics of the light exposure including intensity, timing and duration, spectral composition and previous light exposure, or light history. The aim of the present study was to report on the natural pattern of diurnal and seasonal light exposure and to examine seasonal variations in the circadian change of melatonin and cortisol concentrations for a group of Swedish office workers.Fifteen subjects participated in a field study that was carried out in the south of Sweden. Ambulatory equipment was used for monthly measurements of the daily exposure to light radiation across the year. The measurements included illuminance and irradiance. The subjects collected saliva samples every 4 h during 1 day of the monthly measuring period.	The results showed that there were large seasonal differences in daily amount of light exposure across the year. Seasonal differences were observed during the time periods 04:00-08:00, 08:00-12:00, 12:00-16:00, 16:00-20:00, and 20:00-24:00. Moreover, there were seasonal differences regarding the exposure pattern. The subjects were to a larger extent exposed to light in the afternoon/evening in the summer. During the winter, spring, and autumn, the subjects received much of the daily light exposure in the morning and early afternoon. Regarding melatonin, a seasonal variation was observed with a larger peak level during the winter and higher levels in the morning at 07:00.	This study adds to the results from other naturalistic studies by reporting on the diurnal and seasonal light exposure patterns for a group living at a northern latitude of 56° N, with large annual variations in photoperiod length. It seems to be seasonal variation in the lighting conditions, both concerning intensities as well as regarding the pattern of the light exposure to which people living at high latitudes are exposed which may result in seasonal variation in the circadian profile of melatonin.	
27434852	Photoperiod-synchronized rhythms in non-CSN tissues persist in total darkness. Clock genes involved in maintaining regular biorhythms within the suprachiasmatic nucleus (SCN) of the hypothalamus are expressed in extra-CNS tissues and continue periodic expression in vitro. Understanding the details of how the SCN clock is coupled with peripheral clocks is only incompletely understood and may involve a multiplicity of feedback systems. The present study is an extension of our previous work showing that brain levels of TRH (pGlu-His-Pro-NH2) and TRH-like peptides (X-TRH: pGlu-X-Pro-NH2, where "X" can be any amino acid residue) fluctuate throughout the day-night cycle. Male rats were maintained in a stable environment, lights on 6-18 h. TRH and TRH-like peptides in liver, pancreas, testis, prostate, epididymis, and heart were measured at 3, 10, 16, and 22 h. The greatest change in peptide level was a 12-fold increase for TRH in prostate at 16 h relative to the corresponding value at 3 h. The TRH, Tyr-TRH and Phe-TRH levels in liver declined steadily to about 40% of the 3-h values by 22 h. Changes, in the order of decreasing number of significant increases (↑) and/or decreases (↓), were: testis (5↑, 1↓), liver (3↓), epididymis (2↑), prostate (1↑, 1↓) and heart (1↑). Peptide levels in liver and testis correlated with serum leptin and serum corticosterone, respectively, which are potent releasers of these peptides. Testosterone and glucose were also highly correlated. These tripeptides may participate in the regulation of metabolic and reproductive functions, which change during the day-night cycle.
27432117	Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver. 
27432116	An improvement to our current quantitative model of arousal state dynamics is presented that more accurately predicts sleep propensity as measured with sleep dynamics depending on circadian phase and prior wakefulness. A nonlinear relationship between the circadian variables within the dynamic circadian oscillator model is introduced to account for the skewed shape of the circadian rhythm of alertness that peaks just prior to the onset of the biological night (the "wake maintenance zone") and has a minimum toward the end of the biological night. The revised circadian drive thus provides a strong inhibitory input to the sleep-active neuronal population in the evening, counteracting the excitatory effects of the increased homeostatic sleep drive as originally proposed in the opponent process model of sleep-wake regulation. The revised model successfully predicts the sleep propensity profile as reflected in the dynamics of the total sleep time, sleep onset latency, wake/sleep ratio, and sleep efficiency during a wide range of experimental protocols. Specifically, all of these sleep measures are predicted for forced desynchrony schedules with day lengths ranging from 1.5 to 42.85 h and scheduled time in bed from 0.5 to 14.27 h. The revised model is expected to facilitate more accurate predictions of sleep under normal conditions as well as during circadian misalignment, for example, during shiftwork and jetlag. 
27429864	The Behavioral Approach System (BAS)/Reward Hypersensitivity Theory and the Social Zeitgeber Theory are two biopsychosocial theories of bipolar spectrum disorders (BSD) that may work together to explain affective dysregulation. The present study examined whether BAS sensitivity is associated with affective symptoms via a) increased social rhythm disruption in response to BAS-relevant life events, or b) greater exposure to BAS events leading to social rhythm disruption and subsequent symptoms. Results indicated that high BAS individuals were more likely to experience social rhythm disruption following BAS-relevant events. Social rhythm disruption mediated the association between BAS-relevant events and symptoms (hypothesis a). High BAS individuals experienced significantly more BAS-relevant events, which predicted greater social rhythm disruption, which predicted greater levels of affective symptoms (hypothesis b). Individuals at risk for BSD may be sensitive to BAS-relevant stimuli, experience more BAS-relevant events, and experience affective dysregulation due to the interplay of the BAS and circadian rhythms.
27429799	Purpose. To identify retinal pigment epithelium (RPE)/choroid genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. Methods. Differential gene expression of over 34,000 well-characterized mouse genes in the RPE/choroid of 6-week-old C57BL/6J mice was analyzed after intravitreal steroid injections at 1 week and 1 month postinjection, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpring GX 12.5 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. Results. Both triamcinolone and dexamethasone caused differential activation of genes involved in "Circadian Rhythm Signaling" pathway at both time points tested. Triamcinolone (TAA) uniquely induced significant changes in gene expression in "Calcium Signaling" (1 week) and "Glutamate Receptor Signaling" pathways (1 month). In contrast, dexamethasone (Dex) affected the "GABA Receptor Signaling" (1 week) and "Serotonin Receptor Signaling" (1 month) pathways. Understanding how intraocular steroids affect the gene expression of RPE/choroid is clinically relevant. Conclusions. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections, which likely has consequences in the dysregulation of RPE function and neurodegeneration of the retina. 
27427832	Circadian rhythm regulates multiple metabolic processes and in turn is readily entrained by feeding-fasting cycles. However, the molecular mechanisms by which the peripheral clock senses nutrition availability remain largely unknown. Bile acids are under circadian control and also increase postprandially, serving as regulators of the fed state in the liver. Here, we show that nuclear receptor Small Heterodimer Partner (SHP), a regulator of bile acid metabolism, impacts the endogenous peripheral clock by directly regulating Bmal1. Bmal1-dependent gene expression is altered in Shp knockout mice, and liver clock adaptation is delayed in Shp knockout mice upon restricted feeding. These results identify SHP as a potential mediator connecting nutrient signaling with the circadian clock. 
27426518	Circadian rhythms are deeply rooted in the biology of virtually all organisms. The pervasive use of artificial lighting in modern society disrupts circadian rhythms and can be detrimental to our health. To investigate the relationship between disrupting circadian rhythmicity and disease, we exposed mice to continuous light (LL) for 24 weeks and measured several major health parameters. Long-term neuronal recordings revealed that 24 weeks of LL reduced rhythmicity in the central circadian pacemaker of the suprachiasmatic nucleus (SCN) by 70%. Strikingly, LL exposure also reduced skeletal muscle function (forelimb grip strength, wire hanging duration, and grid hanging duration), caused trabecular bone deterioration, and induced a transient pro-inflammatory state. After the mice were returned to a standard light-dark cycle, the SCN neurons rapidly recovered their normal high-amplitude rhythm, and the aforementioned health parameters returned to normal. These findings strongly suggest that a disrupted circadian rhythm reversibly induces detrimental effects on multiple biological processes. 
27426078	Previous research suggests that the sleep-obesity association varies significantly across individuals. This study examined the associations between actigraphically measured sleep parameters and body mass index and hypothesized that the associations would be stronger in individuals with greater delay discounting, the devaluation of future rewards and response disinhibition and the difficulty in withholding previously rewarded responses. Seventy-eight college students carried a wrist-worn actigraph and completed diaries reporting bedtime, wake time and covariates including physical activity, alcohol and caffeine consumption, daytime nap duration and perceived stress for 7 days and completed the delay discounting and go/no-go response disinhibition tasks. Their height and weight were measured. Only bedtime variability was significantly associated with body mass index in the main effect model controlling for all covariates (B = 0.03, P = 0.001). Delay discounting moderated associations of bedtime (B = 0.03, P < 0.001), sleep duration variability (B = 0.05, P = 0.002), bedtime variability (B = 0.03, P = 0.002) and wake time variability (B = 0.02, P < 0.001) with body mass index; these associations were significant only when the delay discounting rate was high. Response disinhibition moderated the association between bedtime variability and body mass index in a similar pattern (B = 0.01, P = 0.004). The findings suggest that, using actigraphy measures of sleep, circadian desynchrony rather than sleep duration is a risk factor for higher body mass index. The findings support the hypothesis that delay discounting and response disinhibition moderate the associations between sleep and body mass index. Delay discounting and response disinhibition might characterize individuals who are vulnerable to the influence of circadian desynchrony on weight.
27425779	Isoprene emission from plants is very sensitive to environmental temperature both at short-term and long-term scales. Our previous study demonstrated suppression of isoprene emission by cold temperatures in a high emitting tropical tree Ficus septica and revealed a strong correlation of emission to isoprene synthase (IspS) protein levels. When challenged with decreasing daily temperatures from 30 to 12 °C, F. septica completely stopped isoprene emission at 12 °C, only to recover on the second day after re-exposure to 30 °C. Here, we explored this regulation of isoprene emission in response to environmental temperature by a comprehensive analysis of transcriptome data, gene expressions and metabolite pools of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. MEP pathway genes and metabolites dynamics did not support substrate-level limitations as major control over observed basal emission, but transcriptome data, network inferences and putative regulatory elements on IspS promoter suggested transcriptional regulation of IspS gene through circadian rhythm and phytohormone signalling processes. Expression levels of 29 genes involved in these pathways were examined by quantitative real-time PCR. We propose that temperature controls over basal isoprene emission at a time-scale of hours to few days are regulated by phytohormone-mediated transcriptional modulation of IspS gene under synchronization by the circadian clock. 
27423070	We evaluated whether the association between Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Seasonal Affective Disorder (SAD) was mediated by the circadian rhythm.Data of 2239 persons from the Netherlands Study of Depression and Anxiety (NESDA) were used. Two groups were compared: with clinically significant ADHD symptoms (N = 175) and with No ADHD symptoms (N = 2064). Sleep parameters were sleep-onset and offset times, mid sleep and sleep duration from the Munich Chronotype Questionnaire. We identified the prevalence of probable SAD and subsyndromal SAD using the Seasonal Pattern Assessment Questionnaire (SPAQ). Clinically significant ADHD symptoms were identified by using a T score>65 on the Conners Adult ADHD Rating Scale.	The prevalence of probable SAD was estimated at 9.9% in the ADHD group (vs. 3.3% in the No ADHD group) and of probable s-SAD at 12.5% in the ADHD group (vs 4.6% in the No ADHD group). Regression analyses showed consistently significant associations between ADHD symptoms and probable SAD, even after adjustment for current depression and anxiety, age, sex, education, use of antidepressants and benzodiazepines (B = 1.81, p < 0.001). Late self-reported sleep onset was an important mediator in the significant relationship between ADHD symptoms and probable SAD, even after correction for confounders (total model effects: B = 0.14, p ≤ 0.001).	Both seasonal and circadian rhythm disturbances are significantly associated with ADHD symptoms. Delayed sleep onset time in ADHD may explain the increase in SAD symptoms. Treating patients with SAD for possible ADHD and delayed sleep onset time may reduce symptom severity in these complex patients.	
27422761	A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity. 
27420105	Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. 
27418862	Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep-wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder. 
27412912	The circadian clock drives rhythms in multiple physiological processes allowing plants to anticipate and adjust to periodic changes in environmental conditions. These physiological rhythms are associated with robust oscillations in the expression of thousands of genes linked to the control of photosynthesis, cell elongation, biotic and abiotic stress responses, developmental processes such as flowering, and the clock itself. Given its pervasive effects on plant physiology, it is not surprising that circadian clock genes have played an important role in the domestication of crop plants and in the improvement of crop productivity. Therefore, identifying the principles governing the dynamics of the circadian gene regulatory network in plants could strongly contribute to further speed up crop improvement. Here we provide an historical as well as a current description of our knowledge of the molecular mechanisms underlying circadian rhythms in plants. This work focuses on the transcriptional and post-transcriptional regulatory layers that control the very core of the circadian clock, and some of its complex interactions with signaling pathways that help synchronize plant growth and development to daily and seasonal changes in the environment. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer.
27416551	Chronic lymphocytic leukemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical and occupational history, including work shifts and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR = 1.06; 95% CI = 0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR(tertile 3 vs . day-work)  = 1.77; 95% = 1.14-2.74), although no linear trend was observed (P trend = 0.18). This association was observed among those with rotating (OR(tertile 3 vs . day-work)  = 2.29; 95% CI = 1.33-3.92; P trend = 0.07), but not permanent night shifts (OR(tertile 3 vs . day-work) = 1.16; 95% CI = 0.60-2.25; P trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation. 
27413249	Sleep is governed by homeostasis and the circadian clock. Clock genes play an important role in the generation and maintenance of circadian rhythms but are also involved in regulating sleep homeostasis. The lateral habenular nucleus (LHb) has been implicated in sleep-wake regulation, since LHb gene expression demonstrates circadian oscillation characteristics. This study focuses on the participation of LHb clock genes in regulating sleep homeostasis, as the nature of their involvement is unclear. In this study, we observed changes in sleep pattern following sleep deprivation in LHb-lesioned rats using EEG recording techniques. And then the changes of clock gene expression (Per1, Per2, and Bmal1) in the LHb after 6 hours of sleep deprivation were detected by using real-time quantitative PCR (qPCR). We found that sleep deprivation increased the length of Non-Rapid Eye Movement Sleep (NREMS) and decreased wakefulness. LHb-lesioning decreased the amplitude of reduced wake time and increased NREMS following sleep deprivation in rats. qPCR results demonstrated that Per2 expression was elevated after sleep deprivation, while the other two genes were unaffected. Following sleep recovery, Per2 expression was comparable to the control group. This study provides the basis for further research on the role of LHb Per2 gene in the regulation of sleep homeostasis. 
27412611	Hibernation is a complex physiological response that some mammalian species employ to evade energetic demands. Previous work in mammalian hibernators suggests that hibernation is activated not by a set of genes unique to hibernators, but by differential expression of genes that are present in all mammals. This question of universal genetic mechanisms requires further investigation and can only be tested through additional investigations of phylogenetically dispersed species. To explore this question, we use RNA-Seq to investigate gene expression dynamics as they relate to the varying physiological states experienced throughout the year in a group of primate hibernators-Madagascar's dwarf lemurs (genus Cheirogaleus). In a novel experimental approach, we use longitudinal sampling of biological tissues as a method for capturing gene expression profiles from the same individuals throughout their annual hibernation cycle. We identify 90 candidate genes that have variable expression patterns when comparing two active states (Active 1 and Active 2) with a torpor state. These include genes that are involved in metabolic pathways, feeding behavior, and circadian rhythms, as might be expected to correlate with seasonal physiological state changes. The identified genes appear to be critical for maintaining the health of an animal that undergoes prolonged periods of metabolic depression concurrent with the hibernation phenotype. By focusing on these differentially expressed genes in dwarf lemurs, we compare gene expression patterns in previously studied mammalian hibernators. Additionally, by employing evolutionary rate analysis, we find that hibernation-related genes do not evolve under positive selection in hibernating species relative to nonhibernators. 
27411666	Sleep disturbances are commonly observed in older nursing home residents, mainly in combination with dementia. However, sleep-associated circadian motor activity patterns have not been thoroughly investigated in Japanese nursing homes. The present study aimed to respectively clarify the effect of community living and the presence of dementia on sleep disturbances and interrupted activity rhythm of older nursing-home residents with or without dementia and older community-dwelling people without dementia.Actigraph devices worn on the participants' non-dominant wrists for seven days were used to collect objective measurements of the sleep/awake status throughout the night and the circadian motor activity patterns. The presence of dementia was assessed by a trained medical doctor using the residents' records and the Clinical Dementia Rating (CDR). The functional capacity of the participants was determined using the Barthel Index (BI).	Fifty-one older people in Akita prefecture were included in the current study, consisting of 17 residents with dementia (mean age: 82.2 years), 17 residents without dementia (84.5 years), and 17 community-dwelling people (83.6 years). The results showed that older nursing-home residents with dementia had significantly a lower rate of sleep efficiency and a longer awake time throughout the night than the other groups. Older nursing-home residents with and without dementia had more fragmented rhythm than community-dwelling people without dementia.	These results provide evidence of poor sleep/awake status throughout the night and interrupted circadian activity rhythms in nursing-home residents with and without dementia. However, further studies performed according to dementia classifications are needed.	
27411248	Billions of birds migrate at night over North America each year. However, few studies have described the phenology of these movements, such as magnitudes, directions, and speeds, for more than one migration season and at regional scales. In this study, we characterize density, direction, and speed of nocturnally migrating birds using data from 13 weather surveillance radars in the autumns of 2010 and 2011 in the northeastern USA. After screening radar data to remove precipitation, we applied a recently developed algorithm for characterizing velocity profiles with previously developed methods to document bird migration. Many hourly radar scans contained windborne "contamination," and these scans also exhibited generally low overall reflectivities. Hourly scans dominated by birds showed nightly and seasonal patterns that differed markedly from those of low reflectivity scans. Bird migration occurred during many nights, but a smaller number of nights with large movements of birds defined regional nocturnal migration. Densities varied by date, time, and location but peaked in the second and third deciles of night during the autumn period when the most birds were migrating. Migration track (the direction to which birds moved) shifted within nights from south-southwesterly to southwesterly during the seasonal migration peaks; this shift was not consistent with a similar shift in wind direction. Migration speeds varied within nights, although not closely with wind speed. Airspeeds increased during the night; groundspeeds were highest between the second and third deciles of night, when the greatest density of birds was migrating. Airspeeds and groundspeeds increased during the fall season, although groundspeeds fluctuated considerably with prevailing winds. Significant positive correlations characterized relationships among bird densities at southern coastal radar stations and northern inland radar stations. The quantitative descriptions of broadscale nocturnal migration patterns presented here will be essential for biological and conservation applications. These descriptions help to define migration phenology in time and space, fill knowledge gaps in avian annual cycles, and are useful for monitoring long-term population trends of migrants. Furthermore, these descriptions will aid in assessing potential risks to migrants, particularly from structures with which birds collide and artificial lighting that disorients migrants.
27409645	In females, ovarian estradiol modulates kisspeptin (Kiss-1) synthesis to act as an obligatory regulator of downstream gonadotropin release in vivo, via stimulation of GnRH neurons. Changes in the ovarian condition are relayed to the neuroendocrine hypothalamus via two sexually dimorphic Kiss-1 populations, located in the anteroventral periventricular (AVPV) and arcuate nuclei, conveying estradiol-positive and -negative feedback, respectively. To elucidate how differential responsiveness to estradiol is mediated in these populations, we generated two kisspeptin-secreting cell lines from an adult kiss1-green fluorescent protein (GFP) female mouse. These lines recapitulate in vivo responsiveness to estradiol, with KTaV-3 (AVPV) cells demonstrating significantly increased kiss1 expression under high physiological estradiol exposure, whereas KTaR-1 (arcuate) cells exhibit kiss1 suppression after lower estradiol exposure. Baseline expression of estrogen receptor-α (esr1) differs significantly between KTaV-3 and KTaR-1 cells, with KTaR-1 cells demonstrating higher basal expression of esr1. Estradiol stimulation of kiss1 expression in KTaV-3 cells is modulated in a dose-dependent manner up to 25.0 pM, with less responsiveness observed at higher doses (>50.0 pM). In contrast, KTaR-1 kiss1 attenuates at lower estradiol doses (2.0-5.0 pM), returning to baseline levels at 25.0 pM and greater. Furthermore, the expression of the core clock genes bmal1 and per2 show normal rhythms in KTaV-3 cells, regardless of estradiol treatment. Conversely, KTaR-1 antiphasic transcription of bmal1 and per2 is phase delayed by low estradiol treatment. Strikingly, estradiol induces circadian rhythms of kiss1 expression only in KTaV-3 cells. Further exploration into estradiol responsiveness will reveal mechanisms responsible for the differential expression pattern demonstrated in vivo between these cell types. 
27402684	The purpose of this investigation is to examine differences in rest-activity patterns and sleep characteristics in older adults with heart failure (HF) and healthy older adults. The sample included older adults with HF (n = 20) and a reference group of healthy older adults (n = 20). Traditional cosinor analysis was used to assess three parameters of rest-activity from wrist actigraphy data: amplitude (range of activity), mesor (mean activity), and acrophase (time of peak activity). Traditional sleep characteristics were also determined from actigraphy data: total sleep time (TST), sleep latency (SL), sleep efficiency (SE), and wake after sleep onset (WASO). The HF group demonstrated significantly lower mesor and amplitude than the reference group (p < .01). The HF group had significantly greater TST (p < .01), but the groups had similar SE, SL, and WASO. Despite similar sleep characteristics to healthy older adults, overall rest-activity patterns were significantly dampened in those with HF.
27398336	This paper investigated the effect of daylight on morning and night melatonin, subjective general health using GHQ questionnaire, sleepiness and alertness on elderly who lived in nursing houses.Nineteen nursing home residents participated voluntarily. They exposed to daylight from 9 to 10 a.m. and from 4 to 5 p.m. for 6 wk. The level of melatonin in the morning and at night was measured. General health of all participants was evaluated using General Health Questionnaire (GHQ) as well.	Daylight exposure significantly affected morning melatonin from 25.39 pg/ml to 59.77 pg/ml (P=0.001) and night melatonin were changed from 40.30pg/ml to 34.41pg/ml (P=0.081). Mean score of general health changed 36.31 to 29.89 (P=0.003). Karolinska Sleepiness Scale (KSS) and Visual Analogue Scale (VAS) showed increase sleepiness and decrease alertness from 3:00 to 7:00 a.m. Sleepiness decreased and alertness increased during 1:00 p.m. and 20:00 p.m.	Daylight exposure could delay sleep phase and correction of circadian rhythm in elderly. Anxiety and insomnia could be improved with daylight exposure. It suggests that elders should be exposed to scheduled daylight in morning and evening for prevention and improvement of mental disorders. Adequate light should be provided for elder's homes and nursing house.	
27396544	Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short-term recording in an epilepsy monitoring unit (EMU) with altered antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long-term ambulatory intracranial recordings captured by the NeuroPace RNS System.Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84-day period. We analyzed all detections and long device-detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE-SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi-square analysis was used to compare subjects grouped by region of seizure onset.	In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE-SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model.	Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure-onset zone, with implications for treatment and safety, including SUDEP.	
27395462	Dementia, including Alzheimer's disease, is often associated with various sleep disorders such as insomnia, hypersomnia, circadian rhythm sleep disorders, sleep-disordered breathing and sleep debt due to organic damages of sleep/wake-promoting nucleus and circadian center (suprachiasmatic nucleus). These sleep disorders reduce the quality of life of individuals with dementia, and increase the care burden, which are major social issues. Recent studies have revealed that sleep deterioration is not only a comorbid symptom but also a prodrome and a risk factor for the development of dementia. 
27391795	We investigated the influence of cigarette smoking on the levels and circadian patterns of blood pressure (BP), heart rate (HR), and HR variability (HRV) in hypertensive patients. Sixteen hypertensive smokers (57 ± 2 years old) receiving antihypertensive treatments participated in this study. Ambulatory monitoring of BP, HR, and electrocardiograms was performed every 30 min for 24 hours on a smoking day and nonsmoking day in a randomized crossover manner. Average 24-hour BP and daytime BP were significantly higher in the smoking period than in the nonsmoking period. No significant differences were observed in nighttime BP between the two periods. Average 24-hour and daytime HR, but not nighttime HR, were also higher in the smoking period than in the nonsmoking period. The daytime high frequency (HF) component of HRV was attenuated more in the smoking period than in the nonsmoking period. No significant differences were observed in the low frequency (LF) components of HRV or LF/HF ratio between the two periods. These results demonstrated that cigarette smoking increased the daytime and average 24-hour BP and HR, and the increases observed in daytime BP and HR were associated with the attenuation of parasympathetic nerve activity. 
27388366	Recent reports highlight that human decision-making is influenced by the time of day and whether one is a morning or evening person (i.e., chronotype). Here, we test whether these behavioral effects are associated with endogenous biological rhythms. We asked participants to complete two well-established decision-making tasks in the morning or evening: the matrix task (an ethical decision task) and the balloon analog risk task (BART; a risk-taking task), and we measured their chronotype in two ways. First, participants completed a self-report measure, the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ). Second, we measured the expression of two circadian clock-regulated genes-Per3 and Nr1d2-from peripheral clock cells in participants' hair follicle samples. Using a cosinor model, we estimated the phase of the peripheral clock and assigned RNA chronotypes to participants with advanced (larks) or delayed (owls) phases. The behavioral data were analyzed independently for self-reported (MEQ) and RNA-based chronotypes. We find that significant chronotype and/or time-of-day effects between larks and owls in decision-making tasks occur only in RNA-based chronotypes. Our results provide evidence that time-of-day effects on decision-making can be explained by phase differences in oscillating clock genes and suggest that variation in the molecular clockwork may influence inter-individual differences in decision-making behavior. 
27387732	The objectives of this study were to determine daily variation in intradermal reactivity to histamine in dogs and to evaluate a potential influence of glucocorticoids on reactivity. Wheal sizes formed after intradermal injections of histamine were measured every 6 h during a single 24 h period in six healthy dogs. To determine whether glucocorticoids were implicated in daily variation, intradermal reactivity to histamine was evaluated at 9:00 h and at 21:00 h during a single day in dogs that received oral prednisolone (a synthetic glucocorticoid) or oral trilostane (an inhibitor of endogenous glucocorticoid synthesis). Finally, the time required for the histamine reaction to diminish after an intravenous injection of hydrocortisone was also assessed. A significant time-of-day-dependent variation in intradermal reactivity to histamine was detected in dogs, with a larger wheal size observed at 9:00 h than at 21:00 h. Administration of prednisolone or trilostane disrupted this variation. Intradermal reactivity to histamine was significantly reduced 6 h after an intravenous injection of hydrocortisone. These results suggest that glucocorticoid secretion from the adrenal glands could be involved in the regulation of daily variation in histamine-mediated reactions in dogs. 
27386785	This article describes a new methodology for increasing the spatial representativeness of individual monitoring sites. Air pollution levels at a given point are influenced by emission sources in the immediate vicinity. Since emission sources are rarely uniformly distributed around a site, concentration levels will inevitably be most affected by the sources in the prevailing upwind direction. The methodology provides a means of capturing this effect and providing additional information regarding source/pollution relationships. The methodology allows for the division of the air quality data from a given monitoring site into a number of sectors or wedges based on wind direction and estimation of annual mean values for each sector, thus optimising the information that can be obtained from a single monitoring station. The method corrects for short-term data, diurnal and seasonal variations in concentrations (which can produce uneven weighting of data within each sector) and uneven frequency of wind directions. Significant improvements in correlations between the air quality data and the spatial air quality indicators were obtained after application of the correction factors. This suggests the application of these techniques would be of significant benefit in land-use regression modelling studies. Furthermore, the method was found to be very useful for estimating long-term mean values and wind direction sector values using only short-term monitoring data. The methods presented in this article can result in cost savings through minimising the number of monitoring sites required for air quality studies while also capturing a greater degree of variability in spatial characteristics. In this way, more reliable, but also more expensive monitoring techniques can be used in preference to a higher number of low-cost but less reliable techniques. The methods described in this article have applications in local air quality management, source receptor analysis, land-use regression mapping and modelling and population exposure studies. 
27385614	The influence of circadian feeding patterns on weight outcomes has been shown in animal and human studies but not in very young children.We aimed to examine the association of infant circadian feeding patterns at 12 mo of age with subsequent growth and weight status after 1 y.	Mothers from a Singapore birth cohort (n = 349) reported the food given to their infants and the feeding time at 12 mo of age. Predominantly daytime (pDT) (0700-1859; n = 282) and predominantly nighttime (pNT) (1900-0659; n = 67) feeding infants were defined by whether daytime energy intake was >50% or <50% of total energy intake as assessed with the use of a 24-h recall. Body mass index-for-age z scores (BAZs) were computed with the use of the WHO Child Growth Standards 2006 to determine changes in BAZs from 12 to 24 mo of age and weight status at 24 mo of age. Multivariable linear and logistic regression analyses were performed.	Compared with pDT feeding, pNT feeding was associated with a higher BAZ gain from 12 to 24 mo of age (adjusted β = 0.38; 95% CI: 0.11, 0.65; P = 0.006) and increased risk of becoming overweight at 24 mo of age (adjusted OR: 2.78; 95% CI: 1.11, 6.97; P = 0.029) with adjustments for maternal age, education, ethnicity, monthly household income, parity, infant BAZ at 12 mo of age, feeding mode in the first 6 mo of life, and total daily energy intake.	
27385132	The circadian rhythm in older adults is commonly known to change with a decrease in physical activity. However, the association between circadian rhythm metrics and physical activity remains unclear. The objective of this study was to examine circadian activity patterns in older people with and without dementia and to determine the amount of physical activity conducive to a good circadian measurement.Circadian parameters were collected from 117 older community-dwelling people (66 subjects without dementia and 52 subjects with dementia); the parameters were measured continuously using actigraphy for 7 days. A receiver operating characteristic (ROC) curve was applied to determine reference values for the circadian rhythm parameters, consisting of interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA), in older subjects.	The ROC curve revealed reference values of 0.55 for IS, 1.10 for IV, and 0.82 for RA. In addition, as a result of the ROC curve in the moderate-to-vigorous physical Activity (MVPA) conducive to the reference value of the Non-parametric Circadian Rhythm Analysis per day, the optimal reference values were 51 minutes for IV and 55 minutes for RA. However, the IS had no classification accuracy.	Our results demonstrated the reference values derived from the circadian parameters of older Japanese population with or without dementia. Also, we determined the MVPA conducive to a good circadian rest-active pattern. This reference value for physical activity conducive to a good circadian rhythm might be useful for developing a new index for health promotion in the older community-dwelling population.	
27385051	Working during the night can disrupt the normal circadian rhythm by altering the melatonin level. A low level of melatonin is associated with an increased risk of cancer, possibly by decreasing the expression of tumor-suppressor genes, such as p53. To determine whether nighttime work is associated with melatonin level in serum as well as the expression of related genetic markers, we enrolled 100 female nighttime medical technologists employed at a hospital in South Korea. Melatonin concentration and melatonin receptor 1 (MT1) expression were significantly lower in nighttime than in daytime workers (1.84 pg/mL versus 4.04 pg/mL; 1.16 versus 1.61, respectively). However, p53 expression showed no difference between the groups. In summary, nighttime work could be an important risk factor for circadian disruption, but not a direct risk factor for cancer in medical technologists in South Korea.
27384816	Blue light plays an important role in circadian photoentrainment by stimulating the melanopsin-expressing photosensitive retinal ganglion cells. Age-related cataract causes progressive loss of blue light transmission, which may lead to changes in circadian rhythm and sleep quality. In theory, increased light transmission by cataract surgery may improve circadian misalignment and sleep quality, while the effect of cataract surgery on circadian rhythm is not well understood. In this study, we assessed 30 binocular age-related nuclear cataract patients (aged 72.5 ± 7.2, 16 female) who were eligible for cataract surgery. All the patients underwent phacoemulsification cataract extraction and neutral ultraviolet-only blocking intraocular lens (IOLs) implantation. Visual functions including best-corrected visual acuity (BCVA), color perception and dark adaptation were assessed. Salivary samples were collected at 1-hour interval from 19:00 to 23:00 48 hours before and after surgery. Salivary melatonin concentration was measured and dim light melatonin onset (DLMO) was calculated subsequently. Sleep quality and daytime alertness were assessed before and a month after surgery using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). All the operated eyes demonstrated significant improvements in BCVA, color perception and dark adaptation after cataract surgery. Salivary melatonin concentration at 23:00 was significantly increased after surgery (P < 0.001). However, the average DLMO did not change significantly after surgery. In addition, PSQI and ESS scores were significantly decreased a month after surgery (P = 0.027, P < 0.001, respectively). In conclusion, cataract surgery promotes blue-light transmission; consequently, it may lead to the increase in nighttime melatonin concentration and improvement in sleep quality as well as daytime alertness. 
27382750	The present paper reports the effect of pancreatitis induced by cholecystokinin (CCK) on free-running rhythm of locomotor activity of the ICR mice, and analyzes the interaction of inflammatory diseases and acute pancreatitis with circadian rhythm system. In the study, the mice were modeled under different phases of acute pancreatitis in DD status (Double Dark, constant dark condition). By comparing of the inflammatory status and the indicators of rhythm before and after modeling of the running wheel activity group and the rest group, it was observed that the rest group showed more possibility of inflammation than the activity group did in ICR mice model of acute pancreatitis. In the rest phase model, the extension of the period is particularly longer. The results presented indicated that CCK-induced acute pancreatitis impacted free activity rhythm of ICR mice. Also in a free running model under different phase, the inflammation severity was proved significantly different. This study provides possible clues for the research of the pathogenesis of acute pancreatitis severe tendency.
27381914	Two-component systems (TCS) that employ histidine kinases (HK) and response regulators (RR) are critical mediators of cellular signaling in bacteria. In the model cyanobacterium Synechococcus elongatus PCC 7942, TCSs control global rhythms of transcription that reflect an integration of time information from the circadian clock with a variety of cellular and environmental inputs. The HK CikA and the SasA/RpaA TCS transduce time information from the circadian oscillator to modulate downstream cellular processes. Despite immense progress in understanding of the circadian clock itself, many of the connections between the clock and other cellular signaling systems have remained enigmatic. To narrow the search for additional TCS components that connect to the clock, we utilized direct-coupling analysis (DCA), a statistical analysis of covariant residues among related amino acid sequences, to infer coevolution of new and known clock TCS components. DCA revealed a high degree of interaction specificity between SasA and CikA with RpaA, as expected, but also with the phosphate-responsive response regulator SphR. Coevolutionary analysis also predicted strong specificity between RpaA and a previously undescribed kinase, HK0480 (herein CikB). A knockout of the gene for CikB (cikB) in a sasA cikA null background eliminated the RpaA phosphorylation and RpaA-controlled transcription that is otherwise present in that background and suppressed cell elongation, supporting the notion that CikB is an interactor with RpaA and the clock network. This study demonstrates the power of DCA to identify subnetworks and key interactions in signaling pathways and of combinatorial mutagenesis to explore the phenotypic consequences. Such a combined strategy is broadly applicable to other prokaryotic systems.Signaling networks are complex and extensive, comprising multiple integrated pathways that respond to cellular and environmental cues. A TCS interaction model, based on DCA, independently confirmed known interactions and revealed a core set of subnetworks within the larger HK-RR set. We validated high-scoring candidate proteins via combinatorial genetics, demonstrating that DCA can be utilized to reduce the search space of complex protein networks and to infer undiscovered specific interactions for signaling proteins in vivo Significantly, new interactions that link circadian response to cell division and fitness in a light/dark cycle were uncovered. The combined analysis also uncovered a more basic core clock, illustrating the synergy and applicability of a combined computational and genetic approach for investigating prokaryotic signaling networks.	
27380954	Foraging is costly in terms of time and energy. An endogenous food-entrainable system allows anticipation of predictable changes of food resources in nature. Yet the molecular mechanism that controls food anticipation in mammals remains elusive. Here we report that deletion of the clock component Rev-erbα impairs food entrainment in mice. Rev-erbα global knockout (GKO) mice subjected to restricted feeding showed reduced elevations of locomotor activity and body temperature prior to mealtime, regardless of the lighting conditions. The failure to properly anticipate food arrival was accompanied by a lack of phase-adjustment to mealtime of the clock protein PERIOD2 in the cerebellum, and by diminished expression of phosphorylated ERK 1/2 (p-ERK) during mealtime in the mediobasal hypothalamus and cerebellum. Furthermore, brain-specific knockout (BKO) mice for Rev-erbα display a defective suprachiasmatic clock, as evidenced by blunted daily activity under a light-dark cycle, altered free-running rhythm in constant darkness and impaired clock gene expression. Notably, brain deletion of Rev-erbα totally prevented food-anticipatory behaviour and thermogenesis. In response to restricted feeding, brain deletion of Rev-erbα impaired changes in clock gene expression in the hippocampus and cerebellum, but not in the liver. Our findings indicate that Rev-erbα is required for neural network-based prediction of food availability. 
27380315	In Arabidopsis, EARLY FLOWERING3 (ELF3) has pivotal roles in controlling circadian rhythm and photoperiodic flowering. In addition, ELF3 negatively regulates leaf senescence by repressing the transcription of PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PHYTOCHROME-INTERACTING FACTOR5 (PIF5); elf3 mutants senesce earlier and ELF3-overexpressing (ELF3-OX) plants senesce later than wild type (WT). Here, we show that in contrast to Arabidopsis ELF3, which represses senescence, the rice homolog OsELF3.1 promotes leaf senescence; oself3.1 mutants showed delayed senescence and OsELF3.1-OX plants senesced earlier under both dark-induced and natural senescence conditions. Microarray analysis revealed that in the senescing leaves, a number of senescence-associated genes, phytohormone-related genes, and NAC and WRKY family genes (OsNAP, ONAC106, and OsWRKY42) were differentially expressed in oself3.1 mutants compared with WT. Interestingly, we found that Arabidopsis plants overexpressing OsELF3.1 show delayed leaf senescence, produce short petioles, and flower late in long days, just like Arabidopsis ELF3-OX plants. This demonstrates that the regulatory functions of ELF3 and OsELF3.1 are conserved between Arabidopsis and rice, but the downstream regulatory cascades have opposite effects. 
27379013	Bone remodeling is the continuous process of bone resorption by osteoclasts and bone formation by osteoblasts, in order to maintain homeostasis. The activity of osteoclasts and osteoblasts is regulated by a network of signaling pathways, including Wnt, parathyroid hormone (PTH), RANK ligand/osteoprotegrin, and TGF-β, in response to stimuli, such as mechanical loading. During aging there is a gradual loss of bone mass due to dysregulation of signaling pathways. This may be due to a decline in physical activity with age and/or changes in hormones and other signaling molecules. In particular, hormones, such as PTH, have a circadian rhythm, which may be disrupted in aging. Due to the complexity of the molecular and cellular networks involved in bone remodeling, several mathematical models have been proposed to aid understanding of the processes involved. However, to date, there are no models, which explicitly consider the effects of mechanical loading, the circadian rhythm of PTH, and the dynamics of signaling molecules on bone remodeling. Therefore, we have constructed a network model of the system using a modular approach, which will allow further modifications as required in future research. The model was used to simulate the effects of mechanical loading and also the effects of different interventions, such as continuous or intermittent administration of PTH. Our model predicts that the absence of regular mechanical loading and/or an impaired PTH circadian rhythm leads to a gradual decrease in bone mass over time, which can be restored by simulated interventions and that the effectiveness of some interventions may depend on their timing. 
27378529	Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals. 
27377842	The nocturnal peak of melatonin can be altered after anesthesia and surgery. We aimed to examine the melatonin levels during the day and night after anesthesia with three commonly used inhalational anesthetics. Forty-eight male Wistar albino rats were randomized into eight groups. Rats were administered anesthesia between 7:00 am and 1:00 pm (day groups) or 7:00 pm and 1:00 am (night groups) for 6 hours. At the end of the anesthesia, blood samples were collected for assessing melatonin levels. Mean values of melatonin levels after 6 hours of anesthesia during daytime were 43.17±12.95 for control, 59.79±27.83 for isoflurane, 50.75±34.28 for sevoflurane and 212.20±49.56 pg/mL for desflurane groups. The night groups' mean melatonin levels were 136.12±33.20 for control, 139.85±56.29 for isoflurane, 117.48±82.39 for sevoflurane and 128.70±44.63 pg/mL for desflurane groups. Desflurane anesthesia between 7:00 am and 1:00 pm significantly increased melatonin levels (p<0.001). Sevoflurane and desflurane anesthesia between 7:00 pm and 1:00 am decreased the melatonin levels but there were no significant differences (p=0.904 and p>0.99, respectively). Isoflurane anesthesia did not significantly change melatonin levels during day or night (p=0.718 and p>0.99, respectively). Our results demonstrate that during daytime desflurane anesthesia can alter melatonin levels. Altered melatonin rhythm following inhalational anesthesia can be related to sleep disorders observed after anesthesia. 
27376484	The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the α-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway. 
27375446	Central nervous system disorders such as autism as well as the range of neurodegenerative diseases such as Huntington's disease are commonly investigated using genetically altered mouse models. The current system for characterizing these mice usually involves removing the animals from their home-cage environment and placing them into novel environments where they undergo a battery of tests measuring a range of behavioral and physical phenotypes. These tests are often only conducted for short periods of times in social isolation. However, human manifestations of such disorders are often characterized by multiple phenotypes, presented over long periods of time and leading to significant social impacts. Here, we have developed a system which will allow the automated monitoring of individual mice housed socially in the cage they are reared and housed in, within established social groups and over long periods of time. We demonstrate that the system accurately reports individual locomotor behavior within the group and that the measurements taken can provide unique insights into the effects of genetic background on individual and group behavior not previously recognized. 
27373683	It has been reported that metabolites regulate circadian rhythms through direct effects on clock genes. A metabolic network involving PER3 raises the possibility that some metabolic regulators are directly involved in the mammalian clock. Here, we show that the bHLH family transcription factor TFEB regulates PER3 through the CLOCK/BMAL1 complex. In the liver, TFEB expression displays circadian rhythms. A loss of TFEB function disrupts and dampens the expression of PER3 but not the expression of other circadian genes, such as PER1, PER2, CRY1 and CRY2. TFEB physically interacts with CLOCK/BMAL1 through its N-terminal region. In the presence of TFEB, BMAL1/CLOCK-mediated transcription is enhanced. Moreover, the TFEB/CLOCK/BMAL1 complex is regulated by glucose. These results show that TFEB has a role in the mammalian clock mechanism. 
27373158	An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN) of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3(Sci/+), we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3(Sci/+) mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms) and the seconds-to-minutes scale (i.e., anticipating behavioral responses) in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3(Sci/+)-dependent network. 
27371387	The entrainment of circadian rhythms, physiological cycles with a period of about 24 h, is regulated by a variety of mechanisms, including nonvisual photoreception. While circadian rhythms have been shown to be integral to many processes in multicellular organisms, including immune regulation, the effect of circadian rhythms on symbiosis, or host-microbe interactions, has only recently begun to be studied. This review summarizes recent work in the interactions of both pathogenic and mutualistic associations with host and symbiont circadian rhythms, focusing specifically on three mutualistic systems in which this phenomenon has been best studied. One important theme taken from these studies is the fact that mutualisms are profoundly affected by the circadian rhythms of the host, but that the microbial symbionts in these associations can, in turn, manipulate host rhythms. The interplay between circadian rhythms and symbiosis is a promising new field with effects that should be kept in mind when designing future studies across biology.
27371111	The insect neuropeptide prothoracicotropic hormone (PTTH) is a critical regulator of larval development. We recently demonstrated that PTTH is also present in adult Rhodnius prolixus and is released by adult brains in vitro with a clear daily rhythm during egg development. Here, we employ a well-established in vitro bioassay, to show that the daily rhythm of PTTH release by brains in vitro is under circadian control since it persists in aperiodic conditions with a free running period of around 24h that is temperature compensated. Prolonged exposure (3weeks) of insects to continuous constant light (LL) completely eliminated PTTH release. Subsequent transfer of such insects from LL to constant darkness (DD) rapidly induced rhythmic PTTH release, indicating that the circadian rhythm of PTTH release is induced by photic cues. Western analysis identified PTTH in the adult hemolymph, suggesting that PTTH acts as a functional neurohormone in the adult insect. Dot blot analysis revealed that PTTH levels in the hemolymph also cycled with a daily rhythm that persisted in DD and was synchronous with the rhythm of PTTH release by brains in vitro. We conclude that the previously documented photosensitive clock in the brain regulates rhythmic PTTH release and thus generates the rhythm seen in the hemolymph. These results emphasize the importance of rhythmic PTTH release in the adult insect and support a role for PTTH in adult physiology and possibly within the adult circadian system. 
27367919	Disrupted circadian rhythm of melatonin secretion in depression shows a relationship with the exacerbation of inflammatory processes. Proinflammatory mechanisms of depression are sustained by oxidative stress. This contributes to melatonin deficiency and to the malfunction of the defense mechanisms in the brain. Disrupted melatonin secretion in depression may have an influence on the concentrations of neurotrophic factors (NF), such as neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Disturbance in neurotrophin release may affect synaptic plasticity and cause exacerbation of neurodegenerative processes in the central nervous system. The aim of this study was to assess the concentrations of melatonin and NF of the brain in patients with varying levels of depression severity.160 males and females were enrolled in the study, 120 of whom were diagnosed with various types of depression. The control group comprised 40 healthy individuals. At 3:00a.m. all patients had salivary melatonin concentrations determined utilizing a competitive enzyme immunoassay technique (ELISA). In addition, at 7:00a.m. all patients had serum neurotrophin (NT-3, BDNF, NGF) concentrations determined by means of ELISA.	The highest melatonin secretion was observed at 3:00a.m. in severely depressed females. In the groups with mild and moderate depression, melatonin secretion at 3:00a.m. was comparable between males and females. In addition, a decrease in the concentrations of neurotrophins was revealed in patients at all levels of depression severity.	Melatonin may be a significant marker of depression severity. Melatonin and NF in depressed patients show neuroprotective effects.	
27367452	Hypertension is a crucial risk factor for cardiovascular death and loss of residual kidney function. Absence of the nocturnal decline in blood pressure (BP) predicts cardiovascular events and poor prognosis. However, characteristics of hypertension in moderate-to-severe chronic kidney disease (CKD) have not been fully evaluated. We aimed to assess the circadian variation of BP and kidney survival in CKD patients.Patients who were examined by 24-h ambulatory BP monitoring (ABPM) and estimated glomerular filtration rate (eGFR), <45 ml/min/1.73 m(2), were enrolled in the study. The impacts of BP circadian rhythm and brain natriuretic peptide (BNP) on kidney survival were evaluated.	A total of 124 patients were enrolled. The average age was 64 ± 14 years, 57% were male, and 43% had diabetes. Forty-five percent of patients had a non-dipper pattern, 35% had a riser pattern, 19% had a dipper pattern, and 1% had an extreme-dipper pattern. The prevalence of diabetes and plasma BNP levels was higher and eGFR was lower in the riser-pattern group than in the non-riser-pattern group. Kidney survival rates were significantly worse in the riser-pattern group than in the non-riser-pattern group (p < 0.05). Moreover, among riser and non-riser pattern groups divided by BNP levels, the riser group with higher BNP level showed the worst kidney survival (p < 0.05).	The riser pattern is frequently associated with several conditions at higher risk for kidney survival. Patients with a rising pattern and higher BNP levels have a worse kidney prognosis.	
27366928	Why are some healthy male shift workers (SWers) overweight [body mass index (BMI) >25 and <30] if not obese (BMI >30)? Seven risk factors potentially causing overweight and obesity were evaluated, namely (1) age, (2) physical/sports activity, (3) length of exposure to shift work (SW), (4) speed of shift rotation, (5) tolerance to SW, (6) internal desynchronization of circadian rhythms and (8) night eating (nocturnal nibbling). "New" as well as "old" data, acquired from longitudinal and individual time series of 5-56 days recording span, were reanalyzed. The data were analyzed from a set of field studies of 67 SWers and 53 non-shift workers (non-SWers). To estimate the respective weight of these factors, a multiple regression analysis (MRA) was used among other statistical tools. A similar age-related increase in BMI was validated (with p < 0.001) in both SWers and non-SWers. However, in SWers, desynchronization of rhythms increases the effect of age on BMI. Length of exposure to SW, tolerance to SW and speed of rotation do not seem to play a role as risk factors. Major effects are likely to relate to a sedentary lifestyle (lack of regular physical or sport activities) (MRA with p < 0.01), as well as, presumably, to a nocturnal nibbling of carbohydrates, which mimics the night eating syndrome.
27366574	The primary goal of the present study was to demonstrate the existence of a possible circadian variation in urgent operative deliveries.All urgent caesarean sections between 1 January 2014 and 1 January 2015 with known exact onset times of operation were included in this retrospective study. Cases that were previously scheduled for elective caesarean section were excluded. Information regarding age, delivery date, onset time of operation and type of anaesthesia was collected from the database. Analyses were completed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) version 20.0 software. The statistical significance for all analyses was set at p<0.05.	A total of 285 urgent caesarean section deliveries were included in the study. There were 126 (44.2%) deliveries during the day shift and 159 (55.8%) during the night shift. 80 patients (28.1%) received general anaesthesia and 65 (22.8%) received spinal anaesthesia in the morning shift, whereas 54 patients (18.9%) received general anaesthesia and 86 (30.2%) received spinal anaesthesia during the night shift.	The present study suggested that urgent caesarean sections revealed a circadian rhythm during the day.	
27365111	Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation of clock gene expression in depressive patients, many studies have reported single-nucleotide polymorphisms in clock genes in these patients.In the present study we investigated whether a depression-like state in rats is associated with alternations of the diurnal expression of clock genes. The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes: period genes 1 and 2 (Per1 and Per2) and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at a 4h sampling interval within 24h. We quantified expression of clock genes on brain sections in the prefrontal cortex, nucleus accumbens, pineal gland, suprachiasmatic nucleus, substantia nigra, amygdala, ventral tegmental area, subfields of the hippocampus, and the lateral habenula using in situ hybridization histochemistry. Expression of clock genes in the liver was monitored by real-time quantitative polymerase chain reaction (PCR).	We found that the effect of CMS on clock gene expression was selective and region specific. Per1 exhibits a robust diurnal rhythm in most regions of interest, whereas Bmal1 and in particular Per2 were susceptible to CMS.	The present results suggest that altered expression of investigated clock genes is likely associated with the induction of a depression-like state in the CMS model.	
27364888	In female mammals, reproduction shows ovarian and daily rhythms ensuring that the timing of the greatest fertility coincides with maximal activity and arousal. The ovarian cycle, which lasts from a few days to a few weeks, depends on the rhythm of follicle maturation and ovarian hormone production, whereas the daily cycle depends on a network of circadian clocks of which the main one is located in the suprachiasmatic nuclei (SCN). In the last ten years, major progress has been made in the understanding of the neuronal mechanisms governing mammalian reproduction with the finding that two hypothalamic Arg-Phe-amide peptides, kisspeptin (Kp) and RFRP, regulate GnRH neurons. In this review we discuss the pivotal role of Kp and RFRP neurons at the interface between the SCN clock signal and GnRH neurons to properly time gonadotropin-induced ovulation. We also report recent findings indicating that these neurons may be part of the multi-oscillatory circadian system that times female fertility. Finally, we will discuss recent investigations indicating a role, and putative therapeutic use, of these neuropeptides in human reproduction.
27364352	As obesity and metabolic diseases rise, there is need to investigate physiological and behavioural aspects associated with their development. Circadian rhythms have a profound influence on metabolic processes, as they prepare the body to optimise energy use and storage. Moreover, food-related signals confer temporal order to organs involved in metabolic regulation. Therefore food intake should be synchronised with the suprachiasmatic nucleus (SCN) to elaborate efficient responses to environmental challenges. Human studies suggest that a loss of synchrony between mealtime and the SCN promotes obesity and metabolic disturbances. Animal research using different paradigms has been performed to characterise the effects of timing of food intake on metabolic profiles. Therefore the purpose of the present review is to critically examine the evidence of animal studies, to provide a state of the art on metabolic findings and to assess whether the paradigms used in rodent models give the evidence to support a 'best time' for food intake. First we analyse and compare the current findings of studies where mealtime has been shifted out of phase from the light-dark cycle. Then, we analyse studies restricting meal times to different moments within the active period. So far animal studies correlate well with human studies, demonstrating that restricting food intake to the active phase limits metabolic disturbances produced by high-energy diets and that eating during the inactive/sleep phase leads to a worse metabolic outcome. Based on the latter we discuss the missing elements and possible mechanisms leading to the metabolic consequences, as these are still lacking.
27362940	Melatonin is released from the pineal gland into the circulatory system at night in the absence of light, acting as "hormone of darkness" to the brain and body. Melatonin also can regulate circadian phasing of the suprachiasmatic nucleus (SCN). During the day-to-night transition, melatonin exposure advances intrinsic SCN neural activity rhythms via the melatonin type-2 (MT2) receptor and downstream activation of protein kinase C (PKC). The effects of melatonin on SCN phasing have not been linked to daily changes in the expression of core genes that constitute the molecular framework of the circadian clock. Using real-time RT-PCR, we found that melatonin induces an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2). This effect occurs at CT 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides (α ODNs) to Per 1 and Per 2, as well as to E-box enhancer sequences in the promoters of these genes, we show that their specific induction is necessary for the phase-altering effects of melatonin on SCN neural activity rhythms in the rat. These effects of melatonin on Per1 and Per2 were mediated by PKC. This is unlike day-active non-photic signals that reset the SCN clock by non-PCK signal transduction mechanisms and by decreasing Per1 expression. Rather, this finding extends roles for Per1 and Per2, which are critical to photic phase-resetting, to a nonphotic zeitgeber, melatonin, and suggest that the regulation of these clock gene transcripts is required for clock resetting by diverse regulatory cues. 
27362512	Sleep disturbance is common among patients with heart failure (HF) who also experience symptom burden and poor functional performance.We evaluated the extent to which sleep-related, daytime symptoms (fatigue, excessive daytime sleepiness, and depressive symptoms) mediate the relationship between sleep disturbance and functional performance among patients with stable HF.	We recruited patients with stable HF for this secondary analysis of data from a cross-sectional, observational study. Participants completed unattended ambulatory polysomnography from which the Respiratory Disturbance Index was calculated, along with a Six-Minute Walk Test, questionnaires to elicit sleep disturbance (Pittsburgh Sleep Quality Index, Insomnia Symptoms from the Sleep Habits Questionnaire), daytime symptoms (Center for Epidemiologic Studies Depression Scale, Global Fatigue Index, Epworth Sleepiness Scale), and self-reported functional performance (Medical Outcomes Study SF36 V2 Physical Function Scale). We used structural equation modeling with latent variables for the key analysis. Follow-up, exploratory regression analysis with bootstrapped samples was used to examine the extent to which individual daytime symptoms mediated effects of sleep disturbance on functional performance after controlling for clinical and demographic covariates.	The sample included 173 New York Heart Association Class I-IV HF patients (n = 60/34.7% women; M = 60.7, SD = 16.07 years of age). Daytime symptoms mediated the relationship between sleep disturbance and functional performance. Fatigue and depression mediated the relationship between insomnia symptoms and self-reported functional performance, whereas fatigue and sleepiness mediated the relationship between sleep quality and functional performance. Sleepiness mediated the relationship between the respiratory index and self-reported functional performance only in people who did not report insomnia.	Daytime symptoms explain the relationships between sleep disturbance and functional performance in stable HF.	
27354555	The circadian clock helps plants measure daylength and adapt to changes in the day-night rhythm. We found that changes in the light-dark regime triggered stress responses, eventually leading to cell death, in leaves of Arabidopsis thaliana plants with reduced cytokinin levels or defective cytokinin signaling. Prolonged light treatment followed by a dark period induced stress and cell death marker genes while reducing photosynthetic efficiency. This response, called circadian stress, is also characterized by altered expression of clock and clock output genes. In particular, this treatment strongly reduced the expression of CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Intriguingly, similar changes in gene expression and cell death were observed in clock mutants lacking proper CCA1 and LHY function. Circadian stress caused strong changes in reactive oxygen species- and jasmonic acid (JA)-related gene expression. The activation of the JA pathway, involving the accumulation of JA metabolites, was crucial for the induction of cell death, since the cell death phenotype was strongly reduced in the jasmonate resistant1 mutant background. We propose that adaptation to circadian stress regimes requires a normal cytokinin status which, acting primarily through the AHK3 receptor, supports circadian clock function to guard against the detrimental effects of circadian stress. 
27352502	To explore the rhythm regulatory mechanism of interleukin-6 (IL-6) in the process of moxibustion for rheumatoid arthritis (RA).A total of 144 Sprague-Dawley (SD) rats were randomly divided into a blank group, a model group, a moxibustion group, a sham operation group, an operation group, an operation+moxibustion group, 24 rats in each one. Each group was divided into 4 time points (0:00 am, 6:00' am, 12:00 am, 6:00 pm), 6 rats in each time point. The Light-Dark 12 : 12 was given in all rats for light-dark cycle. Except the blank group, rats in the remaining groups were treated with intracutaneous injection of freund's complete adjuvant at right-side foot to establish the model of RA. After the model establishment, bilateral adrenal, glands were removed in the operation group and operation + moxibustion group, while those in the sham operation group were not removed with identical operation procedure. Rats in the moxibustion group and operation + moxibustion group were treated with grain-sized moxibustion from 7:00 am to 9:00 am at "Shenshu" (BL 23) and "Zusanli" (ST 36) once everyday, 6 times were taken as one session and 3 sessions were required tatclly, while rats in the remaining groups received identical fixation without moxibustion. The general health state and foot volume of rats were measured before model establishment, after establishment and after treatment. After treatment, rats were sacrificed at each time point to collect the blood sample and measure the content of IL-6 by using enzymne-immunoassay method.	Compared with the blank group, the foot swelling in the model group was obviously increased (P<0. 05); the IL-6 maintained circadian rhythm (P<0. 05), but the peak phase had a backward trend, famplitude had an increased trend and the median was significantly lifted (P<0. 05). Compared with model group, !the foot swelling in the moxibustion group was obviously decreased (P<0. 05); the IL-6 maintained circadian. rhythm (P<0. 05), and the peak phase had a forward trend, amplitude had a decreased trend and the median was significantly reduced (P<0. 05). Compared with the moxibustion group, the foot swelling in the operation--moxibustion group was obviously increased (P < 0.05); the IL-6 maintained circadian rhythm (P < 0.5), but the peak phase moved forwrd, and the median was significantly elevated (P < 0.05).	The IL-6 in plasma maintains significant pathological circadian rhythm in RA rats; with the complete hypothalamic-pituitary-adrenal axis, moxibustion is likely to regulate the circadian rhythm of IL-6 to play an important role of anti-inflammatory effect in RA rats.	
27350193	Environmental stress (ES) is commonly used in producing chronic unpredictable mild stress to study pathogenesis of depression, including the regulatory role of circadian system on depression. However, the direct effect of ES on the circadian system has been rarely explored. The present study was aimed to investigate the effect of ES on depression-like behaviors and diurnal rhythm of plasma hormone/peptide levels in male rats. Rats were allocated into control group (CON group), low frequency ES group (LF group) and high frequency ES group (HF group). Sucrose preference test (SPT), open field test (OFT), weight gain, food and water intake were conducted to assess depression- and anxiety-like behaviors. A total of 7 times of the tail venous blood was collected with an interval of 4 h during 24 h from other rats who subjected to the same procedures of ES but not the behavioral tests. The alterations of diurnal rhythm of peripheral plasma corticosterone (CORT) and melatonin, and changes of the cholecystokinin (CCK), neuropeptide Y and leptin levels at zeitgeber time (ZT) 0 were detected by using enzyme-linked immunosorbent assay (ELISA). We found that ES led to a disturbance of diurnal rhythm of CORT and melatonin in the plasma. Besides, it also increased plasma leptin level and decreased body weight gain, but it did not produce depression- and anxiety-like behaviors compared with those rats in the control group. In short, our findings indicated that the ES could induce a disturbance of diurnal rhythm of plasma CORT and melatonin in male rats. 
27349605	This is a prospective observational study.The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI).	This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia.	Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers.	Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension.	People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.	
27348167	In recent years, despite some progress in the study of vitiligo many aspects of pathogenesis and treatment of this dermatosis remain unsolved or are highly controversial. It is believed that progression of disease is associated with a genetic predisposition, autoimmune processes and oxidative stress, but the concrete role of stress on the processes having place in the organism of vitiligo patients so far is not investigated. As we know, epiphysis is the main regulator of adaptation of the individual to the environment. An important product of secretion of the pineal gland is the hormone melatonin - a universal regulator of vital functions and biorhythms of the body. Psychoses, neuroses, depression, immunopathology are aspects of disturbances in circadian, seasonal and annual rhythms of the synthesis of this hormone. Clinical and experimental studies indicate that the hormone melatonin, which is one of the links in a stress defense mechanism of the body, has antioxidant and immunomodulatory properties. The purpose of this study was to determine plasma level of melatonin in the blood of vitiligo patients (with stress in anamnesis), depending on the clinical form and duration of the disease. 41 patients with vitiligo (16 with segmental and 25 with non-segmental form) with stress in anamnesis and duration of disease from several months to 20 years were under observation. The level of melatonin in the blood plasma was determined by ELISA (IBL - international - reagent), the results were expressed in units of pg/ml. According to the results of our study, 8 patients with segmental vitiligo had the normal level of plasma melatonin concentration (in the range of 20.2-31.1 pg/ml), in 2 cases - the level was near the norm (19.2 pg/ml). In the group of patients with non-segmental vitiligo, the level of melatonin was below the norm (12.5 pg/ml) and in 2 cases, the content of melatonin was very low - 4.05 pg / ml. Correlation analysis of melatonin levels with duration of disease have shown direct correlation just in the group of patients with non-segmental vitiligo. For a complete analysis of our results concerning of melatonin levels in the blood of patients with stress in anamnesis and for getting of some principal conclusions that will allow outline the ways to effectively treat patients with this pathology, further research is needed. 
27348079	The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (ClockΔ19/Δ19 ) mice in order to determine the effects of clock genes on NOC/NP.Male C57BL/6 mice aged 8-12 weeks (WT) and male C57BL/6 ClockΔ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods.	No significant differences were observed in behavior patterns between ClockΔ19/Δ19 and WT mice. ClockΔ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in ClockΔ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in ClockΔ19/Δ19 mice than in WT mice.	We demonstrated that ClockΔ19/Δ19 mice showed the phenotype of NOC/NP. The ClockΔ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. 36:1034-1038, 2017. © 2016 Wiley Periodicals, Inc.	
27346616	Exploring the putative impact of circadian rhythms is a relatively novel approach to illuminating hormone-related female breast cancer etiology and prognosis. One of several proposed mechanisms underlying breast cancer risk among individuals exposed to light at night involves circadian gene alterations. Although in vitro and animal studies indicate a key role of circadian genes in breast tumor suppression, there is a paucity of data on the role of circadian genes in human breast cancer. This review summarizes recent findings of circadian gene expression and DNA methylation profile from human breast cancer studies in relation to hormonal status, clinicopathological features of tumors, and exposure to night shift work. The major findings from human studies indicate that expression of circadian genes is deregulated in breast cancer. Breast cancer etiology and prognosis-associated PERs, CRYs, CLOCK downregulation, and TIMELESS upregulation may be related to relevant gene methylation in tumor tissue. Alterations and desynchronization of molecular clock machinery found on genetic and epigenetic level were observed in more aggressive breast cancer tumors and those lacking estrogen receptors. 
27346580	Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. 
27346473	Thymus is an immunoendocrine organ, the hormones of which mainly influence its own lymphatic elements. It has a central role in the immune system, the neonatal removal causes the collapse of immune system and the whole organism. The thymic nurse cells select the bone marrow originated lymphocytes and destroy the autoreactive ones, while thymus originated Treg cells suppress the autoreactive cells in the periphery. The involution of the organ starts after birth, however, this truly happens in the end of puberty only, as before this it is overcompensated by developmental processes. From the end of adolescence the involution allows the life, proliferation and enhanced functioning of some autoreactive cells, which gradually wear down the cells and intercellular materials, causing the aging. The enhanced and mass function of autoreactive cells lead to the autoimmune diseases and natural death. This means that the involution of thymus is not a part of the organismic involution, but an originator of it, which is manifested in the lifespan-pacemaker function. Thus, aging can be conceptualized as a thymus-commanded slow autoimmune process. The neonatal removal of pineal gland leads to the complete destruction of the thymus and the crashing down of the immune system, as well as to wasting disease. The involution of the pineal and thymus runs parallel, because the two organs form a functional unit. It is probable that the pineal gland is responsible for the involution of thymus and also regulates its lifespan determining role. However, the data reviewed here do not prove the exclusive role of the pineal-thymus system in the regulation of aging and lifespan, but only call attention to such possibility.
27346154	The present study investigated the daily dynamics of humoral immune defenses and the temporal influence in the sensitivity of these responses to a bacterial endotoxin in Nile tilapia (Oreochromis niloticus). The first experiment subjected the fish to two photoperiod conditions, 12L:12D (LD) and 0L:24D (DD), for 20 days to characterize the rhythms of humoral immunity. Serum alkaline phosphatase (ALP), lysozyme (LYZ), peroxidase (PER) and protease (PRO) exhibited significant rhythmicity under LD but not in DD. No significant rhythms were observed in esterase (ESA) and anti-protease (ANTI) in both photoperiod conditions. Fish reared under LD were subsequently subjected to DD while the group previously under DD was exposed to LD, and this carried on for 3 days before another set of samples was collected. Results revealed that the rhythms of LYZ, PER and PRO but not ALP persisted when photoperiod was changed from LD to DD. Nonetheless, immune parameters remained arrhythmic in the group subjected from DD to LD. Cluster analysis of the humoral immune responses under various light conditions revealed that each photic environment had distinct daily immunological profile. In the second experiment, fish were injected with bacterial endotoxin lipopolysaccharide (LPS) either at ZT3 (day) or at ZT15 (night) to evaluate the temporal sensitivity of humoral immunity to a pathogen-associated molecular pattern. The results demonstrated that responses to LPS were gated by the time of day. LPS significantly modulated serum ALP and ANTI activities but only when the endotoxin was administered at ZT3. Serum LYZ and PER were stimulated at both injection times but with differing response profiles. Modulated LYZ activity was persistent when injected at ZT3 but transient when LPS was applied at ZT15. The magnitude of LPS-induced PER activity was higher when the endotoxin was delivered at ZT3 versus ZT15. It was further shown that plasma cortisol was significantly elevated but only when LPS was administered at ZT3. On the other hand, plasma melatonin was significantly affected by LPS injection but only when exposed at ZT15. Taken together, this study shows that several key components of humoral immunity in tilapia exhibit circadian rhythms and adapt to photoperiodic changes. Further, results of the bacterial endotoxin challenge suggest that responsiveness of serum humoral factors to a biological insult is likely mediated by the time of day, highlighting the importance of circadian rhythm in the immunological functions of fish. 
27345866	The hematopoietic system undergoes many changes during aging, but the causes and molecular mechanisms behind these changes are not well understood. Wang et al. have recently implicated a circadian rhythm gene, Per2, as playing a role in the DNA damage response and in the expression of lymphoid genes in aged hematopoietic stem cells. 
27345439	Real-time imaging of fluorescent reporters plays a critical role in elucidating fundamental molecular mechanisms including circadian rhythms in the model filamentous fungus, Neurospora crassa. However, monitoring N. crassa for an extended period of time with single nucleus resolution is a technically challenging task due to hyphal growth that rapidly moves beyond a region of interest during microscopy experiments. In this report, we have proposed a two-dimensional spiral-based microfluidic platform and applied for monitoring the single-nucleus dynamics in N. crassa for long-term time course experiments. 

27343805	The relationships between biological rhythms and affective disorders are known but their underlying biology not clear. There is difficulty in studying circadian rhythms in humans and appropriate animal models are hard to identify or develop. Some studies show that diurnal rodents can be advantageous model animals for the study of interactions between biological rhythms and affective disorders but previous studies did not include females whereas in humans there are sex differences in affective disorders. The present study tested the effects of short photoperiods in both males and females of the diurnal golden spiny mouse (Acomys russatus). Adult, female and male spiny mice were housed in either neutral photoperiod (12:12 light/dark; NP), or short photoperiod (5:19 light/dark; SP) conditions. After 3weeks acclimatization, animals were tested for spontaneous activity in an open field, elevated plus maze (EPM), sweet solution preference (SSP) and the forced swim test (FST). Both sexes responded to the SP, but while SP males showed increased anxiety-like behavior in the EPM and depression-like behavior in the FST, females showed increased activity, reduced anxiety-like behavior in the EPM, depression-like response in the SSP and no effect in the FST. Differences between sexes were previously demonstrated in behavioral tests that followed a variety of manipulations, and were usually explained in the context of sex hormones. Yet, the current results cannot be compared with previous data from diurnal rodents and further testing of females from other diurnal rodents are needed to explore whether these differences are a general phenomenon or possibly unique to golden spiny mice. 
27343471	Schizophrenia has long been associated with abnormalities in circadian rhythms and sleep. Up until now, there have been no thorough reviews of the potential mechanisms behind the myriad of circadian and sleep abnormalities observed in schizophrenia and psychosis. We present evidence of sleep playing an important role in psychosis predominantly mediated by dopaminergic pathways. A synthesis of both human and animal experimental work suggests that the interplay between sleep and dopamine is important in the generation and maintenance of psychosis. In particular, both animal and human data point to sleep disruption increasing dopamine release and sensitivity. Furthermore, elevated dopamine levels disrupt sleep and circadian rhythms. The synthesis of knowledge suggests that circadian rhythms, dopamine dysregulation, and psychosis are intricately linked. This suggests that treatment of circadian disturbance may be a useful target in improving the lives and symptoms of patients with schizophrenia.
27342243	Cardiovascular autonomic dysfunction (AD) is a particular condition that can be detected by means of ambulatory blood pressure monitoring (ABPM). ABPM is helpful to identify some specific characteristics of haemodynamic AD, including non-dipping/reverse-dipping pattern, orthostatic and post-prandial hypotension and elevated blood pressure variability. These characteristics may be misdiagnosed with traditional, clinic blood pressure measurements. AD is relatively common in the real world. By analysing about 1000 recordings in a Cardiology unit, AD was found in 6.8 % of the exams. Several diseases may be the underlying causes of AD. In our sample half of the subjects were diabetic (54.4 %), 17.7 % were patients with alpha-synucleinopathy (Parkinson disease or multiple system atrophy), and 27.9 % had other underlying causes of AD including chronic kidney disease, α-lytic drug assumption and AD from unknown causes. According to the different aetiology, different clinical characteristics can be found, in particular in diabetics these peculiar aspects are less pronounced compared to the other subgroups. These characteristics have been found to be predictors of cardiovascular events, organ damage, and mortality. For these reasons, early identification of these behaviours is important, in order to better define patient's cardiovascular risk profile. As regard treatment of AD, several drugs have been tested, however none of this showed efficacy in all kinds of patients. Another open aspect is "safe" reference values for supine hypertension. 
27341833	Seasonal changes in environmental conditions are accompanied by significant adjustment of multiple biological processes. In temperate regions, the day fraction, or photoperiod, is a robust environmental cue that synchronizes seasonal variations in neuroendocrine and metabolic function. In this work, we propose a semimechanistic mathematical model that considers the influence of seasonal photoperiod changes as well as cellular and molecular adaptations to investigate the seasonality of immune function. Our model predicts that the circadian rhythms of cortisol, our proinflammatory mediator, and its receptor exhibit seasonal differences in amplitude and phase, oscillating at higher amplitudes in the winter season with peak times occurring later in the day. Furthermore, the reduced photoperiod of winter coupled with seasonal alterations in physiological activity induces a more exacerbated immune response to acute stress, simulated in our studies as the administration of an acute dose of endotoxin. Our findings are therefore in accordance with experimental data that reflect the predominance of a proinflammatory state during the winter months. These changes in circadian rhythm dynamics may play a significant role in the seasonality of disease incidence and regulate the diurnal and seasonal variation of disease symptom severity.
27341473	New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants.Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day.	We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.	

27341138	While the American horseshoe crab, Limulus polyphemus, has robust circadian and circatidal rhythms, virtually nothing is known about the molecular basis of these rhythms in this species or any other chelicerate. In this study, next generation sequencing was used to assemble transcriptomic reads and then putative homologs of known core and accessory circadian genes were identified in these databases. Homologous transcripts were discovered for one circadian clock input gene, five core genes, 22 accessory genes, and two possible output pathways. Alignments and functional domain analyses showed generally high conservation between the putative L. polyphemus clock genes and homologs from Drosophila melanogaster and Daphnia pulex. The presence of both cry1 and cry2 in the L. polyphemus transcriptome would classify its system as an "ancestral", type 2 clock system. In addition, a novel duplication of CYCLE, and a novel triplication of PERIOD were found. Investigations are currently underway to determine if any of these "circadian" genes also participate in the molecular processes that drive the Limulus circatidal clock. 
27340654	Identification of rhythmic gene expression from metabolic cycles to circadian rhythms is crucial for understanding the gene regulatory networks and functions of these biological processes. Recently, two algorithms, JTK_CYCLE and ARSER, have been developed to estimate periodicity of rhythmic gene expression. JTK_CYCLE performs well for long or less noisy time series, while ARSER performs well for detecting a single rhythmic category. However, observing gene expression at high temporal resolution is not always feasible, and many scientists are interested in exploring both ultradian and circadian rhythmic categories simultaneously. In this paper, a new algorithm, named autoregressive Bayesian spectral regression (ABSR), is proposed. It estimates the period of time-course experimental data and classifies gene expression profiles into multiple rhythmic categories simultaneously. Through the simulation studies, it is shown that ABSR substantially improves the accuracy of periodicity estimation and clustering of rhythmic categories as compared to JTK_CYCLE and ARSER for the data with low temporal resolution. Moreover, ABSR is insensitive to rhythmic patterns. This new scheme is applied to existing time-course mouse liver data to estimate period of rhythms and classify the genes into ultradian, circadian, and arrhythmic categories. It is observed that 49.2% of the circadian profiles detected by JTK_CYCLE with 1-hour resolution are also detected by ABSR with only 4-hour resolution. 
27340272	Many aspects of human health and disease display daily rhythmicity. The brain's suprachiasmic nucleus, which interprets recurring external stimuli, and autonomous molecular networks in peripheral cells together, set our biological circadian clock. Disrupted or misaligned circadian rhythms promote multiple pathologies including chronic inflammatory and metabolic diseases such as atherosclerosis. Here, we discuss studies suggesting that circadian fluctuations in the vessel wall and in the circulation contribute to atherogenesis. Data from humans and mice indicate that an impaired molecular clock, disturbed sleep, and shifting light-dark patterns influence leukocyte and lipid supply in the circulation and alter cellular behavior in atherosclerotic lesions. We propose that a better understanding of both local and systemic circadian rhythms in atherosclerosis will enhance clinical management, treatment, and public health policy. 
27340124	In the Neurospora crassa circadian clock, a protein complex of frequency (FRQ), casein kinase 1a (CK1a), and the FRQ-interacting RNA Helicase (FRH) rhythmically represses gene expression by the white-collar complex (WCC). FRH crystal structures in several conformations and bound to ADP/RNA reveal differences between FRH and the yeast homolog Mtr4 that clarify the distinct role of FRH in the clock. The FRQ-interacting region at the FRH N-terminus has variable structure in the absence of FRQ A known mutation that disrupts circadian rhythms (R806H) resides in a positively charged surface of the KOW domain, far removed from the helicase core. We show that changes to other similarly located residues modulate interactions with the WCC and FRQ A V142G substitution near the N-terminus also alters FRQ and WCC binding to FRH, but produces an unusual short clock period. These data support the assertion that FRH helicase activity does not play an essential role in the clock, but rather FRH acts to mediate contacts among FRQ, CK1a and the WCC through interactions involving its N-terminus and KOW module. 
27339810	It is known that our physiology changes throughout the day and that several physiological hormones display circadian rhythmicity. The alteration of this normal pattern is called chronodisruption (CD). In recent years, it has been demonstrated that CD is related to obesity. Although several factors may be causing CD, one important aspect to consider is the failure in our internal clock. Indeed, studies performed in mutant animals have demonstrated that mutations in clock genes are related to obesity. In human subjects, mutations are rare (<1 % of the population). Nevertheless, it is rather common to have genetic variations in one SNP, which underlie differences in our vulnerability to disease. Several SNP in clock genes are related to obesity and weight loss. Taking into account that genetics is behind CD, as has already been demonstrated in twins' models, the question is: Are we predestinated? We will see along these lines that nutrigenetics and epigenetics answer: 'No, we are not predestinated'. Through nutrigenetics we know that our behaviours may interact with our genes and may decrease the deleterious effect of one specific risk variant. From epigenetics the message is even more positive: it is demonstrated that by changing our behaviours we can change our genome. Herein, we propose modifying 'what, how, and when we eat' as an effective tool to decrease our genetic risk, and as a consequence to diminish CD and decrease obesity. This is a novel and very promising area in obesity prevention and treatment.
27338753	Social rhythms are patterns of habitual daily behaviors that may impact the timing of the circadian system directly or indirectly through light exposure. According to the social rhythm hypothesis of depression, depressed individuals possess a vulnerability in the circadian timing system that inhibits natural recovery after disrupting life events. Social rhythm therapies (SRTs) support the implementation of regular, daily patterns of activity in order to facilitate recovery of circadian biological processes and also to improve mood. The majority of SRT research has examined interpersonal and social rhythm therapy (IPSRT) for bipolar disorder. Recent studies have examined IPSRT in inpatient settings, using alternative modes of delivery (group, combined individual and group, internet-based applications) and with brief timeframes. New forms of SRTs are developing that target mood in individuals who have experienced specific types of stressful life events. This manuscript reviews the theoretical and biological bases of SRTs and current literature on SRT outcomes. 
27337421	Suicide is a major public health problem and the 10th leading cause of death in the United States. The identification of modifiable risk factors is essential for reducing the prevalence of suicide. Recently, it has been shown that insomnia and nightmares significantly increase the risk for suicidal ideation, attempted suicide, and death by suicide. While both forms of sleep disturbance may independently confer risk, and potentially be modifiable risk factors, it is also possible that simply being awake at night represents a specific vulnerability for suicide. The present analysis evaluates the frequency of completed suicide per hour while taking into account the percentage of individuals awake at each hour.Archival analyses were conducted estimating the time of fatal injury using the National Violent Death Reporting System for 2003-2010 and the proportion of the American population awake per hour across the 24-hour day using the American Time Use Survey.	The mean ± SD incident rate from 06:00-23:59 was 2.2% ± 0.7%, while the mean ± SD incident rate from 00:00-05:59 was 10.3% ± 4.9%. The maximum incident rate was from 02:00-02:59 (16.3%). Hour-by-hour observed values differed from those that would be expected by chance (P < .001), and when 6-hour blocks were examined, the observed frequency at night was 3.6 times higher than would be expected by chance (P < .001).	Being awake at night confers greater risk for suicide than being awake at other times of the day, suggesting that disturbances of sleep or circadian neurobiology may potentiate suicide risk.	
27337418	Self-reported sleep disturbances may confer elevated risk for suicidal ideation, suicide attempts, and death. However, limited research has evaluated polysomnographically determined sleep disturbance as an acute physiologic risk factor for suicidal thoughts. This study sought to investigate the relationship between nocturnal wakefulness in association with next-day suicidal ideation using overnight polysomnography assessment from data collected between 2006 and 2013.Sixty-five participants with DSM-IV-diagnosed major depressive disorder or bipolar depression underwent overnight polysomnography monitoring in a sleep laboratory. The Hamilton Depression Rating Scale (HDRS) was administered the morning after polysomnography recording to assess next-day suicidal ideation, severity of depressive symptoms, and subjective sleep disturbances.	Using a generalized linear mixed model, a significant time-by-ideation interaction was found indicating greater nocturnal wakefulness at 4:00 am among participants with suicidal ideation (F4,136 = 3.65, P = .007). Increased time awake during the 4:00 am hour (4:00 to 4:59) was significantly associated with elevated suicidal thoughts the next day (standardized β = 0.31, P = .008). This relationship persisted after controlling for age, gender, diagnosis, and severity of depressive symptoms.	Greater nocturnal wakefulness, particularly in the early morning hours, was significantly associated with next-day suicidal thoughts. Polysomnographically documented sleep disruption at specific times of night may represent an acute risk factor of suicidal ideation that warrants additional research.	
27335693	Circadian rhythms play an important role in maintaining homeostasis and solid organ function. The purpose of this study is to assess the implications of burn injury in rats on the underlying circadian patterns of gene expression in liver. Circadian-regulated genes and burn-induced genes were identified by applying consensus clustering methodology to temporally differentially expressed probe sets obtained from burn and sham-burn data sets. Of the liver specific genes which we hypothesize that exhibit circadian rhythmicity, 88% are not differentially expressed following the burn injury. Specifically, the vast majority of the circadian regulated-genes representing central carbon and nitrogen metabolism are "up-regulated" after the burn injury, indicating the onset of hypermetabolism. In addition, cell-cell junction and membrane structure related genes showing rhythmic behavior in the control group were not differentially expressed across time in the burn group, which could be an indication of hepatic damage due to the burn. Finally, the suppression of the immune function related genes is observed in the postburn phase, implying the severe "immunosuppression". Our results demonstrated that the short term response (24-h post injury) manifests a loss of circadian variability possibly compromising the host in terms of subsequent challenges. 
27335282	We investigated whether heat-induced hyperventilation during exercise is affected by time of day, as diurnal variation leads to higher core temperatures in the evening. Nineteen male subjects were divided into two experiments (protocol 1, n = 10 and protocol 2, n = 9). In protocol 1, subjects performed cycle exercise at 50% peak oxygen uptake in the heat (37°C and 50% RH) in the morning (0600) and evening (1800). Results showed that baseline resting and exercising esophageal temperature (Tes) were significantly (0.5°C) higher in the evening than morning. Minute ventilation (V̇e) increased from 54.3 ± 7.9 and 54.9 ± 6.8 l/min at 10 min to 71.4 ± 8.1 and 76.5 ± 11.8 l/min at 48.5 min in the morning and evening, respectively (both P < 0.01). Time of day had no effect on V̇e (P = 0.44). When V̇e as the output response was plotted against Tes as thermal input, the Tes threshold for increases in V̇e was higher in the evening than morning (37.2 ± 0.7 vs. 36.6 ± 0.6°C, P = 0.009), indicating the ventilatory response to the same core temperature is smaller in the evening. In protocol 2, the circadian rhythm-related higher resting Tes seen in the evening was adjusted down to the same temperature seen in the morning by immersing the subject in cold water. Importantly, the time course of changes in V̇e during exercise were smaller in the evening, but the threshold for V̇e remained higher in the evening than morning (P < 0.001). Collectively, those results suggest that time of day has no effect on time course hyperventilation during exercise in the heat, despite the higher core temperatures in the evening. This is likely due to diurnal variation in the control of ventilation in response to rising core temperature. 
27334057	Almost all living organisms, including humans, exhibit diurnal rhythms of physiology and behavior, which are driven by the circadian clock. Many studies have found that chronic misalignment between circadian and environmental/social rhythms carries a significant risk of various disorders, including sleep disorders, metabolic syndrome, cardiovascular diseases and cancer. However, irregular sleep-wake cycles and circadian maladjustment often cause 'social jet lag', which is minor but chronic jet-lag in our daily lives. Establishment of objective and convenient circadian-phase estimation methods in the clinical setting would therefore greatly contribute not only to resolving this global health problem but also to developing chronomedicine, a clinical approach for optimizing the time of day of treatments. Traditional melatonin-based methods have limitations with respect to circadian-phase evaluation; however, estimation methods based on clock gene expression may be able to compensate for these limitations. As a representative application of circadian-phase estimation based on clock gene expression, our method of using hair follicle cells may aid in the rapid clinical detection of circadian-related sleep problems, especially circadian rhythm sleep disorders that are masked because of forced adaptation to social time schedules. 
27330050	The hypothalamic suprachiasmatic nucleus (SCN), a circadian pacemaker, is present in all mammalian brains. It has a complex organization of peptide-containing neurons that is similar among species, but calcium-binding proteins are expressed variably. Neurons containing calretinin have been described in the SCN in a number of species but not with association to circadian function. The objective of the present study is to characterize a calretinin neuron (CAR) group in the rat anterior hypothalamus anatomically and functionally with a detailed description of its location and a quantitative analysis of neuronal calretinin immunoreactivity at 3 times of day, 0600, 1400, and 1900 h, from animals in either light-dark or constant dark conditions. CAR neurons occupy a region in the dorsal and lateral SCN with a circadian rhythm in CAR immunoreactivity with a peak at 0600 h and a rhythm in cytoplasmic CAR distribution with a peak at 1400 h. CAR neurons should be viewed as an anatomical and functional component of the rat SCN that expands the definition from observations with cell stains. CAR neurons are likely to modulate temporal regulation of calcium in synaptic transmission. 
27329942	Various recent studies revealed that the proteins of the Shank family act as major scaffold organizing elements in the post-synaptic density of excitatory synapses and that their expression level is able to influence synapse formation, maturation and ultimately brain plasticity. An imbalance in Shank3 protein levels has been associated with a variety of neuropsychological and neurodegenerative disorders including autism spectrum disorders and Phelan-McDermid syndrome. Given that sleep disorders and low melatonin levels are frequently observed in autism spectrum disorders, and that circadian rhythms may be able to modulate Shank3 signaling and thereby synaptic function, here, we performed in vivo studies on CBA mice using protein biochemistry to investigate the synaptic expression levels of Shank3α during the day in different brain regions. Our results show that synaptic Shank3 protein concentrations exhibit minor oscillations during the day in hippocampal and striatal brain regions that correlate with changes in serum melatonin levels. Furthermore, as circadian rhythms are tightly connected to activity levels in mice, we increased physical activity using running wheels. The expression of Shank3α increases rapidly by induced activity in thalamus and cortex, but decreases in striatum, superimposing the circadian rhythms of different brain regions. We conclude that synaptic Shank3 proteins build highly dynamic platforms that are modulated by the light:dark cycles but even more so driven by activity. Using wild-type CBA mice, we show that Shank3 is a highly dynamic and activity-regulated protein at synapses. In the hippocampus, changes in synaptic Shank3 levels are influenced by circadian rhythm/melatonin concentration, while running activity increases and decreases levels of Shank3 in the cortex and striatum respectively. 
27328980	Synchronization and desynchronization is of great interest in the study of circadian rhythms, metabolic oscillations and time-dependent cell aggregate behaviors. Several recent studies examine synchronization and other dynamics in models of repressilators coupled by a quorum sensing mechanism that uses a diffusive signal. Their numerical simulations have shown the complexity of the collective behavior depends sensitively on which protein upregulates diffusive signal. In this paper, we rigorously prove that the collective dynamics indeed strongly depends on how the signaling network integrates into the repressilator network. In fact we prove a general result for a class of negative cyclic feedback systems with signaling of which the repressilator is but one example. We show that if the feedback along the signaling loop is also negative, the resulting negative feedback, negative signaling (Nf-Ns) system admits either unique stable equilibrium, or a stable oscillation. When a positive signaling feedback is included, the system is no longer (Nf-Ns) and numerically exhibits multistable dynamics (Ullner et al. in Phys Rev Lett 99:148103, 2007; Phys Rev E 78:031904, 2008). We demonstrate that this multistability emerges through saddle node bifurcations of a sole cubic curve-as in generic bistable models. 
27327274	Hypertension (HT) is a common complication in patients with chronic kidney disease (CKD). However, the relationship between circadian rhythm disorder of blood pressure (BP) and intra-renal damage remains unclear.Ninety patients with chronic glomerular disease (CGD) were included in the present study. On the basis of the clinic BP (CBP) and 24 h-ambulatory BP (ABP) measurements, the patients were divided into the following groups; normotension (NT), white coat HT (WHT), masked HT (MHT), and sustained HT (SHT). For renal histopathological assessment, we evaluated each biopsy specimen for sclerotic glomeruli (SG), interstitial fibrosis (IF), intimal thickening of intra-lobular arteries (ILA), and arteriolar hyalinosis (AH).	The prevalence of NT, WHT, MHT and SHT was 60.0%, 3.3%, 23.3%, and 13.4%, respectively. Compared with circadian BP pattern, all-day HT was most prevalent in the SHT group, whereas nighttime HT was most prevalent in the MHT group. The results of histological analysis showed that the SHT group had more severe SG and IF and the MHT group had more severe IF compared to the NT group. As for renal arteriolosclerosis, the MHT and SHT groups had more severe AH compared with the NT group, whereas ILA was comparable among all four groups. Furthermore, multivariate analysis revealed that ILA was significantly correlated only with age, whereas AH was significantly correlated with age and HT based on ABP, but not HT based on CBP.	Our findings suggest that renal AH was severe not only in the SHT group, but also in the MHT group. Careful ABP monitoring should be recommended in patients with CGD.	
27327252	The importance of the circadian rhythm in regulating human food intake behaviour and metabolism has long been recognised. However, little is known as to how energy intake is distributed over the day in existing populations, and its potential association with obesity. The present review describes global trends in time-of-day of energy intake in the general population based on data from cross-sectional surveys and longitudinal cohorts. Evidence of the association between time-of-day of energy intake and obesity is also summarised. Overall, there were a limited number of cross-sectional surveys and longitudinal cohorts that provided data on time-of-day of energy intake. In the identified studies, a wide variation in time-of-day of energy intake was observed, with patterns of energy distribution varying greatly by country and geographical area. In relation to obesity, eight cross-sectional surveys and two longitudinal cohorts were identified. The association between time-of-day of energy intake and obesity varied widely, with several studies reporting a positive link between evening energy intake and obesity. In conclusion, the current review summarises global trends in time-of-day of energy intake. The large variations across countries and global regions could have important implications to health, emphasising the need to understand the socio-environmental factors guiding such differences in eating patterns. Evidence of the association between time-of-day of energy intake and BMI also varied. Further larger scale collaborations between various countries and regions are needed to sum data from existing surveys and cohorts, and guide our understanding of the role of chrono-nutrition in health.
27324142	Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response. 
27323435	To observe the effect of chronological moxibustion on plasma corticosterone (CORT), corticotrophin releasing factor (CRF) and adrenocorticotropic hormone (ACTH) levels in rheumatoid arthritis (RA) rats, so as to explore its mechanisms underlying improvement of RA.A total of 144 SD rats were randomly divided into normal control, model, moxibustion, sham-adrenalectomy (ADX, sham-ADX), ADX and ADX+moxibustion groups which were further separately divided into 4 subgroups (4 time-points: 12 pm, 6 am, 12 am, 6 pm, n = 6/subgroup). The RA model was established by subcutaneous injection of Freund's complete adjuvant (FCA, 0. 1 mL) into the right footpad (for rats of the latter 5 groups). In rats of the ADX and ADX+ moxibustion groups, bilateral adrenal glands were removed under anesthesia. Moxibustion was applied to unilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 10 min, once daily for 6 days in a week, and continuously for 3 weeks. The paw swelling volume was measured and plasma CORT, ACTH and CRF contents were assayed by ELISA and the circadian rhythm was analyzed by cosine curve fitting (cosinor) method.	The paw swelling volume was significantly increased in the model group than in the normal control group (P<0.05), and decreased remarkably in the moxibustion group (P<0.05). The paw volume was markedly increased in the ADX +moxibustion group in comparison with the moxibustion group (P<0.05). In intact rats, plasma CRF and ACTH contents were significantly increased (P<0.05), and plasma CORT was obviously decreased in the model group (P<0.05). After moxibustion, the increased plasma CRF and ACTH contents and the decreased plasma CORT level Nere considerably reversed (P<0.05). In ADX rats, plasma ORE, ACTH and CORT contents of ADX and ADX + moxibustion groups had no significant.changes compared with the sham-ADX group (P>0.05). Results of the cosine curve fitting analysis showed that the peak phases of plasma CORT contents were -355.78 degrees at about 23:43 in the normal control group, -309.05 degrees at about 20:36 in the model group, -326.5 degrees at about 21:46 in the moxibustion group, -291.65 degrees at about 19:27 in the ADX group and -300.87 degrees at about 20:31 in the ADX + moxibustion group. The peak phases of plasma ACTH contents were -324.08 degrees at about 21:37 in the normal control group, -295.39 degrees at about 19:41 in the model group, -310.81 degrees at about 20:43 in the moxibustion group, -146.51 degrees at about 9:46 in the ADX group and -267.64 degrees at about 17:50 in the ADX+ moxibustion group. The peak phases of plasma CRF contents were -257.47 degrees at about 17:10 in the normal control group, -184.74 degrees at about 12:19 in the model group, -263.00 degrees at about 17:32 in the moxibustion group, -202.46 degrees at about 13:30 in the ADX group and -232.84 degrees at about 15:31 in the ADX+ moxibustion group. It suggests that in the intact RA rats, moxibustion intervention may inhibit modeling-induced decrease of the circadian rhythm of plasma CORT, and hyperactivity of ACTH and CRF circadian rhythm.	VAoxibustion intervention can relieve paw swelling in RA rats and modulate the circadian rhythm activities of plasma CORT, ACTH and ORE levels (HPA axis activities) in intact animals.	
27322730	It has been recently discovered that blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We investigated the effect of blue light-blocking glasses in subjects with delayed sleep phase disorder (DSPD). This open-label trial was conducted over 4 consecutive weeks. The DSPD patients were instructed to wear blue light-blocking amber glasses from 21:00 p.m. to bedtime, every evening for 2 weeks. To ascertain the outcome of this intervention, we measured dim light melatonin onset (DLMO) and actigraphic sleep data at baseline and after the treatment. Nine consecutive DSPD patients participated in this study. Most subjects could complete the treatment with the exception of one patient who hoped for changing to drug therapy before the treatment was completed. The patients who used amber lens showed an advance of 78 min in DLMO value, although the change was not statistically significant (p = 0.145). Nevertheless, the sleep onset time measured by actigraph was advanced by 132 min after the treatment (p = 0.034). These data suggest that wearing amber lenses may be an effective and safe intervention for the patients with DSPD. These findings also warrant replication in a larger patient cohort with controlled observations. 
27322464	Inflammatory signaling may play a role in high-fat diet (HFD)-related circadian clock disturbances that contribute to systemic metabolic dysregulation. Therefore, palmitate, the prevalent proinflammatory saturated fatty acid (SFA) in HFD and the anti-inflammatory, poly-unsaturated fatty acid (PUFA), docosahexaenoic acid (DHA), were analyzed for effects on circadian timekeeping and inflammatory responses in peripheral clocks. Prolonged palmitate, but not DHA, exposure increased the period of fibroblast Bmal1-dLuc rhythms. Acute palmitate treatment produced phase shifts of the Bmal1-dLuc rhythm that were larger in amplitude as compared to DHA. These phase-shifting effects were time-dependent and contemporaneous with rhythmic changes in palmitate-induced inflammatory responses. Fibroblast and differentiated adipocyte clocks exhibited cell-specific differences in the time-dependent nature of palmitate-induced shifts and inflammation. DHA and other inhibitors of inflammatory signaling (AICAR, cardamonin) repressed palmitate-induced proinflammatory responses and phase shifts of the fibroblast clock, suggesting that SFA-mediated inflammatory signaling may feed back to modulate circadian timekeeping in peripheral clocks. 
27319057	Autophagic mechanisms play critical roles in cell maintenance. Damaged organelles that are not removed by autophagosomes, which act by engulfing and degrading these cellular components, have been linked to various pathologies. Recently, the progression of aging has also been correlated to a compromised autophagic response. Here, we report for the first time a significant reduction in autophagic levels in synchronized aged normal human skin fibroblasts as compared to young fibroblasts. We measured a 77.9% reduction in autophagy as determined by reverse transcription-polymerase chain reaction for LC3B expression, a microtubule-associated protein correlated to late stage autophagosome formation. In addition, we visualized these same changes by immunocytofluorescence with antibodies directed against LC3B. By harvesting synchronized, as well as unsynchronized cells over time, we were also able to measure for the first time a nighttime peak in autophagy that was present in young but absent in aged fibroblasts. Finally, since human skin is constantly subjected to environmentally induced oxidative stress from sunlight, we exposed fibroblasts to 10 J/cm2 ultraviolet A and found, in good agreement with current literature, not only that irradiation could partially reactivate autophagy in the aged cells, but also that this increase was phase shifted earlier from its endogenous temporal pattern because of its loss of synchronization with circadian rhythm.
27318597	Lithium (Li) is the first-line treatment for bipolar disorder (BD), but its mechanisms of action remain unknown. Although the chronobiological action of Li is well documented in animals, its effects on sleep and chronotypes in remitted BD patients have never been investigated.OPTHYMUM is a multicenter, cross-sectional, observational study conducted in France. We compared the sleep (Pittsburgh Sleep Quality Index, PSQI) and chronotypes (Composite Scale of Morningness, CSM) of 525 euthymic adult bipolar outpatients with (n=149) and without (n=376) current Li treatment. We used a general linear mixed-effects Poisson model to correct for age, gender, BD subtype, and mood symptoms.	In patients with BD type I, women taking Li had significantly lower PSQI (-23% [-37; -7]), but men did not (-4% [-20; +16]). Patients with BD I taking Li had better sleep efficiency (-40% [-61; -7]) and tended to better sleep duration scores (-42% [-68; +3]). A Li effect exists in women for both sleep duration and the use of night sedation (resp. -70% [-90; -10] and -37% [-60; +0.01]) but not in men (resp. -12% [-63;+113] and +9% [-31;+72]). No such associations were observed for BD II. No lithium effect was detected in the CSM score.	No controls for other medications but no between-group differences for sedative or antidepressant intakes.	Euthymic BD I patients with Li have better sleep efficiency and longer sleep duration than those without Li. Women with Li have better sleep quality, longer sleep duration and less frequent use of night sedation.	
27318227	Circadian rhythm sleep-wake disorders (CRSWDs) often manifest during the adolescent years. Measurement of circadian phase such as the dim light melatonin onset (DLMO) improves diagnosis and treatment of these disorders, but financial and time costs limit the use of DLMO phase assessments in clinic. The current analysis aims to inform a cost-effective and efficient protocol to measure the DLMO in older adolescents by reducing the number of samples and total sampling duration.A total of 66 healthy adolescents (26 males) aged 14.8-17.8 years participated in a study; they were required to sleep on a fixed baseline schedule for a week before which they visited the laboratory for saliva collection in dim light (<20 lux). Two partial 6-h salivary melatonin profiles were derived for each participant. Both profiles began 5 h before bedtime and ended 1 h after bedtime, but one profile was derived from samples taken every 30 min (13 samples) and the other from samples taken every 60 min (seven samples). Three standard thresholds (first three melatonin values mean + 2 SDs, 3 pg/mL, and 4 pg/mL) were used to compute the DLMO. An agreement between DLMOs derived from 30-min and 60-min sampling rates was determined using Bland-Altman analysis; agreement between the sampling rate DLMOs was defined as ± 1 h.	Within a 6-h sampling window, 60-min sampling provided DLMO estimates within ± 1 h of DLMO from 30-min sampling, but only when an absolute threshold (3 or 4 pg/mL) was used to compute the DLMO. Future analyses should be extended to include adolescents with CRSWDs.	
27318223	Occupational stress and the serotonin receptor (5-HTR) play a key role in the regulation of sleep quality. Previous studies on the relationship between work-related stress, 5-HTR2A polymorphism, and sleep complaints found that 5-HTR2A modulates the response of the hypothalamic-pituitary-adrenal axis to stress and the maintenance of circadian rhythm. However, the effect of 5-HTR2A polymorphism and occupational stress on sleep quality has not been reported. The present study investigated the effects of 5-HTR2A genotypes, occupational stress, and gene-environment interactions on the sleep quality.Using a three-stage stratified sampling method, 1181 participants were recruited. Then, according to the study exclusion criteria, 810 subjects remained eligible. Finally, because some of subjects did not agree to being involved in this study, 700 workers were included. Of 700 workers finally included in the study, 251 had poor sleep quality based on the Pittsburgh Sleep Quality Index. The 5-HTR2A genotypes were determined with the SNaPshot single nucleotide polymorphism assay. Occupational stress was assessed with the Occupational Stress Inventory-Revised questionnaire.	5-HTR2A genotype was significantly associated with sleep quality. The CT genotype of rs1923884 was detected at a higher frequency among individuals with low sleep efficiency; the AA genotype of rs2070040 was associated with long sleep duration and more daytime dysfunction; and the CC genotype of rs6313 was linked to long sleep latency and duration and poor sleep quality. A high level of occupational stress was linked to higher risk of poor sleep quality than low or moderate levels (odds ratio [OR] = 12.55, 95% confidence interval [CI]: 7.02-22.43). A crossover analysis demonstrated an occupational stress × 5-HTR2A interaction. Compared to participants with low occupational stress and a CT/TT genotype, those with high occupational stress and a CC genotype had a higher risk of poor sleep quality (OR = 7.93, 95% CI: 3.41-18.43), whereas those with low occupational stress and a CC genotype had a lower risk of poor sleep quality (OR = 1.53, 95% CI: 1.07-2.19).	Occupational stress and 5-HTR2A genotypes in workers are associated both independently and in combination with increased risk of poor sleep quality. Our data provide evidence that occupational stress contributes to the risk of poor sleep quality through interaction with 5-HTR2A gene polymorphism.	
27316580	To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application. 
27316552	Manganese (Mn) intoxication is associated with neurological dysfunctions collectively known as Parkinsonism or Manganism. Like in Parkinson's disease, Manganism is associated with motor disturbances, together with non-motor symptoms including cognitive and neuropsychiatric deficits. Although sleep dysfunctions are commonly reported among workers exposed to Mn, their underlying pathophysiology remains unknown. In this study, we investigated the rest-activity rhythms in rats treated daily with MnCl2 (10mg/kg, i.p) for 5weeks. Locomotor activity was assessed under a light-dark (LD) cycle, constant darkness (DD) and during adjustment to 6h shifts of the LD cycle. In LD conditions, Mn-treated rats exhibited a more fragmented and less stable rest-activity rhythm in addition to a reduction in the total 24-h amount of locomotor activity as well as in the activity confined to the active dark phase of the LD. Consequently, a significant decrease in the amplitude of the rest-activity rhythm was observed. These disturbances were displayed during and after Mn treatment. Furthermore, after the 6-h phase advance of the LD cycle, Mn-treated rats failed to re-adjust accurately their behavioral activity to the new shifted LD cycle. Upon release from LD into DD, Mn-treated rats expressed a normal and stable free-running period of their rest-activity rhythm (23.92±0.07h in Mn group vs. 24.01±0.04h in control rats). However, their rest-activity rhythm remained highly fragmented and less stable. Our results provide the first evidence that chronic Mn intoxication leads to impairment of rest-activity rhythms in addition to the motor and non-motor disturbances reported in Manganism. 
27316324	Correlation between blood pressure (BP) and target organ damage, vascular risk, and long-term patient prognosis is stronger for measurements derived from around-the-clock ambulatory BP monitoring (ABPM) than in-clinic daytime ones. Numerous studies consistently substantiate the asleep BP mean is both an independent and much better predictor of cardiovascular disease (CVD) risk than either the awake or 24 h means. Elevated sleep-time BP, i.e., sleep-time hypertension, which can only be diagnosed by around-the-clock ABPM, is much more common than suspected, not only in patients with sleep disorders, but, among others, in those who are elderly or have type 2 diabetes, chronic kidney disease, or resistant hypertension. Hence, medical guidelines increasingly recommend ABPM to make the accurate differential diagnosis of hypertension versus normotension and recognize the marked clinical importance of adequate management of sleep-time BP. The ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly impacts their beneficial, particularly on sleep-time BP control, and/or adverse effects. The MAPEC (monitorización ambulatoria para predicción de eventos cardiovasculares (i.e., ambulatory blood pressure monitoring for prediction of cardiovascular events)) study was the first prospective randomized treatment-time investigation designed to test the worthiness of bedtime chronotherapy with ≥1 conventional hypertension medications to specifically target attenuation of asleep BP. This 5.6 y median follow-up outcomes trial found the bedtime chronotherapy strategy most advantageous, resulting in the differential reduction of total CVD events by 61% and decrease of major CVD events - CVD death, myocardial infarction, and ischemic and hemorrhagic stroke - by 67%. The MAPEC study plus other earlier conducted less refined trials document the asleep BP mean is the most significant prognostic marker of CVD morbidity and mortality. It further substantiates attenuation of the asleep BP mean by a bedtime hypertension treatment strategy entailing the entire daily dose of ≥1 hypertension medications significantly reduces CVD risk, both in the general hypertension population and in more vulnerable patients, i.e., those diagnosed with chronic kidney disease, diabetes, and resistant hypertension.
27315745	Markers of renal function are widely used in intensive care and sudden changes are important indicators of acute kidney injury. The problem is to distinguish between disease progression/improvement from the natural variation in the patient. The aim of the present study was thus to study the normal intraday variation in ICU patients.We studied the intra-day variation of creatinine, cystatin C and estimated GFR based on these two markers in 28 clinically stable ICU patients.	The median diurnal coefficient of variation sCV) for creatinine was 3.70% (1.92-9.25%) while the median CV for cystatin C was 3.66% (1.36-8.11%). The corresponding CVs for the estimated GFRs were 2.00% (0.89-9.82%) for eGFRcreatinine and 4.60% (1.65-10.24%) for eGFRcystc.	The eGFRcreatinine values in individual patients were clearly higher than the eGFRcystc values. The median CV for creatinine, cystatin C and the eGFR measurements were below 5% which means that 95% of the test results will vary by <10% between sampling times in stable ICU patients. Differences >10% between sampling times are thus likely to be an indication of changes in biomarker levels due to the disease/treatment.	
27315150	Until now, different approaches have been published to resolve the problem of predicting epileptic seizures. The results are reminiscent of a substantial need for improvements in these methods to reach the stage of the clinical application. Our aim is to develop a reliable epileptic seizure prediction algorithm based on the Heart Rate Variability (HRV) analysis.We analyzed the HRV of sixteen epileptic patients with a total of 170 seizures, to predict the occurrence of seizures based on the dynamic changes of Electrocardiogram (ECG) during the pre-ictal period. Time and frequency-domain features were computed forthe consecutive time windows with a length of five minutes. An adaptive decision threshold method was used for raising alarms. Predictions were made when selected features exceeded the decision thresholds.	For the seizure occurrence period (SOP) of 4:30 minutes, and intervention time (IT) of 110 Sec, the presented method showed an average sensitivity of 78.59%, and average false prediction rate of 0.21/Hr, which indicates that the system has superiority to the random predictor.	The proposed approach shows a potential in the monitoring of epileptic patients and improving their life quality. The overall performance of the algorithm is a step forward for clinical implementation.	
27314577	While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = -0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer. 
27313482	Robust circadian rhythms in metabolic processes have been described in both humans and animal models, at the whole body, individual organ, and even cellular level. Classically, these time-of-day-dependent rhythms have been considered secondary to fluctuations in energy/nutrient supply/demand associated with feeding/fasting and wake/sleep cycles. Renewed interest in this field has been fueled by studies revealing that these rhythms are driven, at least in part, by intrinsic mechanisms and that disruption of metabolic synchrony invariably increases the risk of cardiometabolic disease. The objectives of this paper are to provide a comprehensive review regarding rhythms in glucose, lipid, and protein/amino acid metabolism, the relative influence of extrinsic (eg, neurohumoral factors) versus intrinsic (eg, cell autonomous circadian clocks) mediators, the physiologic roles of these rhythms in terms of daily fluctuations in nutrient availability and activity status, as well as the pathologic consequences of dyssynchrony. 
27312974	Our objectives were to investigate the period lengths (i.e., taus) of the endogenous core body temperature rhythm and melatonin rhythm in delayed sleep-wake phase disorder patients (DSWPD) and non-24-h sleep-wake rhythm disorder patients (N24SWD) compared with normally entrained individuals. Circadian rhythms were measured during an 80-h ultradian modified constant routine consisting of 80 ultrashort 1-h "days" in which participants had 20-min sleep opportunities alternating with 40 min of enforced wakefulness. We recruited a community-based sample of 26 DSWPD patients who met diagnostic criteria (17 males, 9 females; age, 21.85 ± 4.97 years) and 18 healthy controls (10 males, 8 females; age, 23.72 ± 5.10 years). Additionally, 4 full-sighted patients (3 males, 1 female; age, 25.75 ± 4.99 years) were diagnosed with N24SWD and included as a discrete study group. Ingestible core temperature capsules were used to record minute temperatures that were averaged to obtain 80 hourly data points. Salivary melatonin concentration was assessed every half-hour to determine time of dim light melatonin onset at the beginning and end of the 80-h protocol. DSWPD patients had significantly longer melatonin rhythm taus (24 h 34 min ± 17 min) than controls (24 h 22 min ± 15 min, p = 0.03, d = 0.70). These results were further supported by longer temperature rhythm taus in DSWPD patients (24 h 34 min ± 26 min) relative to controls (24 h 13 min ± 15 min, p = 0.01, d = 0.80). N24SWD patients had even longer melatonin (25 h ± 19 min) and temperature (24 h 52 min ± 17 min) taus than both DSWPD (p = 0.007, p = 0.06) and control participants (p < 0.001, p = 0.02, respectively). Between 12% and 19% of the variance in DSWPD patients' sleep timing could be explained by longer taus. This indicates that longer taus of circadian rhythms may contribute to the DSWPD patients' persistent tendency to delay, their frequent failure to respond to treatment, and their relapse following treatment. Additionally, other factors can contribute to misalignments in DSWPD and N24SWD disorders. 
27312903	The aim of this study was to evaluate the effects of a dorzolamide-timolol fixed combination (DTFC) on intraocular pressure (IOP), heart rate (HR), blood pressure (BP), ocular perfusion pressure (OPP), and diastolic ocular perfusion pressure (DOPP) in patients with normal-tension glaucoma (NTG).A prospective, interventional, single-blind, single-center study was conducted. Newly diagnosed NTG patients that had not been treated with a glaucoma medication in the most recent 4 weeks were included. Patients were examined at baseline (without medication) and week 4 (under medication). Baseline IOP, HR, systolic and diastolic BP, OPP, and DOPP were measured at 8 am, 12 pm, and 4 pm. At week 4, IOP, HR, systolic and diastolic BP, OPP, and DOPP were measured at 10 am and 8 pm as well.	After 4 weeks of DTFC treatment, IOP was significantly reduced at all time points (1.6-2.6 mmHg, P < 0.001), and the average IOP reduction was 14.4 %. HR and systolic BP showed no statistically significant difference at all time points; however, diastolic BP was decreased significantly at 12 pm and 4 pm (P = 0.004 and 0.001). OPP and DOPP showed no statistical significant difference after DTFC.	DTFC has favorable effects on IOP and can be used without concerns of DOPP in patients with NTG.	
27312400	Night shift work has been classified as a probable human carcinogen by the International Agency for Research on Cancer, based on experimental studies and limited evidence on human breast cancer risk. Evidence at other cancer sites is scarce. We evaluated the association between night shift work and stomach cancer risk in a population-based case-control study.A total of 374 incident stomach adenocarcinoma cases and 2481 population controls were included from the MCC-Spain study. Detailed data on lifetime night shift work were collected including permanent and rotating shifts, and their cumulative duration (years). Adjusted unconditional logistic regression models were used in analysis.	A total of 25.7% of cases and 22.5% of controls reported ever being a night shift worker. There was a weak positive, non-significant association between ever having had worked for at least 1 year in permanent night shifts and stomach cancer risk compared to never having worked night shifts (OR=1.2, 95% CI 0.9 to 1.8). However, there was an inverse 'U' shaped relationship with cumulative duration of permanent night shifts, with the highest risk observed in the intermediate duration category (OR 10-20 years=2.0, 95% CI 1.1 to 3.6) (p for trend=0.19). There was no association with ever having had worked in rotating night shifts (OR=0.9, 95% CI 0.6 to 1.2) and no trend according to cumulative duration (p for trend=0.68).	We found no clear evidence concerning an association between night shift work and stomach cancer risk.	
27311142	The operational role of the occupational health physician in the assessment and management of health risks related to night work. Night work, in the last 30-40 years, has been extended to almost all areas of employment. The potential effects on workers' health--related to the disruption of circadian rhythms--are now well defined and studied in the Literature. All issues about the protection of safety and health for night workers are governed by the Italian Legislative Decree no. 66/2003 and subsequent amendments. The management of night work hasn't been included into the main Law on Occupational Safety and Health (Italian Legislative Decree no. 81/2008 and subsequent amendments) and a coordination between the two disciplines is desirable. The occupational health physician, as a global consultant for the protection of all health issues into a company, has to evaluate the potential effects of night work on health, both individually and as a group of workers. In this way, the physician may use either traditional tools (history, physical examination, blood tests) or innovative tools (questionnaires, health promotion programs, interventions on shift schedules). In the management of night work is useful to employ schedules that respect both psychophysical integrity and social welfare of workers and the needs of the production. The occupational health physician plays a significant role in information and training of workers, both individually and as a group of workers, and in the organization of health promotion programs (whit a voluntary participation by the workers).
27308960	Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson's disease; Smith-Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain β-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it. 
27307647	Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken.We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp.	All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/	fagostin@uci.edu or pfbaldi@uci.edu	Supplementary data are available at Bioinformatics online.	
27307380	The current study investigated performance on a dual auditory task during a simulated night shift.Night shifts and sleep deprivation negatively affect performance on vigilance-based tasks, but less is known about the effects on complex tasks. Because language processing is necessary for successful work performance, it is important to understand how it is affected by night work and sleep deprivation.	Sixty-two participants completed a simulated night shift resulting in 28 hr of total sleep deprivation. Performance on a vigilance task and a dual auditory language task was examined across four testing sessions.	The results indicate that working at night negatively impacts vigilance, auditory attention, and comprehension. The effects on the auditory task varied based on the content of the auditory material. When the material was interesting and easy, the participants performed better. Night work had a greater negative effect when the auditory material was less interesting and more difficult.	These findings support research that vigilance decreases during the night. The results suggest that auditory comprehension suffers when individuals are required to work at night. Maintaining attention and controlling effort especially on passages that are less interesting or more difficult could improve performance during night shifts.	The results from the current study apply to many work environments where decision making is necessary in response to complex auditory information. Better predicting the effects of night work on language processing is important for developing improved means of coping with shiftwork.	

27307287	Stress, circadian patterns, and sleep-related factors may have a role on occupational injuries. We investigated the association between occupational injuries among the workers of an Italian hospital and their secretion of salivary melatonin and cortisol. We used a case-control study design. 27 injured cases and 31 non-injured controls provided 5 salivary samples every 60 min from 9 pm to 1 am. Melatonin and cortisol concentrations were measured, and the Dim Light Melatonin Onset (DLMO) derived using two fixed thresholds (1 and 3 pg/mL). The associations between injury, melatonin, cortisol, and DLMO were assessed through univariate and multivariate analyses. Non-injured controls had higher melatonin (median 2.28 pg/mL) and lower cortisol concentrations (0.71 ng/mL), as well as earlier DLMO times (9:00 pm with the 1 pg/mL melatonin cutoff) than cases (1.01 pg/mL, 1.14 ng/mL and 9:12 pm, respectively), although only few results were statistically significant. Measuring these hormones might be helpful to characterize the risk of injury among hospital workers. 
27307003	Oxidative DNA damage may be increased among nightshift workers because of suppression of melatonin, a cellular antioxidant, and/or inflammation related to sleep disruption. However, oxidative DNA damage has received limited attention in previous studies of nightshift work.From two previous cross-sectional studies, urine samples collected during a night sleep period for 217 dayshift workers and during day and night sleep (on their first day off) periods for 223 nightshift workers were assayed for 8-hydroxydeoxyguanosine (8-OH-dG), a marker of oxidative DNA damage, using high-performance liquid chromatography with electrochemical detection. Urinary measures of 6-sulfatoxymelatonin (aMT6s), a marker of circulating melatonin levels, and actigraphy-based sleep quality data were also available.	Nightshift workers during their day sleep periods excreted 83% (p=0.2) and 77% (p=0.03) of the 8-OH-dG that dayshift workers and they themselves, respectively, excreted during their night sleep periods. Among nightshift workers, higher aMT6s levels were associated with higher urinary 8-OH-dG levels, and an inverse U-shaped trend was observed between 8-OH-dG levels and sleep efficiency and sleep duration.	Reduced excretion of 8-OH-dG among nightshift workers during day sleep may reflect reduced functioning of DNA repair machinery, which could potentially lead to increased cellular levels of oxidative DNA damage. Melatonin disruption among nightshift workers may be responsible for the observed effect, as melatonin is known to enhance repair of oxidative DNA damage. Quality of sleep may similarly impact DNA repair. Cellular levels of DNA damage will need to be evaluated in future studies to help interpret these findings.	
27306582	Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock.Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine.	Both levels of tumor necrosis factor α, interleukin 1β, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA.	Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.	
27306141	Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable (h(2)  > 0.75). Variance component-based analysis of 28 000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 (LOD = 2.814, nominal P < 0.03). This genomic region contains several functionally plausible genes, including GRID1 and ATAD1 that regulate glutamate receptor channels mediating synaptic transmission, NRG3 with functions in brain development and HRT7 involved in the serotonergic system and circadian rhythm. Our data suggest that the alpha oscillation is in part genetically regulated, and that it may be possible to identify its regulators by genetic analyses on a realistically modest number of samples. 
27305851	Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field. 

27305519	While much is known about the circadian systems of rodents, chronobiological studies of other mammalian groups have been limited. One of the most extensively studied nonrodent species, both in the laboratory and in the wild, is the European rabbit. The aim of this study was to extend knowledge of the rabbit circadian system by examining its phasic response to light. Twelve Dutch-Himalayan cross rabbits of both sexes were allowed to free-run in constant darkness and then administered 1 h light pulses (1000 lux) at multiple predetermined circadian times. Changes in the phase of the rabbits' circadian wheel-running rhythms were measured after each light pulse and used to construct a phase-response curve (PRC). The rabbits' PRC and free-running period (τ) conformed to the empirical regularities reported for other predominantly nocturnal animals, including rodents and predatory marsupials. The results of the study are thus consistent with reports that the rabbit is essentially a nocturnal animal and show that it can entrain to light/dark (LD) cycles via discrete phase shifts. Knowledge about the rabbit's circadian range of entrainment to LD cycles gained in this study will be useful for examining the putative circadian processes believed to underlie the unusual rhythm of very brief, once-daily nest visits by nursing rabbit mothers and other nursing lagomorphs. 


27305041	Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB). We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1), pups were randomly assigned to one of the following conditions: intact pups (INT), intact pups fed by enteral gavage (INT+ENT), sham operated pups (SHAM), pups with unilateral lesions of the olfactory bulb (OBx-UNI), and pups with bilateral lesions of the olfactory bulb (OBx-BI). At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00), and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb. 

27304506	Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interventions into feasible, effective, and inexpensive treatments with the potential to improve healthspan. 
27303633	This is a review of hypnotic drug risks and benefits, reassessing and updating advice presented to the Commissioner of the Food and Drug Administration (United States FDA). Almost every month, new information appears about the risks of hypnotics (sleeping pills). This review includes new information on the growing USA overdose epidemic, eight new epidemiologic studies of hypnotics' mortality not available for previous compilations, and new emphasis on risks of short-term hypnotic prescription. The most important risks of hypnotics include excess mortality, especially overdose deaths, quiet deaths at night, infections, cancer, depression and suicide, automobile crashes, falls, and other accidents, and hypnotic-withdrawal insomnia. The short-term use of one-two prescriptions is associated with greater risk per dose than long-term use. Hypnotics are usually prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse, not better, and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders might offer safer and more effective alternative approaches to insomnia. 
27302542	Melatonin plays a major role in maintaining circadian rhythm. Previous studies showed that its secretion pattern and levels could be disturbed in persons with dementia, psychiatric disorders, sleep disorders or with cancer. Also ageing is a factor that could alter melatonin levels, although previous research provides contradicting results. As melatonin supplementation is increasingly applied in older persons as sleep medication, it is important to know if melatonin levels decrease in healthy ageing and/or secretion patterns change. The objective of this study is to determine physiological levels and secretion patterns of melatonin in healthy older people.We performed a systematic review and searched PubMed and Embase for studies published between January 1st 1980 and October 5th 2015 that measured melatonin in healthy persons aged ≥65years.	Nineteen studies were retrieved. The number of participants ranged from 5 to 60 per study. Melatonin was mostly measured by radioimmunoassay (RIA) and the number of measurements per 24hours varied from 1 to 96. Sixteen studies showed a secretion pattern with a clear peak concentration, mostly at 0200h or 0300h. Maximum concentrations varied greatly from 11.2 to 91.3pgml(-1). Maximum melatonin level in studies with participants mean aged 65-70years was 49.3pgml(-1) and in studies with participants mean aged ≥75years 27.8pgml(-1), p-value <0.001.	Total melatonin production in 24hours seems not to change in healthy ageing, but the maximal nocturnal peak concentration of melatonin might decline. It is important to take this into account when prescribing melatonin supplementation to older people.	
27301334	Circadian clocks give rise to daily oscillations in behavior and physiological functions that often anticipate upcoming environmental changes generated by the Earth rotation. In model organisms a relationship exists between several genes affecting the circadian rhythms and latitude. We investigated the allele distributions at 116 000 single-nucleotide polymorphisms (SNPs) of 25 human clock and clock-related genes from the 1000Genomes Project, and at a reference data set of putatively neutral polymorphisms. The global genetic structure at the clock genes did not differ from that observed at the reference data set. We then tested for evidence of local adaptation searching for FST outliers under both an island and a hierarchical model, and for significant association between allele frequencies and environmental variables by a Bayesian approach. A total of 230 SNPs in 23 genes, or 84 SNPs in 19 genes, depending on the significance thresholds chosen, showed signs of local adaptation, whereas a maximum of 190 SNPs in 23 genes had significant covariance with one or more environmental variables. Only two SNPs from two genes (NPAS2 and AANAT) exhibit both elevated population differentiation and covariance with at least one environmental variable. We then checked whether the SNPs emerging from these analyses fall within a set of candidate SNPs associated with different chronotypes or sleep disorders. Correlation of five such SNPs with environmental variables supports a selective role of latitude or photoperiod, but certainly not a major one. 
27300111	Menopause can affect the physiological timing system, which could result in circadian rhythm changes and development of napping habits. Whether longtime napping in postmenopausal women is associated with cardiovascular disease is, however, still debated. The present study aims to investigate this association.We conducted a population-based study in 4,616 postmenopausal Chinese women. Information on sleep duration was self-reported. The Framingham General Cardiovascular Risk Score was calculated and used to identify participants at high risk of coronary heart disease (CHD).	Increased daytime napping hours were positively associated with cardiovascular disease risk factors in postmenopausal women, such as age, waist circumference, systolic blood pressure, triglycerides, fasting glucose, postload glucose, and hemoglobin A1C (all P for trend <0.05). The prevalence of high risk of CHD increased with daytime napping hours, and was 3.7%, 4.3%, and 6.9% in the no daytime napping group, the 0.1 to 1 hour group, and the more than 1 hour group, respectively (P for trend = 0.005). Compared with the no daytime napping group, postmenopausal women with daytime napping more than 1 hour had higher risk of CHD in both univariate (odds ratio 1.94, 95% CI, 1.29-2.95) and multivariate (odds ratio 1.61, 95% CI, 1.03-2.52) logistic regression analyses. No statistically significant association was detected between night sleeping hours and high risk of CHD in postmenopausal participants.	Daytime napping is positively associated with estimated 10-year CHD risk in postmenopausal Chinese women.	
27299514	In recent years, bright light therapy (BLT) has been used to treat depression and to stabilize circadian rhythms. In this study we evaluated whether it is also helpful for comorbid symptoms of affective and behavioral dysregulation in depressive inpatients.This article reports a secondary analysis comparing two subgroups of depressive participants with comorbid affective and behavioral dysregulation, captured with the dysregulation-profile of the Strengths and Difficulties Questionnaire (SDQ-DP; n = 16 vs. n = 11). Participants were randomly allocated to active BLT (10,000 lux) or control BLT (approx. 100 lux), and received 45 minutes of BLT for 2 weeks. SDQ-DP scores, sleep parameters, and circadian preference were assessed at baseline, after the intervention, and 3 weeks later.	No direct effects on SDQ-DP scores were observed. Sleep improved in both conditions. Only in the active BLT condition was a circadian phase advance found. Correlation and regression analyses indicated an indirect, circadian effect for improved SDQ-DP scores.	The data of this pilot trial should be considered preliminary and merely descriptive. Further research is warranted.	
27298427	The daily susceptibility rhythm of the cotton aphid, Aphis gossypii Glover, to diazinon and the corresponding changes in the activity of three xenobiotic detoxifying enzymes-cytochrome P450 monooxygenases (P450), glutathione S-transferases (GSTs), and esterases-were investigated. Bioassays were conducted to estimate the median lethal doses (LD50) of diazinon at six different zeitgeber times (ZT0, 4, 8, 12, 16, and 20) under constant light (LL) and lighting conditions of 16 h of light and 8 h of darkness (LD). The results showed that the highest susceptibility occurred at the onset of night (ZT16) and 4 h before this time point (ZT12) under the LD condition. The endogenous rhythmicity of susceptibility was ensured, as the highest susceptibility occurred at the same time under the LL condition. The circadian changes in susceptibility to diazinon were almost coincident with changes in esterase and GSTs activity, but not in P450 activity. We also found rhythmic changes in energy components of whole-body aphids, with similar patterns of circadian changes of proteins, lipids, and soluble carbohydrates, but not glycogen, under LL and LD conditions. These photoperiod conditions (LD and LL) showed different fluctuation in trends of energy resources and of course, different quantities. Our study represents the first report of circadian control of insecticide susceptibility in aphids and provides insights into more efficient control of these pests by unveiling the times of day during which aphids are more susceptible to insecticides with attention to endogenous physiological phenomena. 
27297470	Dormancy has evolved in all major metazoan lineages. It is critical for survival when environmental stresses are not conducive to growth, maturation, or reproduction. Embryonic diapause is a form of dormancy where development is reversibly delayed and metabolism is depressed. We report the diapause transcriptome of the annual killifish Nematolebias whitei, and compare gene expression between diapause embryos and free-living larvae to identify a candidate set of 945 differentially expressed "diapause" genes for this species. Similarity of transcriptional patterns among N. whitei and other diapausing animals is striking for a small set of genes associated with stress resistance, circadian rhythm, and metabolism, while other genes show discordant patterns. Although convergent evolution of diapause may require shared molecular mechanisms for fundamental processes, similar physiological phenotypes also may arise through modification of alternative pathways. Annual killifishes are a tractable model system for comparative transcriptomic studies on the evolution of diapause. 
27296158	Bedtime administration of antihypertensive drugs currently receives more at-tention, but no clear consensus has been reached on the blood pressure (BP)-lowering effect of this strategy.We systematically searched literature for clinical trials of ingestion time of anti-hypertensive drugs evaluated by ambulatory blood pressure monitoring (ABPM) to perform a meta-analysis which aimed at determining the difference in diurnal, nocturnal, and 24-h mean of systolic BP (SBP) and diastolic BP (DBP), absolute BP reduction from baseline between bedtime administration group (experimental group) and morning (awaking) administration group (control group).	The synthesis analysis showed that the level of BP in bedtime administration group was lower than the morning administration group, which reduced diurnal SBP/DBP by 1.67/1.13 mm Hg (p = 0.36/0.48), 24-h SBP/DBP by 2.78/0.36 mm Hg (p = 0.09/0.62), nocturnal SBP/DBP by 6.32/3.17 mm Hg (p = 0.03/0.007). Furthermore, there was lack of statistically significant differences in the diurnal mean of SBP/DBP reduction from baseline between the two groups (p = 0.94/0.85), but bedtime administration resulted in significant reduction from baseline in the nocturnal mean of SBP/DBP, by -4.72/-3.57 mm Hg (p = 0.01/0.05). Funnel plot demonstrated that there was no evidence of publication bias.	Administration of ≥ 1 antihypertensive drugs at bedtime or evening results in a greater reduction of nocturnal hypertension than dosing in the morning without loss of efficacy of diurnal and 24 h mean BP reduction.	
27294991	To describe sleeping behaviors and trends over time among an ethnically diverse group of community-living older adults.A descriptive secondary data analysis of a subsample (n = 217) from the Lifestyle Redesign randomized controlled trial was done to explore baseline napping and sleeping patterns as well as 6-mo changes in these outcomes.	At baseline, the average time sleeping was 8.2 hr daily (standard deviation = 1.7). Among all participants, 29% reported daytime napping at baseline, of which 36% no longer napped at follow-up. Among participants who stopped napping, those who received an occupation-based intervention (n = 98) replaced napping time with nighttime sleep, and those not receiving an intervention (n = 119) experienced a net loss of total sleep (p < .05).	Among participants who stopped napping, the occupation-based intervention may be related to enhanced sleep. More research examining the role of occupation-based interventions in improving sleep is warranted.	
27295373	Internal appraisal styles, in addition to circadian and social rhythm instability, have been implicated in the development of mood experiences in bipolar disorder (BD), yet potential interactions between these variables remain under researched.This study used online questionnaires to examine relationships between social and circadian rhythm instability, appraisal style and mood within populations at varying vulnerability for BD.	Participants with BD (n=51), and those at behavioural high-risk (BHR; n=77), exhibited poor sleep quality and a stronger tendency to form internal appraisals of both positive and negative experiences compared to non-clinical controls (n=498) and participants with fibromyalgia (n=80). Participants with BD also exhibited a stronger tendency to adopt an internal, negative appraisal style compared to individuals at BHR. Sleep disturbance and internal appraisal styles were significantly associated with low mood in BD.	Sleep quality and social rhythm stability were assessed using self-report measures only, which may differ from objective measures. Causal relationships between constructs could not be examined due to the cross-sectional design.	The findings suggest the importance of attending to internal appraisal styles and sleep quality when working therapeutically with individuals diagnosed with BD. Potential differences in the effect of appraisal style at the state and trait level warrant further exploration.	
27294193	Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability and is a disorder that is also highly associated with autism. FXS occurs as a result of an expanded CGG repeat sequence leading to transcriptional silencing. In an animal model of FXS in which Fmr1 is knocked out (Fmr1 KO), many physical, physiological, and behavioral characteristics of the human disease are recapitulated. Prior characterization of the mouse model was conducted during the day, the inactive phase of the circadian cycle. Circadian rhythms are an important contributor to behavior and may play a role in the study of disease phenotype. Moreover, changes in the parameters of circadian rhythm are known to occur in FXS animal models. We conducted an investigation of key behavioral phenotypes in Fmr1 KO mice during their active phase. We report that phase did not alter the Fmr1 KO phenotype in open field activity, anxiety, and learning and memory. There was a slight effect of phase on social behavior as measured by time in chamber, but not by time spent sniffing. Our data strengthen the existing data characterizing the phenotype of Fmr1 KO mice, indicating that it is independent of circadian phase. 
27294030	For many studies, participants' sleep-wake patterns are monitored and recorded prior to, during and following an experimental or clinical intervention using actigraphy, i.e. the recording of data generated by movements. Often, these data are merely inspected visually without computation of descriptive parameters, in part due to the lack of user-friendly software. To address this deficit, we developed a package for R Core Team [6], that allows computing several non-parametric measures from actigraphy data. Specifically, it computes the interdaily stability (IS), intradaily variability (IV) and relative amplitude (RA) of activity and gives the start times and average activity values of M10 (i.e. the ten hours with maximal activity) and L5 (i.e. the five hours with least activity). Two functions compute these 'classical' parameters and handle either single or multiple files. Two other functions additionally allow computing an L-value (i.e. the least activity value) for a user-defined time span termed 'Lflex' value. A plotting option is included in all functions. The package can be downloaded from the Comprehensive R Archives Network (CRAN). •The package 'nparACT' for R serves the non-parametric analysis of actigraphy data.•Computed parameters include interdaily stability (IS), intradaily variability (IV) and relative amplitude (RA) as well as start times and average activity during the 10 h with maximal and the 5 h with minimal activity (i.e. M10 and L5). 
27291858	The α2 adrenergic receptors which abundantly express in the CA1 region of the hippocampus play an important role in the regulation of sleep and memory retention processes. Based on the available evidence, the aim of our study was to investigate consequences of the activation and deactivation of CA1 α2 adrenergic receptors (by clonidine and yohimbine, respectively) on the impairment of memory retention induced by total sleep deprivation (TSD) and the reversal of circadian rhythm (RCR) in a rat model. To this end, the water box apparatus and passive avoidance task were in turn used to induce sleep deprivation and assess memory retention. Our findings suggested that TSD (for 24 and 36, but not 12h) and RCR (12h/day for 3 consecutive days) impair memory function. The post-training intra-CA1 administration of yohimbine (α2 adrenergic receptor antagonist) on its own, at the dose of 0.1μg/rat, decreased the step-through latency and locomotor activity in the TSD- sham treated but not undisturbed sleep rats. Unlike yohimbine, clonidine (α2 adrenergic receptor agonist), in all applied doses (0.001, 0.01 and 0.1μg/rat), failed to induce such an effect. While the subthreshold dose of yohimbine (0.001μg/rat) abrogated the impairment of memory retention induced by the 24-h TSD, it could potentiate the impairment of memory retention induced by 36-h TSD, suggesting the modulatory effect of yohimbine. Moreover, the subthreshold dose of clonidine (0.1μg/rat) restored the memory retention deficit in TSD rats (24 and 36h). On the other hand, the subthreshold dose of clonidine (0.1μg/rat), but not yohimbine (0.001μg/rat) restored the memory retention deficit in RCR rats. Such interventions however did not alter the locomotor activity. The above observations proposed that CA1 α2 adrenergic receptors play a potential role in memory retention deficits induced by TSD and RCR. 
27288990	Responses of plant to drought largely depend on the intensity, duration and developmental stage at which water stress occurs. The purpose of this study was to analyze the dynamic of cotton physiology response to different levels sustained soil water deficit during reproductive growth stage at leaf basis. Three levels of steady-state water regimes [soil relative water content (SRWC) maintained at (75 ± 5)%, (60 ± 5)% and (45 ± 5)%] were imposed when the white flowers had opened on the first fruiting position of the 6-7th fruiting branches (FB6-7), which was the first day post anthesis (i.e. 1 DPA) and lasted to 50 DPA. Results showed decreasing SRWC slowed cotton growth on the base of biomass and leaf area. However, carbon metabolites levels were globally increased under drought despite of notably inhibited photosynthesis throughout the treatment period. Clear diurnal pattern of sucrose and starch concentrations was obtained and sucrose levels were evaluated while starch concentration was reduced with decreasing soil water content during a 24-h cycle. Osmotic adjustment (OA) was observed at most of the sampling dates throughout the drought period. K(+) was the main contributor to osmotic adjustment (OA) at 10 and 24 DPA then turned out to be amino acid at 38 and 50 DPA. The stressed cotton gradually failed to scavenge reactive oxygen species (ROS) with increasing days post anthesis, primarily due to the permanent decrease in SOD activity. Elevated carbohydrates levels suggest cotton growth was more inhibited by other factors than carbon assimilation. OA and antioxidant could be important protective mechanisms against soil water deficit in this species, and transition of these mechanisms was observed with drought intensity and duration increased. 
27286820	Tungsten inert gas (TIG) welding represents one of the most widely used metal joining processes in industry. It has been shown to generate a large majority of particles at the nanoscale and to have low mass emission rates when compared to other types of welding. Despite evidence that TIG fume particles may produce reactive oxygen species (ROS), limited data is available for the time course changes of particle-associated oxidative stress in exposed TIG welders.Twenty non-smoking male welding apprentices were exposed to TIG welding fumes for 60 min under controlled, well-ventilated settings. Exhaled breathe condensate (EBC), blood and urine were collected before exposure, immediately after exposure, 1 h and 3 h post exposure. Volunteers participated in a control day to account for oxidative stress fluctuations due to circadian rhythm. Biological liquids were assessed for total reducing capacity, hydrogen peroxide (H2O2), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations at each time point. A linear mixed model was used to assess within day and between day differences.	Significant increases in the measured biomarkers were found at 3 h post exposure. At 3 h post exposure, we found a 24 % increase in plasma-H2O2 concentrations ([95%CI: 4 % to 46 %], p = 0.01); a 91 % increase in urinary-H2O2 ([2 % to 258 %], p = 0.04); a 14 % increase in plasma-8-OHdG ([0 % to 31 %], p = 0.049); and a 45 % increase in urinary-8-OHdG ([3 % to 105 %], p = 0.03). Doubling particle number concentration (PNC) exposure was associated with a 22 % increase of plasma-8-OHdG at 3 h post exposure (p = 0.01).	A 60-min exposure to TIG welding fume in a controlled, well-ventilated setting induced acute oxidative stress at 3 h post exposure in healthy, non-smoking apprentice welders not chronically exposed to welding fumes. As mass concentration of TIG welding fume particles is very low when compared to other types of welding, it is recommended that additional exposure metrics such as PNC are considered for occupational risk assessments. Our findings highlight the importance of increasing awareness of TIG welding fume toxicity, especially given the realities of welding workplaces that may lack ventilation; and beliefs among interviewed welders that TIG represents a cleaner and safer welding process.	
27286798	Sleep-wake disturbances are defined as perceived or actual alterations in sleep that result in impaired daytime functioning. Unlike other cancers, there is limited information about sleep-wake disturbances in adults with primary brain tumors throughout the illness trajectory. Sleep-wake disturbance is among the most severe and common symptoms reported by primary brain-tumor patients, particularly those undergoing radiation therapy. As with other cancers and neurologic illness, sleep-wake disturbance may also be clustered or related to other symptoms such as fatigue, depression, and cognitive impairment. There is increasing evidence for a genetic basis of normal sleep and sleep regulation in healthy adults. Specific mutations and single nucleotide variants have been reported to be associated with both fatigue and sleep-wake disorders, and both inflammation and alterations in circadian rhythms have been postulated to have a potential role. Guidelines for assessment and interventions have been developed, with cognitive behavioral therapy, exercise, and sleep hygiene demonstrating benefit in patients with other solid tumors. Further research is needed to identify risk and appropriate treatment in the brain-tumor patient population.
27285820	Clock genes are expressed throughout the body, although how they oscillate in unrestrained animals is not known. Here, we show an in vivo imaging technique that enables long-term simultaneous imaging of multiple tissues. We use dual-focal 3D tracking and signal-intensity calibration to follow gene expression in a target area. We measure circadian rhythms of clock genes in the olfactory bulb, right and left ears and cortices, and the skin. In addition, the kinetic relationship between gene expression and physiological responses to experimental cues is monitored. Under stable conditions gene expression is in phase in all tissues. In response to a long-duration light pulse, the olfactory bulb shifts faster than other tissues. In Cry1(-/-) Cry2(-/-) arrhythmic mice circadian oscillation is absent in all tissues. Thus, our system successfully tracks circadian rhythms in clock genes in multiple tissues in unrestrained mice. 
27285754	Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTOR-mediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling.
27285327	Fibroblast growth factor 21 (FGF21) gene expression is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid were repeatedly shown to induce FGF21 expression and circulating levels. These effects are usually more pronounced in liver or isolated hepatocytes than in adipose tissue or isolated fat cells. Although peroxisome proliferator-activated receptor α (PPARα) is a key mediator of hepatic FGF21 expression and function, including the regulation of gluconeogenesis, ketogenesis, torpor, and growth inhibition, there is increasing evidence of PPARα-independent transactivation of the FGF21 gene by dietary molecules. FGF21 expression is believed to follow the circadian rhythm and be placed under the control of first order clock-controlled transcription factors, retinoic acid receptor-related orphan receptors (RORs) and nuclear receptors subfamily 1 group D (REV-ERBs), with FGF21 rhythm being anti-phase to REV-ERBs. Key metabolic hormones such as glucagon, insulin, and thyroid hormone have presumed or clearly demonstrated roles in regulating FGF21 transcription and secretion. The control of the FGF21 gene by glucagon and insulin appears more complex than first anticipated. Some discrepancies are noted and will need continued studies. The complexity in assessing the significance of FGF21 gene expression resides in the difficulty to ascertain (i) when transcription results in local or systemic increase of FGF21 protein; (ii) if FGF21 is among the first or second order genes upregulated by physiological, metabolic, and environmental stimuli, or merely an epiphenomenon; and (iii) whether FGF21 may have some adverse effects alongside beneficial outcomes.
27284410	Basic helix-loop-helix (bHLH) transcription factor DEC2 (bHLHE41/Sharp1) is one of the clock genes that show a circadian rhythm in various tissues. DEC2 regulates differentiation, sleep length, tumor cell invasion and apoptosis. Although studies have been conducted on the rhythmic expression of DEC2 mRNA in various tissues, the precise molecular mechanism of DEC2 expression is poorly understood. In the present study, we examined whether DEC2 protein had a rhythmic expression. Western blot analysis for DEC2 protein revealed a rhythmic expression in mouse liver, lung and muscle and in MCF-7 and U2OS cells. In addition, AMP-activated protein kinase (AMPK) activity (phosphorylation of AMPK) in mouse embryonic fibroblasts (MEFs) exhibited a rhythmic expression under the condition of medium change or glucose-depleted medium. However, the rhythmic expression of DEC2 in MEF gradually decreased in time under these conditions. The medium change affected the levels of DEC2 protein and phosphorylation of AMPK. In addition, the levels of DEC2 protein showed a rhythmic expression in vivo and in MCF-7 and U2OS cells. The results showed that the phosphorylation of AMPK immunoreactivity was strongly detected in the liver and lung of DEC2 knockout mice compared with that of wild-type mice. These results may provide new insights into rhythmic expression and the regulation between DEC2 protein and AMPK activity.
27280355	Culex pipiens and Cx. restuans are the main vectors of West Nile virus and the primary target species of surveillance and control programs in Pennsylvania. Performing adult control, specifically ultra-low volume (ULV) applications, at night during peak oviposition activity time(s) is necessary to control these species. In July and August of 2009, collections were made at 15-min intervals starting at sunset and continuing until 3 h after sunset to establish a more accurate timeline of Cx. pipiens and Cx. restuans oviposition flight activity. The highest numbers of Cx. pipiens and Cx. restuans were collected during the 15-30, 30-45, and 45-60 min postsunset time intervals (P < 0.05). Oviposition activity began to decrease after 60 min postsunset. These observations have identified a smaller oviposition activity period for Cx. pipiens and Cx. restuans than noted from other studies, thus potentially improving the timing of ULV operations to control these 2 vector species. 
27276394	The goal of this study was to evaluate the relationship between serum albumin levels and 24-hour ambulatory blood pressure monitoring (24-h ABPM) recordings in non-diabetic essential hypertensive patients.A total of 354 patients (mean [SD] age: 55.5 [14.3] years, 50% females) with essential hypertension and 24-h ABPM recordings were included. Patient 24-h nighttime and daytime ABPM values, systolic and diastolic dipping status and average nocturnal dipping were recorded. The correlations between serum albumin levels and nocturnal systolic and diastolic dipping were evaluated, and correlates of average nocturnal systolic dipping were determined via a linear regression model.	Overall, 73.2% of patients were determined to be non-dippers. The mean (SD) levels of serum albumin (4.2 [0.3] g/dL vs. 4.4 [0.4] g/dL, p<0.001) and the average nocturnal systolic (15.2 [4.8] mmHg vs. 0.3 [6.6] mmHg, p<0.001) and diastolic dipping (4.2 [8.6] mmHg vs. 18.9 [7.0] mmHg, p<0.001) were significantly lower in non-dippers than in dippers. A significant positive correlation was noted between serum albumin levels and both systolic (r=0.297, p<0.001) and diastolic dipping (r=0.265, p<0.001). The linear regression analysis revealed that for each one-unit increase in serum albumin, the average nocturnal dip in systolic BP increased by 0.17 mmHg (p=0.033).	Our findings indicate an association between serum albumin levels and the deterioration of circadian BP rhythm among essential hypertensive patients along with the identification of a non-dipper pattern in more than two-thirds of patients. Our findings emphasize the importance of serum albumin levels, rather than urinary albumin excretion, as an independent predictor of nocturnal systolic dipping, at least in non-diabetic essential hypertensive patients with moderate proteinuria.	
27276063	Light plays a critical role in the regulation of numerous aspects of physiology and behaviour, including the entrainment of circadian rhythms and the regulation of sleep. These responses involve melanopsin (OPN4)-expressing photosensitive retinal ganglion cells (pRGCs) in addition to rods and cones. Nocturnal light exposure in rodents has been shown to result in rapid sleep induction, in which melanopsin plays a key role. However, studies have also shown that light exposure can result in elevated corticosterone, a response that is not compatible with sleep. To investigate these contradictory findings and to dissect the relative contribution of pRGCs and rods/cones, we assessed the effects of light of different wavelengths on behaviourally defined sleep. Here, we show that blue light (470 nm) causes behavioural arousal, elevating corticosterone and delaying sleep onset. By contrast, green light (530 nm) produces rapid sleep induction. Compared to wildtype mice, these responses are altered in melanopsin-deficient mice (Opn4-/-), resulting in enhanced sleep in response to blue light but delayed sleep induction in response to green or white light. We go on to show that blue light evokes higher Fos induction in the SCN compared to the sleep-promoting ventrolateral preoptic area (VLPO), whereas green light produced greater responses in the VLPO. Collectively, our data demonstrates that nocturnal light exposure can have either an arousal- or sleep-promoting effect, and that these responses are melanopsin-mediated via different neural pathways with different spectral sensitivities. These findings raise important questions relating to how artificial light may alter behaviour in both the work and domestic setting. 
27275157	Proteinuria and nighttime blood pressure (BP) elevation are notable risk markers of chronic kidney disease and correlate closely with each other. However, daily urinary protein excretion (UPE) always fluctuates. In patients with minimal change nephrotic syndrome (MCNS), serum albumin concentrations (SAC) decrease but fluctuate less than UPE. We evaluated whether SAC is a reliable marker for proteinuria, and compared the relations among circadian BP changes, SAC, and UPE.In patients with MCNS (12 men and 11 women, 43 ± 18 years), blood and spot urine samples were collected on three consecutive days before treatment, and 24-hour BP was also measured on the three days. Then, an intervention study was conducted in the patients to examine circadian BP changes induced by treatment. Sleeping/waking BP ratio was analyzed as an indicator of circadian BP rhythm.	In the three-day measurements before treatment, mean coefficient of variation, an index of dispersion of data, for SAC was 7.4 ± 7.4%, which was markedly lower (p < 0.01) than 35.7 ± 15.4% for UPE. SAC correlated inversely with sleeping/waking systolic and diastolic BP ratios on all three days, whereas UPE did not correlate significantly with sleeping/waking diastolic BP ratio on day 3. Sleeping/waking systolic and diastolic BP ratios were 96 ± 5 and 95 ± 6%, and were higher (p < 0.05) than in healthy subjects (89 ± 8 and 88 ± 10%). Treatment improved hyperproteinuria and hypoalbuminemia, and was accompanied by decreases (p < 0.05) in sleeping and waking systolic/diastolic BP ratio to 91 ± 8 and 89 ± 9%.	These findings suggest that reduced SAC in patients with proteinuria is associated with disrupted circadian BP rhythm.	
27274533	Tandem affinity purification coupled with mass spectrometry (TAP-MS) analysis is a powerful biochemical approach to identify protein-protein associations. Here we describe two datasets generated by a series of TAP-MS analyses to co-purify proteins associated with either ELF3 or ELF4 of the Evening Complex (EC) ("Identification of Evening Complex Associated Proteins in Arabidopsis by Affinity Purification and Mass Spectrometry" (Huang et al., 2016a) [1]) or proteins associated with PCH1, which is a newly identified output of the circadian clock to regulate photoperiodic growth in Arabidopsis thaliana ("PCH1 integrates circadian and light-signaling pathways to control photoperiod-responsive growth in Arabidopsis" (Huang et al. 2016b) [2]). We used either ELF3, ELF4 or PCH1 fused to a C-terminal tandem affinity tag (6xHis-3xFLAG) as baits and conducted purifications in various genetic mutant backgrounds. These data are discussed in recent publications [1,2], and are deposited at the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PRIDE: PXD002606 (for EC) and PRIDE: PXD003352 (for PCH1). 
27272934	Alarm reaction to clinical blood pressure (BP) measurement, defined white-coat effect (WCE), can cause overestimation of true BP values.To assess whether ambulatory blood pressure monitoring (ABPM) can similarly affect BP values during the initial hours of recording.	In 420 ABPMs selected for a first systolic BP (SBP) reading at least 10 mmHg higher than the mean daytime SBP, we calculated mean diurnal and 24 h SBP with and without the exclusion of the two first hours of recording defined as the WCE window (WCEw). We also calculated the magnitude and duration of WCE. These analyses were also performed separately in patients off anti-hypertensive treatment (n = 156), and on treatment with and without the inclusion of beta-blockers (respectively n = 113 and 151).	Exclusion of WCEw period reduced mean diurnal and 24 h SBP respectively from 135 ± 0.5 to 133 ± 0.5 (p < 0.01) and from 131 ± 0.5 to 130 ± 0.5 (p < 0.02). As a result the percentage of patients diagnosed as having diurnal or 24 h hypertension was reduced respectively from 48 to 40 % and from 52 to 47 %. The magnitude of WCEw was similar in both genders but the duration was longer in females (66 ± 2 vs. 56 ± 2 min, p < 0.01). Treatment with beta-blockers was associated with a shorter duration of WCE in both genders but this effect was statistically significant only in males.	In some patients ABPM is not free from WCE. WCE may affect the overall estimation of BP profile and is longer but less blunted by beta-blockers in females than in males.	
27272272	The liver is innervated by both the sympathetic and the parasympathetic nerve systems. These nerves are derived from the splanchnic and vagal nerves that surround the portal vein, hepatic artery, and bile duct. The afferent fiber delivers information regarding osmolality, glucose level, and lipid level in the portal vein to the central nervous system (CNS). In contrast, the efferent fiber is crucial in the regulation of metabolism, blood flow, and bile secretion. Furthermore, liver innervation has been associated with hepatic fibrosis, regeneration, and circadian rhythm. Knowledge of these mechanisms can be applied for potential liver disease treatment.
27271772	Temporal and spatial patterns of locomotion reflect both resting periods and the movement from one place to another to satisfy physiological and behavioural needs. Locomotion is studied in diverse areas of biology such as chronobiology and physiology, as well as in biomathematics. Herein, the locomotion of 24 visually-isolated Japanese quails in their home-box environment was recorded continuously over a 6.5 days at a 0.5 s sampling rate. Three time series are presented for each bird: (1) locomotor activity, (2) distance ambulated, and (3) zone of the box where the bird is located. These high resolution, week-long, time series consisting of 1.07×10(6) data points represent, to our knowledge, a unique data set in animal behavior, and are publically available on FigShare. The data obtained can be used for analyzing dynamic changes of daily or several day locomotion patterns, or for comparison with existing or future data sets or mathematical models across different taxa.
27271308	Insufficient sleep and circadian rhythm disturbances have been each associated with adverse cardiovascular outcomes in epidemiological studies, but experimental evidence for a causal link is scarce. The present study compares the impact of circadian misalignment (CM) to circadian alignment (CA) on human autonomic function using a nonrandomized parallel group design to achieve the same total sleep time in both conditions. After baseline assessments (3 days with 10-hour bedtimes), 26 healthy young adults were assigned to sleep restriction (SR; eight 5-hour bedtimes) with either fixed nocturnal bedtimes (CA; n=13) or bedtimes delayed by 8.5 hours on 4 of the 8 days (CM; n=13). Daytime ambulatory blood pressure and heart rate (HR; CA, n=11; CM, n=10) and 24-hour urinary norepinephrine levels (CA, n=13; CM, n=13) were assessed at baseline and the end of SR. Nocturnal HR and HR variability were analyzed during sleep at baseline and during the fourth and seventh nights of SR (CA, n=8; CM, n=12). SR resulted in a significant increase in daytime HR in both groups, without changes in blood pressure. SR increased 24-hour urinary norepinephrine in the CM group (30±4 versus 21±2 μg), but not in the circadian alignment group (group×condition, P=0.005). In contrast to the lack of detectable impact of CM on daytime autonomic function, SR with CM elicited greater increases in nocturnal HR, as well as greater reductions in vagal indices of HR variability, than SR without CM (group×condition, P<0.05). In conclusion, SR and CM both result in impaired autonomic function that could lead, under chronic conditions, to enhanced cardiovascular risk. 
27271267	Exercise during the inactive period can entrain locomotor activity and peripheral circadian clock rhythm in mice; however, mechanisms underlying this entrainment are yet to be elucidated. Here, we showed that the bioluminescence rhythm of peripheral clocks in PER2::LUC mice was strongly entrained by forced treadmill and forced wheel-running exercise rather than by voluntary wheel-running exercise at middle time during the inactivity period. Exercise-induced entrainment was accompanied by increased levels of serum corticosterone and norepinephrine in peripheral tissues, similar to the physical stress-induced response. Adrenalectomy with norepinephrine receptor blockers completely blocked the treadmill exercise-induced entrainment. The entrainment of the peripheral clock by exercise is independent of the suprachiasmatic nucleus clock, the main oscillator in mammals. The present results suggest that the response of forced exercise, but not voluntary exercise, may be similar to that of stress, and possesses the entrainment ability of peripheral clocks through the activation of the adrenal gland and the sympathetic nervous system. 
27269519	Phase response curves (PRCs) for light or temperature stimuli have been shown to be most valuable in understanding how circadian clocks are entrained to daily environmental cycles. Nowadays, PRC experiments in which clock neurons are manipulated in a temporally restricted manner by thermogenetic or optogenetic tools are also useful to comprehend clock network properties. Here, we temporally depolarized specific clock neurons of Drosophila melanogaster by activating temperature-sensitive dTrpA1 channels to unravel their role in phase shifting the flies' activity rhythm. The depolarization of all clock neurons caused a PRC resembling the flies' light PRC, with strong phase delays in the first half of the subjective night and modest phase advances in its second half. However, the activation of the flies' pigment-dispersing factor (PDF)-positive morning (M) neurons (s-LNvs) only induced phase advances, and these reached into the subjective day, where the light PRC has its dead zone. This indicates that the M neurons are very potent in accelerating the clock, which is in line with previous observations. In contrast, the evening (E) neurons together with the PDF-positive l-LNvs appear to mediate phase delays. Most interestingly, the molecular clock (Period protein cycling) of the depolarized clock neurons was shifted in parallel to the behavior, and this shift was already visible within the first cycle after the temperature pulse. We identified cAMP response element binding protein B (CREB) as a putative link between membrane depolarization and the molecular clock. 
27269050	The hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation.Brain slices containing the SCN were prepared from male Wistar rats and maintained in a recording chamber. Changes in firing rates of SCN neurons were recorded after perfusion of drugs.	SCN firing rates were dose-dependently suppressed by 19.2-80.9% following perfusion of 0.04-0.32mM agomelatine (p<0.001, IC50=0.14mM). Perfusion with melatonin (0.4-3.2mM) resulted in 16.6-62.5% dose-dependent reductions in firing rates (at least p<0.01, IC50=1.59mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32mM) and a 5-HT2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16mM agomelatine by 35% and 50.2%, respectively. A 5-HT2C receptor antagonist (S32006; 0.03-0.12mM) significantly decreased SCN firing rates (19.6-91.8%; at least p<0.05, IC50=0.05mM). Co-perfusion of S32006 (0.06mM) with a 5-HT2C agonist (Ro60-0175; 0.003mM) reduced suppressions evoked by S32006 alone by ~72.1%.	These results are consistent with the hypothesis that agomelatine acts directly on the SCN via both agonist effects at melatonergic receptors and antagonist effects at 5-HT2C receptors, which parallel its mechanisms of action as an antidepressant.	
27267863	Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-β-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and cAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smad6/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and glucocorticoid in the adrenal medulla.

27263179	Ultrafine particles (UFPs) are ubiquitous in urban air and have been recognized as a risk to human health. The aim of this study was to measure the relationships among ultrafine particles and other ambient air pollutants and meteorological factors in the Tampa Bay Area. This study measured continuous UFPs, black carbon, oxides of nitrogen (NO(x)), nitrogen dioxide (NO2), nitric oxide (NO), carbon monoxide (CO), ozone (O3), sulfur dioxide (SO2), particulate matter having an aerodynamic diameter of 10 microns or less (PM10), relative humidity, wind speed, and ambient temperature during January to March 2014. Moreover, the study compared the relationship between UFPs and various co-pollutants daily, including during morning rush hour periods. This study found a moderate correlation among UFPs and black carbon, NO(x), NO2, and NO during hourly continuous measurements and rush hour periods, and a low level of correlation among UFPs and CO, O3, SO2, PM10, relative humidity, wind speed, and ambient temperature. This study indicates that co-pollutants should not be used as a surrogate to assess the human health risk from ultrafine particles exposure.
27263061	Physicians are often alleged responsible for the manipulation of delivery timing. We investigate this issue in a setting that negates the influence of financial incentives on physician's behavior. Working on a sample of women admitted at the onset of labor in a big public hospital in Italy we estimate a model for the exact time of delivery as driven by individual Indication to Cesarean Section (ICS) and covariates. We find that ICS does not affect the day of delivery but leads to a circadian rhythm in the likelihood of delivery. The pattern is consistent with the postponement of high ICS deliveries in the late night\early morning shift. Our evidence hardly supports the manipulation of timing of births as driven by medical staff's "demand for leisure". Physicians seem to manipulate the exact timing of delivery to reduce exposure to risk factors extant during off-peak periods. 
27262897	The prevalence of binge drinking (BD), found especially among young people, is increasing worldwide and has become an important social and health concern. We studied, for the first time, the personality profile, using the Alternative Five Factor Model, among university students with BD and healthy controls, taking into account the possible influence of sex.70 participants with BD (30 men) and 70 healthy controls (30 men) were included, selected to control for characteristics that are known to be related to BD (physical and mental disorders, consumption of other drugs, circadian rhythms), completed the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ).	The scores on Neuroticism-Anxiety and Impulsive Sensation-Seeking were higher in the BD group compared to the controls (p<0.001 in both cases). The higher scores in the BD group in Neuroticism-Anxiety are due to higher scores in the women's group (p=0.014), while those in Impulsive Sensation-Seeking are due to higher scores in the men's group (p=0.009), both in the Impulsivity and in the Sensation-Seeking subscales (p<0.045).	Sex could be a factor that modulates the endophenotype of drug dependence (impulsive and anxious personality) and the prevention and/or treatment programs for BD should include not only the management of the personality risk factors but also different tailored approaches according to sex.	
27262794	The aim of the study was to determine whether epicardial adipose tissue volume (EATV), a new cardiometabolic risk factor, is associated with circadian changes of blood pressure (BP) in patients with newly diagnosed essential hypertension. Ninety patients with newly diagnosed essential hypertension underwent ambulatory blood pressure monitoring for 24 h. EATV was measured using cardiac computed tomography. These patients were categorized into three groups according to their BP patterns (group 1, n=46, dipper hypertension, also called normal pattern; group 2, n=24, non-dipper hypertension; group 3, n=20, anti-dipper hypertension; group 2 and 3 are also called abnormal pattern). Data were collected retrospectively and compared between hypertensive patients with normal pattern and abnormal pattern. The normal pattern hypertensive patient had significant lower mean EATV and BP ((EATV, 91.3±29.4 cm3) than those of abnormal pattern patients including group 2 (EATV, 116.2±31.06cm3, <0.01) and group 3 (EATV, 124.8±28.5cm3, P<0.01). Mean systolic BP over 24 h (BPs24) and mean diastolic BP over 24 h (BPd24) of group 1 (BPs24, 135.7 ± 12.6 mmHg; BPd24, 83.6 ± 10.6 mmHg) were significantly lower than those of group 2 (BPs24, 150.1± 17.6 mmHg, P<0.01; BPd24, 93.2 ± 16.5 mmHg, P<0.01) and group 3 (BPs24, 154.1 ± 16.6mmHg, P<0.01; BPd24, 93.8 ± 17.5 mmHg; P<0.01). Bivariate correlation analysis showed that correlation coefficient of EATV with abnormal blood pressure mode was 0.500 (p<0.001), partial correlation coefficient after adjustment for waist circumference and body mass index was 0.469 (p<0.001). When multivariate backward logistic regression analysis was performed to assess the correlation of BP pattern with EAT volume, it showed that the prevalence of abnormal BP pattern (non-dipper and anti-dipper BP pattern) increased by 1.54 times after adjusting for age and gender per additional 10 cm3 of EAT volume. Receiver operating characteristic curve for EAT alone indicated that the cutoff value of 95.17cm3 had the best performance in predicting abnormal BP pattern with a sensitivity of 75.0% and a specificity of 72.7%. EATV was elevated in newly diagnosed and untreated patients with non-dipper hypertension and anti-dipper hypertension. EATV measured by cardiac computed tomography can be used to indicate the increased risk of circadian rhythm of blood pressure. 
27261939	To assess diurnal changes in the signs and symptoms of dry eyes and their relationship to diurnal interblink interval (IBI) in normal subjects and in subjects with dry eye.Blink data were collected from 9:00 AM to 8:00 PM during 2 days of normal activity using an electrocardiogram monitoring device. All subjects recorded ocular discomfort (0-5 scale) and primary activity hourly each day in a diary. Inferior and central fluorescein staining was graded by slit lamp (0-4) at the start and end of each day. Blink activity was detected using an algorithm based on recognition of the waveform corresponding to the kinematic properties of the blink signal.	Normal subjects (N = 12) reported negligible symptoms, and results did not show a diurnal change in group hourly IBI. Mean daily IBI for the group with dry eye (N = 15) (4.63 ± 1.63 s) was shorter than that for the normal group (5.28 ± 1.48 s) (P = 0.0483). Correlation of diurnal symptoms and mean hourly IBI was relatively weak (r = -0.248). A repeated-measures model found IBI to be significantly associated with the time of day (P = 0.0028). Inferior corneal staining showed a small but significant diurnal increase for both normal group and group with dry eyes.	Diurnal blink tracking reveals significant trending with symptoms. Diurnal change in IBI may be an appropriate surrogate for symptoms in the study of dry eye.	
27261553	Biological rhythms in infants are described as evolving from an ultradian to a circadian pattern along the first months of life. Recently, the use of actigraphy and thermistors with memory has contributed to the understanding of temporal relations of different variables along development. The aim of this study was to describe and compare the development of the rhythmic pattern of wrist temperature, activity/rest cycle, sleep/wake and feeding behavior in term and preterm newborns maintained in a neonatal intensive care unit (NICU).Nineteen healthy preterm and seven fullterm newborns had the following variables monitored continuously while they were in the NICU: activity recorded by actigraphy, wrist temperature recorded with a thermistor and observed sleep and feeding behavior recorded by the NICU staff with diaries. Subjects were divided in 3 groups according to their gestational age at birth and rhythmic parameters were compared.	A dominant daily rhythm was observed for wrist temperature since the first two weeks of life and no age relation was demonstrated. Otherwise, a daily pattern in activity/rest cycle was observed for most preterm newborns since 35 weeks of postconceptional age and was more robust in term babies. Feeding and sleep/wake data showed an almost exclusive 3h rhythm, probably related to a masking effect of feeding schedules.	We found that wrist temperature develops a daily pattern as soon as previously reported for rectal temperature, and with acrophase profile similar to adults. Moreover, we were able to find a daily rhythm in activity/rest cycle earlier than previously reported in literature. We also suggest that sleep/wake rhythm and feeding behavior follow independent developmental courses, being more suitable to masking effects.	
27261065	Calcium oxalate crystals are widespread among animals and plants. In land plants, crystals often reach high amounts, up to 80% of dry biomass. They are formed within specific cells, and their accumulation constitutes a normal activity rather than a pathological symptom, as occurs in animals. Despite their ubiquity, our knowledge on the formation and the possible role(s) of these crystals remains limited. We show that the mesophyll crystals of pigweed (Amaranthus hybridus) exhibit diurnal volume changes with a gradual decrease during daytime and a total recovery during the night. Moreover, stable carbon isotope composition indicated that crystals are of nonatmospheric origin. Stomatal closure (under drought conditions or exogenous application of abscisic acid) was accompanied by crystal decomposition and by increased activity of oxalate oxidase that converts oxalate into CO2 Similar results were also observed under drought stress in Dianthus chinensis, Pelargonium peltatum, and Portulacaria afra Moreover, in A. hybridus, despite closed stomata, the leaf metabolic profiles combined with chlorophyll fluorescence measurements indicated active photosynthetic metabolism. In combination, calcium oxalate crystals in leaves can act as a biochemical reservoir that collects nonatmospheric carbon, mainly during the night. During the day, crystal degradation provides subsidiary carbon for photosynthetic assimilation, especially under drought conditions. This new photosynthetic path, with the suggested name "alarm photosynthesis," seems to provide a number of adaptive advantages, such as water economy, limitation of carbon losses to the atmosphere, and a lower risk of photoinhibition, roles that justify its vast presence in plants.
27260966	Intensive researches on modified-release hydrocortisone compounds developed in the last decade have paved the way for obtaining near-physiological glucocorticoid replacement in the adrenal insufficient patient. The dual-release Duocort (Plenadren) allows a unique morning intake and closely mimics the circadian rhythm of cortisol secretion, except for the progressive nocturnal increase and the morning cortisol peak observed in healthy subjects. Duocort treatment during a 6-month period was associated with favorable changes in weight, blood pressure and glycemic control in patients with diabetes mellitus. Chronocort, a multiparticulate formulation with sustained-release properties replaces endogenous cortisol in a near-physiologic manner and fully restores the end of night cortisol peak. A twice-daily Chronocort regimen was effective in controlling androgen excess in adults with CAH. Recently, the new multiparticulate formulation Infacort was designed for the treatment of adrenal insufficiency during infancy. Long term effectiveness and safety studies are needed until these promising hydrocortisone formulations become routine therapeutic tools in adrenal insufficiency. 
27259817	Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder.Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death was used to test associations with circadian rhythms.	SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p = .003) and SZ (Nt, p = .02). In normal control subjects, Nt of SST-IR neurons varied according to time of death. This pattern was altered in BD subjects, characterized by decreases of SST-IR neurons selectively in subjects with time of death corresponding to the day (6:00 am to 5:59 pm). Numbers of neuropeptide Y-IR neurons were not affected.	Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.	
27259202	The physiological identity of every cell is maintained by highly specific transcriptional networks that establish a coherent molecular program that is in tune with nutritional conditions. The regulation of cell-specific transcriptional networks is accomplished by an epigenetic program via chromatin-modifying enzymes, whose activity is directly dependent on metabolites such as acetyl-coenzyme A, S-adenosylmethionine, and NAD+, among others. Therefore, these nuclear activities are directly influenced by the nutritional status of the cell. In addition to nutritional availability, this highly collaborative program between epigenetic dynamics and metabolism is further interconnected with other environmental cues provided by the day-night cycles imposed by circadian rhythms. Herein, we review molecular pathways and their metabolites associated with epigenetic adaptations modulated by histone- and DNA-modifying enzymes and their responsiveness to the environment in the context of health and disease. 
27257555	Background. Diurnal rhythms of protein synthesis controlled by the biological clock underlie the rhythmic physiology in the fruit fly, Drosophila melanogaster. In this study, we conducted a proteome-wide investigation of rhythmic protein accumulation in D. melanogaster. Materials and Methods. Total protein collected from fly samples harvested at 4 h intervals over the 24 h period were subjected to two-dimensional gel electrophoresis, trypsin digestion and MS/MS analysis. Protein spots/clusters were identified with MASCOT search engine and Swiss-Prot database. Expression of proteins was documented as percentage of volume contribution using the Image Master 2D Platinum software. Results. A total of 124 protein spots/clusters were identified using MS/MS analysis. Significant variation in the expression of 88 proteins over the 24-h period was observed. A relatively higher number of proteins was upregulated during the night compared to the daytime. The complexity of temporal regulation of the D. melanogaster proteome was further reflected from functional annotations of the differently expressed proteins, with those that were upregulated at night being restricted to the heat shock proteins and proteins involved in metabolism, muscle activity, protein synthesis/folding/degradation and apoptosis, whilst those that were overexpressed in the daytime were apparently involved in metabolism, muscle activity, ion-channel/cellular transport, protein synthesis/folding/degradation, redox homeostasis, development and transcription. Conclusion. Our data suggests that a wide range of proteins synthesized by the fruit fly, D. melanogaster, is under the regulation of the biological clock. 
27257077	Although RNA-Seq data provide unprecedented isoform-level expression information, detection of alternative isoform regulation (AIR) remains difficult, particularly when working with an incomplete transcript annotation. We introduce JunctionSeq, a new method that builds on the statistical techniques used by the well-established DEXSeq package to detect differential usage of both exonic regions and splice junctions. In particular, JunctionSeq is capable of detecting differential usage of novel splice junctions without the need for an additional isoform assembly step, greatly improving performance when the available transcript annotation is flawed or incomplete. JunctionSeq also provides a powerful and streamlined visualization toolset that allows bioinformaticians to quickly and intuitively interpret their results. We tested our method on publicly available data from several experiments performed on the rat pineal gland and Toxoplasma gondii, successfully detecting known and previously validated AIR genes in 19 out of 19 gene-level hypothesis tests. Due to its ability to query novel splice sites, JunctionSeq is still able to detect these differences even when all alternative isoforms for these genes were not included in the transcript annotation. JunctionSeq thus provides a powerful method for detecting alternative isoform regulation even with low-quality annotations. An implementation of JunctionSeq is available as an R/Bioconductor package. 
27256623	In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P < 0.00001). Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. 
27256384	The circadian oscillator is based on transcription-translation feedback loops that generate 24 h oscillations in gene expression. Although circadian regulation of mRNA expression at the transcriptional level is one of the most important steps for the generation of circadian rhythms within the cell, multiple lines of evidence point to a disconnect between transcript oscillation and protein oscillation. This can be explained by regulatory RNA-binding proteins acting on the nascent transcripts to modulate their processing, export, translation and degradation rates. In this chapter we will review what is known about the different steps involved in circadian gene expression from transcription initiation to mRNA stability and translation efficiency. The role of ribonucleoprotein particles in the generation of rhythmic gene expression is only starting to be elucidated, but it is likely that they cooperate with the basal transcriptional machinery to help to maintain the precision of the clock under diverse cellular and environmental conditions. 
27255838	Petunia hybrida is a popular bedding plant that has a long history as a genetic model system. We report the whole-genome sequencing and assembly of inbred derivatives of its two wild parents, P. axillaris N and P. inflata S6. The assemblies include 91.3% and 90.2% coverage of their diploid genomes (1.4 Gb; 2n = 14) containing 32,928 and 36,697 protein-coding genes, respectively. The genomes reveal that the Petunia lineage has experienced at least two rounds of hexaploidization: the older gamma event, which is shared with most Eudicots, and a more recent Solanaceae event that is shared with tomato and other solanaceous species. Transcription factors involved in the shift from bee to moth pollination reside in particularly dynamic regions of the genome, which may have been key to the remarkable diversity of floral colour patterns and pollination systems. The high-quality genome sequences will enhance the value of Petunia as a model system for research on unique biological phenomena such as small RNAs, symbiosis, self-incompatibility and circadian rhythms. 
27254968	This qualitative study describes the temporal patterns of fatigue found as part of a larger study designed to elicit a description of the experience and self-management of fatigue for patients on hemodialysis. Two patterns of fatigue were identified. The first pattern, continuous fatigue, was characterized by participants who experienced fatigue at all times, which was their normal, baseline feeling. Within this group, two subgroups were identified. The second pattern of fatigue, post-dialysis fatigue only, was characterized by participants who experienced fatigue only after their hemodialysis session. This study is unique because it expands our knowledge about hemodialysis and fatigue by describing the patterns that fatigue follows over time from one hemodialysis session to the next. Insight into these phenomena could help ameliorate fatigue and allow nurses to tailor interventions for patients on hemodialysis.
27254002	Circadian clock desynchronization has been implicated in the pathophysiology of cardiovascular disease and related risk factors (eg, obesity, diabetes). Thus, we examined the extent to which circadian desynchronization exacerbates ischemic stroke outcomes and whether its detrimental effects on stroke severity and functional impairments are further modified by biological sex. Circadian entrainment of activity rhythms in all male and female rats was observed during exposure to a fixed light-dark (LD) 12:12 cycle but was severely disrupted when this LD cycle was routinely shifted (12 h advance/5 d) for approximately 7 weeks. In contrast to the regular estrous cycles in fixed LD animals, cyclicity was abolished and persistent estrus was evident in all shifted LD females. The disruption of estrous cyclicity in shifted LD females was associated with a significant increase in serum estradiol levels relative to that observed in fixed LD controls. Circadian rhythm disruption exacerbated stroke outcomes in both shifted LD male and female rats and further amplified sex differences in stroke impairments. In males, but not females, circadian disruption after exposure to the shifted LD cycle was marked by high rates of mortality. In surviving females, circadian desynchronization after exposure to shifted LD cycles produced significant increases in stroke-induced infarct volume and sensorimotor deficits with corresponding decreases in serum IGF-1 levels. These results suggest that circadian rhythm disruption associated with shift work schedules or the irregular nature of our everyday work and/or social environments may interact with other nonmodifiable risk factors such as biological sex to modulate the pathological effects of stroke. 
27253997	The critical regulation of the peripheral circadian gene implicated in osteoarthritis (OA) has been recently recognized; however, the causative role and clinical potential of the peripheral circadian rhythm attributable to such effects remain elusive. The purpose of this study was to elucidate the role of a circadian gene Bmal1 in human cartilage and pathophysiology of osteoarthritis. In our present study, the mRNA and protein levels of circadian rhythm genes, including nicotinamide adenine dinucleotide oxidase (NAD(+)) and sirtuin 1 (Sirt1), in human knee articular cartilage were determined. In OA cartilage, the levels of both Bmal1 and NAD(+) decreased significantly, which resulted in the inhibition of nicotinamide phosphoribosyltransferase activity and Sirt1 expression. Furthermore, the knockdown of Bmal1 was sufficient to decrease the level of NAD(+) and aggravate OA-like gene expression changes under the stimulation of IL-1β. The overexpression of Bmal1 relieved the alteration induced by IL-1β, which was consistent with the effect of the inhibition of Rev-Erbα (known as NR1D1, nuclear receptor subfamily 1, group D). On the other hand, the transfection of Sirt1 small interfering RNA not only resulted in a reduction of the protein expression of Bmal1 and a moderate increase of period 2 (per2) and Rev-Erbα but also further exacerbated the survival of cells and the expression of cartilage matrix-degrading enzymes induced by IL-1β. Overexpression of Sirt1 restored the metabolic imbalance of chondrocytes caused by IL-1β. These observations suggest that Bmal1 is a key clock gene to involve in cartilage homeostasis mediated through sirt1 and that manipulating circadian rhythm gene expression implicates an innovative strategy to develop novel therapeutic agents against cartilage diseases. 
27253676	On trips with multiple transmeridian flights, pilots experience successive non-24 h day/night cycles with circadian and sleep disruption. One study across a 9-day sequence of transpacific flights (no in-flight sleep, 1-day layovers between flights) reported an average period in the core body temperature rhythm of 24.6 h (circadian drift). Consequently, pilots were sometimes flying through the circadian performance nadir and had to readapt to home base time at the end of the trip. The present study examined circadian drift in trip patterns with longer flights and in-flight sleep. Thirty-nine B747-400 pilots (19 captains, 20 first officers, mean age = 55.5 years) were monitored on 9- to 13-day trips with multiple return flights between East Coast USA and Japan (in 4-pilot crews) and between Japan and Hawaii (in 3-pilot crews), with 1-day layovers between each flight. Measures included total in-flight sleep (actigraphy, log books) and top of descent (TOD) measures of sleepiness (Karolinska Sleepiness Scale), fatigue (Samn-Perelli Crew Status Check) and psychomotor vigilance task (PVT) performance. Circadian rhythms of individual pilots were not monitored. To detect circadian drift, mixed-model analysis of variance examined whether for a given flight, total in-flight sleep and TOD measures varied according to when the flight occurred in the trip sequence. In addition, sleep propensity curves for pre-trip and post-trip days were examined (Chi-square periodogram analyses). Limited data suggest that total in-flight sleep of relief crew at landing may have decreased across successive East Coast USA-Japan (flights 1, 3, 5 or 7; median arrival 03:45 Eastern Daylight Time (EDT)). However, PVT response speed at TOD was faster on East Coast USA-Japan flights later in the trip. On these flights, circadian drift would result in flights later in the trip landing closer to the evening wake maintenance zone, when sleep is difficult and PVT response speeds are fastest. On Japan-East Coast USA flights (flights 2, 4, 6 or 8; median arrival time 14:52 EDT), PVT response speeds were slower on flight 8 than on flight 2. Circadian drift would move these arrivals progressively earlier in the SCN pacemaker cycle, where PVT response speeds are slower. Across the five post-trip days, 12 pilots (Group A) immediately resumed their pre-trip sleep pattern of a single nocturnal sleep episode; 9 pilots (Group B) had a daytime nap on most days that moved progressively earlier until it merged with nocturnal sleep and 17 pilots (Group C) had nocturnal sleep and intermittent naps. Chi-square periodogram analyses of the sleep propensity curves for each group across baseline and post-trip days suggest full adaptation to EDT from post-trip day 1 (dominant period = 24 h). However, in Groups B and C, the patterns of split sleep post-trip compared to pre-trip suggest that this may be misleading. We conclude that the trends in total in-flight sleep and significant changes in PVT performance speed at TOD provide preliminary evidence for circadian drift, as do persistent patterns of split sleep post-trip. However, new measures to track circadian rhythms in individual pilots are needed to confirm these findings. 
27253213	The aims of this observational study of patients with euthymic bipolar disorder and sleep disturbance were to 1) compare characteristics related to mood and sleep between two groups with stable and unstable rest-activity cycles and 2) detect between-group differences in motor activity patterns.43 patients wore an actigraph for 6-8 days while reporting daily mood and sleep. Patients were defined as having an unstable rest-activity cycle if their diurnal active period duration presented variation above 2h from the mean during one week: 22 patients had stable and 21 unstable rest-activity cycles. Mood variability was defined as at least moderate symptoms and a change across two levels on a 7-point mood scale during one week.	Patients with unstable rest-activity cycles were younger (37 vs. 48 years, p=0.01) and displayed more mood variability (p=0.02). Ten of 11 patients diagnosed with delayed sleep phase disorder were in the unstable group (p<0.01), and the unstable group had later and more variable get-up-times and bedtimes. In actigraphy recordings, the mean activity counts per minute did not differ between groups, but the minute-to-minute variability was elevated (p=0.04) and increased relative to the overall variability (p=0.03).	A relatively small study sample and a 1-week study period prevent exploration of long-term clinical implications of results.	A subgroup of euthymic patients with bipolar disorder displayed unstable rest-activity cycles combined with mood variability and motor activity patterns that resemble findings in affective episodes.	
27252858	A functional lesion in corticotrophin (ACTH)-independent Cushing's syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and (131)I-6β-iodomethyl-19-norcholesterol ((131)I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and (131)I-NP-59 scintigraphy are good diagnostic methods for Cushing's syndrome presenting with bilateral adrenal masses.The clinical presentation of Cushing' syndrome includes symptoms and signs of fat redistribution and protein-wasting features.The diagnosis of patients with ACTH-independent Cushing's syndrome with bilateral adrenal masses is challenging for localisation of the lesion.Both adrenal venous sampling and (131)I-NP-59 scintigraphy are good methods to use in these patients with Cushing's syndrome presenting with bilateral adrenal masses.	
27252486	Sleep disturbances and alterations of diurnal endocrine rhythms are associated with increased risk of type 2 diabetes (T2D). We previously showed that young men born small for gestational age (SGA) and with increased risk of T2D have elevated fat and decreased glucose oxidation rates during nighttime. In this study, we investigated whether SGA men have an altered diurnal profile of hormones, substrates and inflammatory markers implicated in T2D pathophysiology compared with matched individuals born appropriate for gestational age (AGA).We collected hourly blood samples for 24 h, to measure levels of glucose, free fatty acids (FFA), triglycerides (TG), insulin, C-peptide, leptin, resistin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), incretins (GLP-1 and GIP), and inflammatory markers (TNF-α and IL-6) in 13 young men born SGA and 11 young men born AGA.	Repeated measurements analyses were used to analyze the diurnal variations and differences between groups. The SGA subjects had increased 24-h glucose (P=0.03), glucagon (P=0.03) and resistin (P=0.003) levels with no difference in diurnal rhythms compared with AGA controls. We found significant diurnal variations in levels of blood glucose, plasma TG, FFA, insulin, C-peptide, GLP-1, GIP, leptin, visfatin, TNF-α, IL-6 and PAI-1. The variation in FFA levels differed between the groups during the evening. Plasma ghrelin and glucagon levels did not display diurnal variations.	Young men born SGA exhibit elevated 24-h blood glucose, and plasma glucagon and resistin levels with no major differences in diurnal rhythms of these or other key metabolic hormones, substrates or inflammatory markers implicated in the origin of adiposity and T2D.	
27252218	In many species of phytoplankton, simple photoreceptors monitor ambient lighting. Photoreceptors provide a number of selective advantages including the ability to assess the time of day for circadian rhythms, seasonal changes, and the detection of excessive light intensities and harmful UV light. Photoreceptors also serve as depth gauges in the water column for behaviors such as diurnal vertical migration. Photoreceptors can be organized together with screening pigment into visible eyespots. In a wide variety of motile phytoplankton, including Chlamydomonas, Volvox, Euglena, and Kryptoperidinium, eyespots are light-sensitive organelles residing within the cell. Eyespots are composed of photoreceptor proteins and typically red to orange carotenoid screening pigments. This association of photosensory pigment with screening pigment allows for detection of light directionality, needed for light-guided behaviors such as positive and negative phototaxis. In Chlamydomonas, the eyespot is located in the chloroplast and Chlamydomonas expresses a number of photosensory pigments including the microbial channelrhodopsins (ChR1 and ChR2). Dinoflagellates are unicellular protists that are ecologically important constituents of the phytoplankton. They display a great deal of diversity in morphology, nutritional modes and symbioses, and can be photosynthetic or heterotrophic, feeding on smaller phytoplankton. Dinoflagellates, such as Kryptoperidinium foliaceum, have eyespots that are used for light-mediated tasks including phototaxis. Dinoflagellates belonging to the family Warnowiaceae have a more elaborate eye. Their eye-organelle, called an ocelloid, is a large, elaborate structure consisting of a focusing lens, highly ordered retinal membranes, and a shield of dark pigment. This complex eye-organelle is similar to multicellular camera eyes, such as our own. Unraveling the molecular makeup, structure and function of dinoflagellate eyes, as well as light-guided behaviors in phytoplankton can inform us about the selective forces that drove evolution in the important steps from light detection to vision. We show here that the evolution from simple photoreception to vision seems to have independently followed identical paths and principles in phytoplankton and animals, significantly strengthening our understanding of this important biological process.
27252212	Daily rhythms for hormonal traits are likely widespread and important aspects of organismal (e.g., life history) adaptation. Yet they remain substantially understudied, especially with respect to variable rhythms within species. The cricket, Gryllus firmus, exhibits a genetically polymorphic circadian rhythm for the blood titer of the key hormone, juvenile hormone (JH). Gryllus firmus is also wing-polymorphic, consisting of a dispersing morph that delays reproduction and a flightless morph with substantially enhanced egg production. JH circadian phenotype strongly covaries with morph type: The blood JH titer is strongly rhythmic in multiple populations artificially-selected for the dispersing morph (LW(f) = long wings with functional flight muscles) and is essentially arrhythmic in populations selected for the SW (short-winged) morph. Association between JH titer cycle and LW(f) morph is also found in natural populations of G. firmus and in several related species in the field. This is one of the very few studies of endocrine titer variation in natural populations of an insect. The morph-specific cycle is underlain by a circadian rhythm in hormone biosynthesis, which in turn is underlain by a rhythm in a brain neuropeptide regulator of JH biosynthesis. The morph-specific JH titer circadian cycle is also strongly correlated with a morph-specific daily rhythm in global gene expression. This is currently the only example of a genetically-variable hormone circadian rhythm in both the laboratory and field that is strongly associated with an ecologically important polymorphism. The extensive information on the underlying causes of the morph-specific JH titer rhythm, coupled with the strong association between the JH circadian rhythm and wing polymorphism makes this system in G. firmus an exceptional experimental model to investigate the mechanisms underlying circadian hormonal adaptations. Genetic polymorphism for the JH titer circadian rhythm in G. firmus is discussed in context of circadian rhythms for endocrine traits reported for vertebrates and insects. Consequences of the failure to identify endocrine circadian rhythms on the accuracy of estimation of quantitative-genetic parameters, such as heritability and correlations between hormonal and fitness-related traits, are also discussed. 
27252076	Sleep disorders are associated with an increased risk of cancer, including breast cancer (BC). Physical activity (PA) can produce beneficial effects on sleep.We designed a randomized controlled trial to test the effect of 3 months of physical activity on sleep and circadian rhythm activity level evaluated by actigraphy.	40 BC women, aged 35-70 years, were randomized into an intervention (IG) and a control group (CG). IG performed a 3 month of aerobic exercise. At baseline and after 3 months, the following parameters were evaluated both for IG and CG: anthropometric and body composition measurements, energy expenditure and motion level; sleep parameters (Actual Sleep Time-AST, Actual Wake Time-AWT, Sleep Efficiency-SE, Sleep Latency-SL, Mean Activity Score-MAS, Movement and Fragmentation Index-MFI and Immobility Time-IT) and activity level circadian rhythm using the Actigraph Actiwatch.	The CG showed a deterioration of sleep, whereas the IG showed a stable pattern. In the CG the SE, AST and IT decreased and the AWT, SL, MAS and MFI increased. In the IG, the SE, IT, AWT, SL, and MAS showed no changes and AST and MFI showed a less pronounced change in the IG than in the CG. The rhythmometric analysis revealed a significant circadian rhythm in two groups. After 3 months of PA, IG showed reduced fat mass %, while CG had improved weight and BMI.	Physical activity may be beneficial against sleep disruption. Indeed, PA prevented sleep worsening in IG. PA can represent an integrative intervention therapy able to modify sleep behaviour.	
27250813	For centuries the scope of sleep disorders in medical writings was limited to those disturbances which were either perceived by the sleeper him- or herself as troublesome, such as insomnia, or which were recognized by an observer as strange behavioral acts during sleep, such as sleepwalking or sleep terrors. Awareness of other sleep disorders, which are caused by malfunction of a physiological system during sleep, such as sleep-related respiratory disorders, were widely unknown or ignored before sleep monitoring techniques became available, mainly in the second half of the 20(th) century. Finally, circadian sleep-wake disorders were recognized as a group of disturbances by its own only when chronobiology and sleep research began to interact extensively in the last two decades of the 20(th) century. Sleep medicine as a medical specialty with its own diagnostic procedures and therapeutic strategies could be established only when key findings in neurophysiology and basic sleep research allowed a breakthrough in the understanding of the sleeping brain, mainly since the second half of the last century.
27249952	In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure. 
27247803	It is well established that local field potentials (LFP) in the rodent olfactory bulb (OB) follow respiration. This respiration-related rhythm (RR) in OB depends on nasal air flow, indicating that it is conveyed by sensory inputs from the nasal epithelium. Recently RR was found outside the olfactory system, suggesting that it plays a role in organizing distributed network activity. It is therefore important to measure RR and to delineate it from endogenous electrical rhythms like theta which cover similar frequency bands in small rodents. In order to validate such measurements in freely behaving mice, we compared rhythmic LFP in the OB with two respiration-related biophysical parameters: whole-body plethysmography (PG) and nasal temperature (thermocouple; TC). During waking, all three signals reflected respiration with similar reliability. Peak power of RR in OB decreased with increasing respiration rate whereas power of PG increased. During NREM sleep, respiration-related TC signals disappeared and large amplitude slow waves frequently concealed RR in OB. In this situation, PG provided a reliable signal while breathing-related rhythms in TC and OB returned only during microarousals. In summary, local field potentials in the olfactory bulb do reliably reflect respiratory rhythm during wakefulness and REM sleep but not during NREM sleep. 
27247614	Objective. The aim of this study is to define the normal range for average real variability (ARV) and to establish whether it can be considered as an additional cardiovascular risk factor. Methods. In this observational study, 110 treated hypertensive patients were included and admitted for antihypertensive treatment adjustment. Circadian blood pressure was recorded with validated devices. Blood pressure variability (BPV) was assessed according to the ARV definition. Based on their variability, patients were classified into low, medium, and high variability groups using the fuzzy c-means algorithm. To assess cardiovascular risk, blood samples were collected. Characteristics of the groups were compared by ANOVA tests. Results. Low variability was defined as ARV below 9.8 mmHg (32 patients), medium as 9.8-12.8 mmHg (48 patients), and high variability above 12.8 mmHg (30 patients). Mean systolic blood pressure was 131.2 ± 16.7, 135.0 ± 12.1, and 141.5 ± 11.4 mmHg in the low, medium, and high variability groups, respectively (p = 0.0113). Glomerular filtration rate was 78.6 ± 29.3, 74.8 ± 26.4, and 62.7 ± 23.2 mL/min/1.73 m(2) in the low, medium, and high variability groups, respectively (p = 0.0261). Conclusion. Increased values of average real variability represent an additional cardiovascular risk factor. Therefore, reducing BP variability might be as important as achieving optimal BP levels, but there is need for further studies to define a widely acceptable threshold value. 
27247408	Absolute values of protein expression levels in cells are crucial information for understanding cellular biological systems. Precise quantification of proteins can be achieved by liquid chromatography (LC)-mass spectrometry (MS) analysis of enzymatic digests of proteins in the presence of isotope-labeled internal standards. Thus, development of a simple and easy way for the preparation of internal standards is advantageous for the analyses of multiple target proteins, which will allow systems-level studies. Here we describe a method, termed MS-based Quantification By isotope-labeled Cell-free products (MS-QBiC), which provides the simple and high-throughput preparation of internal standards by using a reconstituted cell-free protein synthesis system, and thereby facilitates both multiplexed and sensitive quantification of absolute amounts of target proteins. This method was applied to a systems-level dynamic analysis of mammalian circadian clock proteins, which consist of transcription factors and protein kinases that govern central and peripheral circadian clocks in mammals. Sixteen proteins from 20 selected circadian clock proteins were successfully quantified from mouse liver over a 24-h time series, and 14 proteins had circadian variations. Quantified values were applied to detect internal body time using a previously developed molecular timetable method. The analyses showed that single time-point data from wild-type mice can predict the endogenous state of the circadian clock, whereas data from clock mutant mice are not applicable because of the disappearance of circadian variation.
27246400	Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus, sculpturing time-of-day-dependent memory formation. This molecular mechanism constitutes the functional link between circadian rhythms and learning efficiency. In hippocampal neurons of wild-type mice, pP90RSK translocates into the nucleus upon stimulation with forskolin (left), whereas in Period1-knockout (Per1(-/-) ) mice (right) the kinase is trapped at the nuclear periphery, unable to efficiently phosphorylate nuclear CREB. Consequently, the presence of PER1 in hippocampal neurons is a prerequisite for the time-of-day-dependent phosphorylation of CREB, as it regulates the shuttling of pP90RSK into the nucleus. Representative immunofluorescence images show a temporal difference in phosphorylated cAMP response element-binding protein (pCREB; green color) levels in all regions of the dorsal hippocampus between a wild-type C3H mouse (WT; left) and a Period1-knockout (Per1(-/-) ; right) mouse. Images were taken 2 h after lights on, thus, when fluctuating levels of pCREB peak in WT mouse hippocampus. Insets show a representative hippocampal neuron, in response to activating cAMP signaling, stained for the neuronal marker NeuN (red), the nuclear marker DAPI (blue) and the activated CREB kinase pP90RSK (green). The image was taken 2 h after light onset (at the peak of the endogenous CREB phosphorylation that fluctuates with time of day). Magnification: 100X, inset 400X. Read the Editorial Highlight for this article on page 650. Cover image for this issue: doi: 10.1111/jnc.13332. 
27246334	Application of bioluminescence resonance energy transfer (BRET) assay has been of special value in measuring dynamic events such as protein-protein interactions (PPIs) in vitro or in vivo. It was only in the late 1990s the BRET assay using RLuc-YFP was introduced for biological research showing its use in determining interaction of two proteins involved in circadian rhythm. Several inherent attributes such as rapid and fairly sensitive ratiometric measurements, assessment of PPI irrespective of protein location in cellular compartment, and cost-effectiveness consenting to high-throughput assay development make BRET a popular genetic reporter-based assay for PPI studies. In BRET-based screening, within a defined proximity range of 10-100 Å, excited state energy of the luminescence molecule can excite the acceptor fluorophore in the form of resonance energy transfer, causing it to emit at its characteristic emission wavelength. Based on this principle, several such donor-acceptor pairs, using the Renilla luciferase or its mutants as donor and either GFP2, YFP, mOrange, TagRFP, or TurboFP as acceptor, have been reported for use.In recent years, BRET-related research has become significantly versatile in the assay format and its applicability by adopting the assay on multiple detection devices such as small-animal optical imaging platform or bioluminescence microscope. Beyond the scope of quantitative measurement of PPIs and protein dimerization, molecular optical imaging applications based on BRET assays have broadened its scope for screening of pharmacological compounds by unifying in vitro, live cell, and in vivo animal/plant measurement all on one platform. Taking examples from the literature, this chapter contributes to in-depth methodological details on how to perform in vitro and in vivo BRET experiments, and illustrates its advantages as a single-format assay. 
27246263	Cryptochromes are flavin- and pterin-containing photoreceptors of the cryptochrome/photolyase family. They play critical roles in organisms, among are which light-dependent and light-independent roles in biological rhythms. The present work aimed at describing a cryptochrome gene in the oyster Crassostrea gigas by (i) a characterization and phylogenetic analysis and (ii) by studying its expression in the relationship to rhythmic valve behavior in different entrainment regimes. Cryptochrome expression was focused on the adductor muscle of the oyster, the effector of the valve behavior. The results suggest involvement of Cgcry1 in oyster rhythmicity as a sensor of environmental zeitgebers, associated with circadian rhythms and potentially to tidal activity. The characterized gene belongs to type 1 cryptochrome/insect-type cry. Additionally, Cgcry1 presented a daily oscillation under L:D entrainment, which disappeared in constant darkness. Transcript expression of Cgcry1 also oscillated at tidal frequency under tidal entrainment and in constant darkness. Finally, exposure of tidally entrained oysters to saxitoxin (STX)-producing alga Alexandrium minutum induced a dose effect response in oysters by first altering Cgcry1 expression and then the behavior of oysters with increasing concentrations of toxins. This study initiates the characterization of the molecular clock in the oyster C. gigas and its interactions with environmental zeitgebers. 
27242972	Most of the biological functions, including the immune system, are linked to circadian rhythms in living organisms. Changes occurring to biological parameters as the result of these circadian rhythms can therefore affect the outcome of a disease. For decades, model organisms have proven to be a great tool to understanding biological mechanisms such as circadian cycle and immunity. In this review, we created an inventory of the use of model organisms in order to decipher the relation between circadian rhythms and antibacterial immunity. 
27242875	As a well-known animal hormone, melatonin (N-acetyl-5-methoxytryptamine) is also involved in multiple plant biological processes, especially in various stress responses. Rice is one of the most important crops, and melatonin is taken in by many people everyday from rice. However, the transcriptional profiling of melatonin-related genes in rice is largely unknown. In this study, the expression patterns of 11 melatonin related genes in rice in different periods, tissues, in response to different treatments were synthetically analyzed using published microarray data. These results suggest that the melatonin-related genes may play important and dual roles in rice developmental stages. We highlight the commonly regulation of rice melatonin-related genes by abscisic acid (ABA), jasmonic acid (JA), various abiotic stresses and pathogen infection, indicating the possible role of these genes in multiple stress responses and underlying crosstalks of plant hormones, especially ABA and JA. Taken together, this study may provide insight into the association among melatonin biosynthesis and catabolic pathway, plant development and stress responses in rice. The profile analysis identified candidate genes for further functional characterization in circadian rhythm and specific stress responses. 
27242805	Poorly grown plants that result from differences in individuals lead to large profit losses for plant factories that use large electric power sources for cultivation. Thus, identifying and culling the low-grade plants at an early stage, using so-called seedlings diagnosis technology, plays an important role in avoiding large losses in plant factories. In this study, we developed a high-throughput diagnosis system using the measurement of chlorophyll fluorescence (CF) in a commercial large-scale plant factory, which produces about 5000 lettuce plants every day. At an early stage (6 days after sowing), a CF image of 7200 seedlings was captured every 4 h on the final greening day by a high-sensitivity CCD camera and an automatic transferring machine, and biological indices were extracted. Using machine learning, plant growth can be predicted with a high degree of accuracy based on biological indices including leaf size, amount of CF, and circadian rhythms in CF. Growth prediction was improved by addition of temporal information on CF. The present data also provide new insights into the relationships between growth and temporal information regulated by the inherent biological clock. 

27242664	Aldosterone is a homeostatic hormone, rising in volume depletion, sodium deficiency, and potassium loading, in response to angiotensin11 and elevation of plasma potassium. Pathophysiologically, in primary aldosteronism (PA) aldosterone levels are inappropriate for the patient's sodium and potassium status, and thus outside the normal feedback loop. ACTH is equivalent with A11 and [K(+)] in elevating aldosterone: its effects differ from those of the other secretagogues in four ways. First, it is not sustained; second, it raises aldosterone and cortisol secretion with equal potency; third, it is outside the normal feedback loops, reflecting the epithelial action of aldosterone; and finally its possible role in driving inappropriate aldosterone secretion (aka PA) is not widely recognized. Thirty years ago, it was shown that on a fixed sodium intake of 175 meq/day 36 of 100 unselected hypertensives, in whom PA has been excluded on contemporary criteria, had 24 h urinary aldosterone levels above the upper limit of normotensive controls. More recently, the dexamethasone enhanced fludrocortisone suppression test (FDST) showed 29% of unselected hypertensives to have plasma aldosterone concentrations above the upper limit of normotensive controls. In subjects negative for PA on the FDST, 27% were extremely hyper-responsive to ultra-low dose ACTH infusion; the remaining 73% showed minimal aldosterone elevation, as did normotensive controls: all three groups had negligible cortisol responses. On treadmill testing, no differences were found between groups in (minimally altered) ACTH and cortisol levels: hyper-responders to ultra-low ACTH, however, showed a major elevation in PAC. The implications of these studies, when validated, are substantial for PA, in that approximately half of hypertensive patients appear to show inappropriate aldosterone levels for their sodium status. The physiological role(s) of ACTH as an acute aldosterone secretagogue, and the mechanisms whereby its continuous secretion is curtailed, remain to be established. 
27242548	One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations-similar fluctuation structure at different time scales-that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)-a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)-the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day-night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light-entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity. 
27242171	Mood disorders are characterized by disabling symptoms and cognitive difficulties which may vary in intensity throughout the course of the illness. Sleep-wake cycles and circadian rhythms influence emotional regulation and cognitive functions. However, the relationships between the sleep-wake disturbances experienced commonly by people with mood disorders and the longitudinal changes in their clinical and cognitive profile are not well characterized. This study investigated associations between initial sleep-wake patterns and longitudinal changes in mood symptoms and cognitive functions in 50 young people (aged 13-33 years) with depression or bipolar disorder. Data were based on actigraphy monitoring conducted over approximately 2 weeks and clinical and neuropsychological assessment. As part of a longitudinal cohort study, these assessments were repeated after a mean follow-up interval of 18.9 months. No significant differences in longitudinal clinical changes were found between the participants with depression and those with bipolar disorder. Lower sleep efficiency was predictive of longitudinal worsening in manic symptoms (P = 0.007). Shorter total sleep time (P = 0.043) and poorer circadian rhythmicity (P = 0.045) were predictive of worsening in verbal memory. These findings suggest that some sleep-wake and circadian disturbances in young people with mood disorders may be associated with less favourable longitudinal outcomes, notably for subsequent manic symptoms and memory difficulties.
27241553	Circadian rhythms in the level of intracellular Mg appear to be widely conserved phylogenetically, and have the potential to impact nearly all aspects of metabolism. Moreover, the clock regulates the ion channels that generate the rhythm, demonstrating that the whole cell operates as a circadian system. 
27241550	The body circardian rhythm affects blood pressure variability at day and night, therefore blood pressure at day and night might be different. Nocturnal hypertension is defined as increase of blood pressure >120/70mmHg at night, which is caused by disturbed circadian rhythm, and associated with higher cardiovascular and cerebrovascular events also mortality in hypertensive patients. Nocturnal hypertension and declining blood pressure pattern, can only be detected by continuous examination for 24 hours, also known as ambulatory blood pressure measurement (ABPM). Chronotherapy, has become a strategy for managing the hypertensive nocturnal patients, by taking hypertensive medication at night to obtain normal blood pressure decrease in accordance with the normal circadian rhythm and, improving blood pressure control. 
27240972	Circadian clocks allow the temporal compartmentalization of biological processes. In Arabidopsis, circadian rhythms display organ specificity but the underlying molecular causes have not been identified. We investigated the mechanisms responsible for the similarities and differences between the clocks of mature shoots and roots in constant conditions and in light : dark cycles. We developed an imaging system to monitor clock gene expression in shoots and light- or dark-grown roots, modified a recent mathematical model of the Arabidopsis clock and used this to simulate our new data. We showed that the shoot and root circadian clocks have different rhythmic properties (period and amplitude) and respond differently to light quality. The root clock was entrained by direct exposure to low-intensity light, even in antiphase to the illumination of shoots. Differences between the clocks were more pronounced in conditions where light was present than in constant darkness, and persisted in the presence of sucrose. We simulated the data successfully by modifying those parameters of a clock model that are related to light inputs. We conclude that differences and similarities between the shoot and root clocks can largely be explained by organ-specific light inputs. This provides mechanistic insight into the developing field of organ-specific clocks. 
27238267	Large conductance Ca(2+)- and voltage-activated K(+) (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca(2+) concentrations. In neurons, they regulate the timing and duration of K(+) influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals. In addition, BK channels located in astrocytes and arterial myocytes modulate cerebral blood flow. Not surprisingly, both loss and gain of BK channel function have been associated with CNS disorders such as epilepsy, ataxia, mental retardation, and chronic pain. On the other hand, the neuroprotective role played by BK channels in a number of pathological situations could potentially be leveraged to correct neurological dysfunction. 
27238018	Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBα-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBα is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBα repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition. 

27237337	Ketoprofen lysinate (KL) is one of the most widely used non-steroidal anti-inflammatory drugs in the symptomatic treatment of some chronic inflammatory diseases. Compared to ketoprofen, KL shows better pharmacokinetics and tolerability. However, due to its short half-life of 1-2 h, a multiple dose regimen is required for oral administration. Thus, the present work deals with its encapsulation in a hydrogel-based system by prilling in order to prolong its activity.In this paper, we propose alginate and pectin as carriers and release tailoring agent for the development of hydrogel-based beads for KL retarded and sustained release.	Beads were produced by a Nisco Encapsulator® using alginate or pectin. Operative variables were optimized to produce beads with desired morphology and size. Solid state properties were analyzed by SEM and DSC. Drug release performance was studied by Pharmacopeia pH-change assay to simulate gastrointestinal environment.	Prilling technique was successfully used to encapsulate high soluble drugs as KL in polysaccharides-based hydrogels. Pectin proved to be a proper polymer able to encapsulate ketoprofen lysine salt. Formulation (F8) showed good morphological properties and size, high drug content (15.6%) and encapsulation efficiency (93.5%) and promising drug release profiles. Hosting F8 in an acid-resistant capsule (DR®caps) a delivery platform has been developed to control KL release in a delayed (90 min lag time) and prolonged way (270 min complete release).	The platform may be proposed as potentially useful in the oral administration of NSAIDs in chronic inflammatory diseases affected by circadian rhythm.	
27236605	The cortisol response to awakening (CAR) has been reported to be enhanced in symptomatic patients with anorexia nervosa (AN). However, it has been not established whether the dysregulation of CAR was a primary phenomenon or a change secondary to malnutrition. Therefore, we aimed to explore the salivary CAR in both underweight and weigh-restored women with AN. Fifty-nine women volunteered for the study. They were 18 underweight AN women, 15 weight-restored AN women and 26 normal-weight healthy women. Saliva samples were collected in the morning, immediately on awakening and after 15, 30 and 60min to measure saliva levels of cortisol. Participants' anxiety levels in the morning of sampling were measured by the State-Trait Anxiety Inventory. As compared to control women, underweight AN patients showed an enhanced CAR whereas weight-restored patients had a normal CAR. These results could be not explained by group differences in body mass index or levels of anxiety. These findings show, for the first time, that the enhanced CAR occurring in the acute phase of AN is not seen in weight-recovered patients, suggesting that the dysregulated activity of the hypothalamus-pituitary-adrenal axis of symptomatic AN patients is a state-dependent phenomenon. 
27236020	In the mammalian nervous system, the neural cell adhesion molecule NCAM is the major carrier of the glycan polymer polysialic acid (PSA) which confers important functions to NCAM's protein backbone. PSA attached to NCAM contributes not only to cell migration, neuritogenesis, synaptic plasticity, and behavior, but also to regulation of the circadian rhythm by yet unknown molecular mechanisms. Here, we show that a PSA-carrying transmembrane NCAM fragment enters the nucleus after stimulation of cultured neurons with surrogate NCAM ligands, a phenomenon that depends on the circadian rhythm. Enhanced nuclear import of the PSA-carrying NCAM fragment is associated with altered expression of clock-related genes, as shown by analysis of cultured neuronal cells deprived of PSA by specific enzymatic removal. In vivo, levels of nuclear PSA in different mouse brain regions depend on the circadian rhythm and clock-related gene expression in suprachiasmatic nucleus and cerebellum is affected by the presence of PSA-carrying NCAM in the cell nucleus. Our conceptually novel observations reveal that PSA attached to a transmembrane proteolytic NCAM fragment containing part of the extracellular domain enters the cell nucleus, where PSA-carrying NCAM contributes to the regulation of clock-related gene expression and of the circadian rhythm. 
27235372	Increasing evidence suggests that nocturnal transpiration rate (TRN ) is a non-negligible contributor to global water cycles. Short-term variation in nocturnal vapor pressure deficit (VPDN ) has been suggested to be a key environmental variable influencing TRN . However, the long-term effects of VPDN on plant growth and development remain unknown, despite recent evidence documenting long-term effects of daytime VPD on plant anatomy, growth and productivity. Here we hypothesized that plant anatomical and functional traits influencing leaf and root hydraulics could be influenced by long-term exposure to VPDN . A total of 23 leaf and root traits were examined on four wheat (Triticum aestivum) genotypes, which were subjected to two long-term (30 day long) growth experiments where daytime VPD and daytime/nighttime temperature regimes were kept identical, with variation only stemming from VPDN , imposed at two levels (0.4 and 1.4 kPa). The VPDN treatment did not influence phenology, leaf areas, dry weights, number of tillers or their dry weights, consistently with a drought and temperature-independent treatment. In contrast, vein densities, adaxial stomata densities, TRN and cuticular TR, were strongly increased following exposure to high VPDN . Simultaneously, whole-root system xylem sap exudation and seminal root endodermis thickness were decreased, hypothetically indicating a change in root hydraulic properties. Overall these results suggest that plants 'sense' and adapt to variations in VPDN conditions over developmental scales by optimizing both leaf and root hydraulics.
27235338	The adrenal and gonadal stress steroids [i.e., cortisol, testosterone and dehydroepiandrosterone (DHEA)] have gathered considerable attention in the last few decades due to their very broad physiological and psychological actions. Their diurnal patterns have become a particular focus following new data implicating altered diurnal hormone patterns in various endocrine, behavioral and cardiovascular risk profiles. In this review of the current literature, we present a brief overview of the altered diurnal patterns of these hormones that may occur in relation to chronic stress, nutritional behaviors, physical exercise, drugs and sleep deprivation/shift. We also present data on the altered diurnal hormone patterns implicated in cardiometabolic and psychiatric/neurologic diseases, cancer and other complex pathologies. We consider the occasionally discrepant results of the studies, and summarize the current knowledge in this new field of interest, underlining the potential effects on both biological and psychological functioning, and assess the implications of these effects. Last, we conclude with some practical considerations and perspectives. 
27234180	Melatonin, which plays an important role for regulation of circadian rhythms and the sleep/wake cycle has been linked to the pathophysiology of major depressive and bipolar disorder. Here we investigated melatonin levels in cerebrospinal fluid (CSF) and serum of depression and bipolar patients to elucidate potential differences and commonalities in melatonin alterations across the two disorders.Using enzyme-linked immunosorbent assays, CSF and serum melatonin levels were measured in 108 subjects (27 healthy volunteers, 44 depressed and 37 bipolar patients). Covariate adjusted multiple regression analysis was used to investigate group differences in melatonin levels.	In CSF, melatonin levels were significantly decreased in bipolar (P<0.001), but not major depressive disorder. In serum, we observed a significant melatonin decrease in major depressive (P=0.003), but not bipolar disorder. No associations were found between serum and CSF melatonin levels or between melatonin and measures of symptom severity or sleep disruptions in either condition.	This study suggests the presence of differential, body fluid specific alterations of melatonin levels in bipolar and major depressive disorder. Further, longitudinal studies are required to explore the disease phase dependency of melatonin alterations and to mechanistically explore the causes and consequences of site-specific alterations.	


27231897	Circadian rhythms, ≈24 h oscillations in behavior and physiology, are reflected in all cells of the body and function to optimize cellular functions and meet environmental challenges associated with the solar day. This multi-oscillatory network is entrained by the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which directs an organism's rhythmic expression of physiological functions and behavior via a hierarchical system. This system has been highly conserved throughout evolution and uses transcriptional-translational autoregulatory loops. This master clock, following environmental cues, regulates an organism's sleep pattern, body temperature, cardiac activity and blood pressure, hormone secretion, oxygen consumption and metabolic rate. Mammalian peripheral clocks and clock gene expression have recently been discovered and are present in all nucleated cells in our body. Like other essential organ of the body, the skin also has cycles that are informed by this master regulator. In addition, skin cells have peripheral clocks that can function autonomously. First described in 2000 for skin, this review summarizes some important aspects of a rapidly growing body of research in circadian and ultradian (an oscillation that repeats multiple times during a 24 h period) cutaneous rhythms, including clock mechanisms, functional manifestations, and stimuli that entrain or disrupt normal cycling. Some specific relationships between disrupted clock signaling and consequences to skin health are discussed in more depth in the other invited articles in this IJMS issue on Sleep, Circadian Rhythm and Skin. 
27231117	Disorders of thyroid function are common, and screening, diagnosis, and management are often performed by primary care providers. While management of significant biochemical abnormalities is reasonably straight forward, laboratory tests only slightly outside, or even within, the normal range are becoming more difficult to appropriately manage. A large part of this increasing difficulty in appropriate management is caused by patients requesting, and even demanding, certain tests or treatments that may not be indicated. Symptoms of thyroid dysfunction are non-specific and extremely prevalent in the general population. This, along with a growing body of information available to patients via the lay press and internet suggesting that traditional thyroid function testing is not reliable, has fostered some degree of patient mistrust. Increasingly, when a physician informs a patient that their thyroid is not the cause of their symptoms, the patient is dissatisfied and even angry. This review aims to clarify the interpretation of normal and mild abnormalities of thyroid function tests by describing pituitary-thyroid physiology and through an in depth review of, arguably, the three most important biochemical tests of thyroid function: TSH, free T4, and anti-TPO antibodies. It is important for primary care providers to have an understanding of the shortcomings and proper interpretation of these tests to be better able to discuss thyroid function with their patients. 
27229890	Investigate the association between depressive symptoms severity and amplitude of diurnal variations in depression symptoms in patients with chronic obstructive pulmonary disease (COPD).Prospective, observational proof-of-concept study.	Fourteen participants with moderate/severe COPD completed a 20-item Center for Epidemiologic Studies Depression scale (CES-D) estimating depressive symptoms severity. Throughout 1 week, the 4-item very short version of the CES-D was completed every day in the morning, afternoon, and evening.	Strong positive correlations were observed between depressive severity and the mean range of diurnal variations in positive (r = .61) and depressed affects (r = .67), somatic complaints (r = .82) and disturbed interpersonal relationships (r = .71).	In COPD patients, a greater diurnal variation in depression symptoms was associated with greater depression severity. This relationship seems independent of COPD severity.	Diurnal variation in the symptoms of depression is a new method of identifying depression severity in COPD.	
27227556	To evaluate the reliability of intraocular pressure measured by patients with glaucoma themselves using a new hand-held tonometer and to observe whether the intraocular pressure (IOP) variations have the same pattern on different days while glaucoma treatment is constant.Eighty-seven patients diagnosed with open-angle glaucoma or ocular hypertension were recruited to the study. Intraocular pressure measured using Goldmann applanation tonometry (GAT) was compared with IOP measured using tonometry at baseline and on the second visit. Patients measured their IOP at home using the hand-held tonometers.	The mean difference between GAT and iCare® values varies from 0 to 1 mmHg. Seventy-eight per cent of iCare® measurements were within 3 mmHg of the GAT measurements. Approximately 64% of the study eyes had higher IOP in the morning than in the afternoon/evening. Circadian patterns differed between consecutive days in 47% of the study eyes. There were IOP peaks outside office hours in up to 16% of the study eyes.	Measurements made using rebound self-tonometry are accurate and could be used to complement the investigation of patients with glaucoma. Intraocular pressure curves provide valuable data usable when adapting glaucoma treatment.	
27227370	Surgical care is delivered 24 h a day at most institutions. Alarmingly, some authors have found that certain operative start times are associated with greater morbidity and mortality rates. This effect has been noted in both the public and private sector. Although some of these differences may be related to process, they may also be caused by the human circadian rhythm and corresponding changes in host defenses. We hypothesized that the time of day of an operation would impact the frequency of certain post-operative outcomes significantly.Cases at a single tertiary-care center reported to the American College of Surgeons National Surgical Quality Improvement Program over a 10-year period were identified. Operative start times were divided into six-hour blocks, with 6 am to noon serving as the reference. Standard univariable techniques were applied. Multivariable logistic regression with mixed effects modeling then was used to determine the relation between operative start times and infectious outcomes, controlling for surgeon clustering. Statistical significance was set at p < 0.01.	A total of 21,985 cases were identified, of which 2,764 (12.6%) were emergency procedures. Overall, 9.7% (n = 2,142) of patients experienced some post-operative infectious complication. Seventy percent of these infections (n = 1,506) were surgical site infections. On univariable analysis considering all cases, nighttime and evening operations had higher rates of post-operative infections than those in performed during the day (9.1% from 6 am to noon; 9.7% from noon to 6 pm; 14.8% from 6 pm to midnight; and 14.4% from midnight to 6 am; p < 0.001). On multivariable analysis, operative start time was not associated with the risk of post-operative infection, even when emergency cases were considered independently.	Our data suggest that operative start times have no correlation with post-operative infectious complications. Further work is required to identify the source of the time-dependent outcome variability observed in previous studies.	
27227072	Circadian rhythm may be understood as a temporal organization that works to orchestrate physiological processes and behavior in a period of approximately 24 h. Because such temporal organization has evolved in the presence of predictable environmental clues, such as day length, tides, seasons, and temperature, the organism has confronted the natural selection in highly precise intervals of opportunities and risks, generating temporal programs and resetting mechanisms, which are well conserved among different taxa of animals. The present review brings some evidence of how these programs may have co-evolved in systems able to deal with 2 or more environmental clues, and how they similarly function in different group of animals, stressing how important temperature and light were to establish the temporal organizations. For example, melanopsin and rhodopsin, photopigments present respectively in circadian and visual photoreceptors, are required for temperature discrimination in Drosophila melanogaster. These pigments may signal light and temperature via activation of cationic membrane channel, named transient-receptor potential channel (TRP). In fact, TRPs have been suggested to function as thermal sensor for various groups of animals. Another example is the clock machinery at the molecular level. A set of very-well conserved proteins, known as clock proteins, function as transcription factors in positive and negative auto-regulatory loops generating circadian changes of their expression, and of clock-controlled genes. Similar molecular machinery is present in organisms as diverse as cyanobacteria (Synechococcus), fungi (Neurospora), insects (Drosophila), and vertebrates including humans. 
27227026	The fruit fly Drosophila melanogaster is a poikilothermic organism that must detect and respond to both fine and coarse changes in environmental temperature in order maintain optimal body temperature, synchronize behavior to daily temperature fluctuations, and to avoid potentially injurious environmental hazards. Members of the Transient Receptor Potential (TRP) family of cation channels are well known for their activation by changes in temperature and their essential roles in sensory transduction in both invertebrates and vertebrates. The Drosophila genome encodes 13 TRP channels, and several of these have key sensory transduction and modulatory functions in allowing larval and adult flies to make fine temperature discriminations to attain optimal body temperature, detect and avoid large environmental temperature fluctuations, and make rapid escape responses to acutely noxious stimuli. Drosophila use multiple, redundant signaling pathways and neural circuits to execute these behaviors in response to both increases and decreases in temperature of varying magnitudes and time scales. A plethora of powerful molecular and genetic tools and the fly's simple, well-characterized nervous system have given Drosophila neurobiologists a powerful platform to study the cellular and molecular mechanisms of TRP channel function and how these mechanisms are conserved in vertebrates, as well as how these channels function within sensorimotor circuits to generate both simple and complex thermosensory behaviors. 
27226820	Systemic Lupus Eritematosus (SLE) is a systemic inflammatory disease often treated with the agent cyclophosphamide (CY), known by provoking important adverse reactions to the organism. Ader and Cohen have demonstrated an alternative way of administrating this agent based on pavlovian conditioning, in order to reduce the aggression caused by CY. Considering the influence of the temporal organization on learning and memory processes, the purpose of this study was to understand the temporal aspects involved in the conditioned immunomodulation. In a search for circadian modulation, we selected NZB/W (F1) female mice, a strain that spontaneously develop SLE. Divided into two major groups, the animals were submitted, in different phases of day, to a classical conditioning immunomodulation protocol, consisting in weekly parings of saccharin solution and CY injections. The success of the paradigm was evaluated by comparing lifespan among the groups. Simultaneously, it was monitored the water intake behavior, in order to correlate the stability of two rhythmic parameters, amplitude and spectral power density of the 24-h rhythm, with the progression of SLE. Our results indicate that mice could benefit from the conditioning task performed either in the light phase or in the dark phase of the LD cycle, as expressed by an increased lifespan. Concerning the rhythmic parameters, there was evidence of association between the rhythmic stability and the evolution of SLE, demonstrated by the maintenance of healthy levels of amplitude and spectral potency of the 24-h rhythm in animals exposed to the conditioning paradigm. 
27226819	In humans, a person's chronotype depends on environmental cues and on individual characteristics, with late chronotypes prevailing in youth. Social jetlag (SJL), the misalignment between an individual׳s biological clock and social time, is higher in late chronotypes. Strong SJL is expected in Uruguayan university students with morning class schedules and very late entertainment activities. Sleep disorders have been reported in Antarctic inhabitants, that might be a response to the extreme environment or to the strictness of Antarctic life. We evaluated, for the first time in Uruguay, the chronotypes and SJL of 17 undergraduate students of the First Uruguayan Summer School on Antarctic Research, using Munich Chronotype Questionnaire (MCTQ) and sleep logs (SL) recorded during 3 phases: pre-Antarctic, Antarctic, and post-Antarctic. The midsleep point of free days corrected for sleep debt on work days (MSFsc,) was used as proxy of individuals' chronotype, whose values (around 6 a.m.) are the latest ever reported. We found a SJL of around 2 h in average, which correlated positively with MSFsc, confirming that late chronotypes generate a higher sleep debt during weekdays. Midsleep point and sleep duration significantly decreased between pre-Antarctic and Antarctic phases, and sleep duration rebounded to significant higher values in the post-Antarctic phase. Waking time, but not sleep onset time, significantly varied among phases. This evidence suggests that sleep schedules more likely depended on the social agenda than on the environmental light-dark shifts. High motivation of students towards Antarctic activities likely induced a subjective perception of welfare non-dependent on sleep duration. 
27226618	Leptin and TNFα can individually work in the brain to affect blood pressure; however, it remains unknown whether these two cytokines might have an interactive role in this process and, if so, how. In this work, we found that leptin stimulation led to TNFα production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNFα gene expression in the hypothalamus. Signaling analysis showed that leptin stimulation led to a rapid and strong STAT3 activation followed by a second-phase moderate STAT3 activation, which was selectively abolished by anti-inflammatory chemical PS1145 or TNFα antagonist WP9QY. Physiological study in normal mice revealed that diurnal rise of blood pressure was abrogated following central administration of PS1145 or a leptin receptor antagonist. Central TNFα pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNFα pretreatment in promoting leptin-induced blood pressure rise, and this effect was blocked by central treatment with either PS1145 or WP9QY. Hence, central leptin employs TNFα to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development.
27226028	Myocardial infarction (MI) is the leading cause of death in Western countries. Epidemiological studies show acute MI to be more prevalent in the morning and to be associated with a poorer outcome in terms of mortality and recovery. The mechanisms behind this association are not fully understood. Here, we report that circadian oscillations of neutrophil recruitment to the heart determine infarct size, healing, and cardiac function after MI Preferential cardiac neutrophil recruitment during the active phase (Zeitgeber time, ZT13) was paralleled by enhanced myeloid progenitor production, increased circulating numbers of CXCR2(hi) neutrophils as well as upregulated cardiac adhesion molecule and chemokine expression. MI at ZT13 resulted in significantly higher cardiac neutrophil infiltration compared to ZT5, which was inhibited by CXCR2 antagonism or neutrophil-specific CXCR2 knockout. Limiting exaggerated neutrophilic inflammation at this time point significantly reduced the infarct size and improved cardiac function. 
27225642	The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.
27223608	We report measurements of intraocular pressure (IOP) in growing domestic chicks at 12 h intervals, with three different lighting conditions. One group of chicks was raised in 12 h light and 12 h darkness (N), another in constant light (CL), and the third group was initially exposed to CL for three weeks then returned to N for either one week or four weeks (CLN). Pressures were measured in the middle of the light and dark periods (noon and midnight) for N and CLN birds, and at corresponding 12 h intervals for CL birds (also noon and midnight). The IOP of N chicks fluctuated from a light period average value of 25 mm Hg ( ±1.3 SD), to a dark period average value of 17.5 mm Hg ( ±1.1 SD mm Hg; P < 0.0001). These pressures were established by 4 days of age. At 7 weeks, (N) IOP continued to fluctuate: light values were 21.7 mm Hg (±1.2 SD), and dark values were 18.3 mm Hg ( ±0.7 SD). The IOP of CL birds did not fluctuate, remaining steady at 17 mm Hg ( ±1.4 SD). Chicks exposed to CL for 3 weeks required more than one week in N to re-establish (N) IOP values. We conclude that IOP fluctuates in hatchling chicks under N light conditions, that fluctuation is suppressed in CL light conditions, and that IOP recovery from 3 weeks suppression in CL requires more than one week in N light conditions. 
27223247	New ways of working (NWW) is a type of work organization that is characterized by temporal and spatial flexibility, often combined with extensive use of information and communication technologies (ICT) and performance-based management. In a three-wave intervention study, we examined the effects of NWW on both the organization of work (changes in control over time and place of work; working hours and work location; and other key job characteristics), and on employees' outcomes (work-nonwork balance; health and well-being; and job-related outcomes). We applied a quasi-experimental design within a large Dutch financial company (N = 2,912). We studied an intervention group (n = 2,391) and made comparisons with a reference group (n = 521). There were three study waves: (i) one/two months before, and (ii) 4 months and (iii) 10 months after implementation of NWW. Repeated measures analyses of covariance (involving 361 participants from the intervention group and 80 participants from the reference group) showed a large and significant shift from hours worked at the office to hours worked at home after implementation of NWW. Accordingly, commuting time was reduced. Employees remained working on week days and during day time. Psychosocial work-characteristics, work-nonwork balance, stress, fatigue, and job-related outcomes remained favourable and largely unaffected, but the health score in the intervention group decreased (medium effect). These findings suggest that the implementation of NWW does not necessarily lead to changes in psychosocial work characteristics, well-being or job-related outcomes.
27222536	The growing number of sequenced genomes allows us now to address a key question in genetics and evolutionary biology: which genomic changes underlie particular phenotypic changes between species? Previously, we developed a computational framework called Forward Genomics that associates phenotypic to genomic differences by focusing on phenotypes that are independently lost in different lineages. However, our previous implementation had three main limitations. Here, we present two new Forward Genomics methods that overcome these limitations by (1) directly controlling for phylogenetic relatedness, (2) controlling for differences in evolutionary rates, and (3) computing a statistical significance. We demonstrate on large-scale simulated data and on real data that both new methods substantially improve the sensitivity to detect associations between phenotypic and genomic differences. We applied these new methods to detect genomic differences involved in the loss of vision in the blind mole rat and the cape golden mole, two independent subterranean mammals. Forward Genomics identified several genes that are enriched in functions related to eye development and the perception of light, as well as genes involved in the circadian rhythm. These new Forward Genomics methods represent a significant advance in our ability to discover the genomic basis underlying phenotypic differences between species. Source code: https://github.com/hillerlab/ForwardGenomics/. 

27221952	This article describes the rationale, objectives, design and conduct of the ambulatory blood pressure monitoring (ABPM)-based Hygia Project. Given the substantial evidence of the significantly better prognostic value of ABPM compared to clinic BP measurements, several international guidelines now propose ABPM as a requirement to confirm the office diagnosis of hypertension. Nonetheless, all previous ABPM outcome investigations, except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study (MAPEC) study, relied upon only a single, low-reproducible 24 h ABPM assessment per participant done at study inclusion, thus precluding the opportunity to explore the potential reduction in cardiovascular disease (CVD) risk associated with modification of prognostic ABPM-derived parameters by hypertension therapy. The findings of the single-center MAPEC study, based upon periodic systematic 48 h ABPM evaluation of all participants during a median follow-up of 5.6 years, constitute the first proof-of-concept evidence that the progressive reduction of the asleep systolic blood pressure (SBP) mean and correction of the sleep-time relative SBP decline toward the normal dipper BP profile, most efficiently accomplished by a bedtime hypertension treatment strategy, best attenuates the risk of CVD, stroke and development of new-onset diabetes. The Hygia Project, primarily designed to extend the use of ABPM in primary care as a requirement for diagnosis of hypertension, evaluation of response to treatment and individualized assessment of CVD and other risks, is a research network presently composed of 40 clinical sites and 292 investigators. Its main objectives are to (i) investigate whether specific treatment-induced changes in ABPM-derived parameters reduce risk of CVD events, stroke, new-onset diabetes and/or development of chronic kidney disease (CKD); and (ii) test the hypothesis that bedtime chronotherapy entailing the entire daily dose of ≥1 conventional hypertension medications exerts better ambulatory BP control and CVD, metabolic and renal risk reduction than all such medications ingested in the morning upon awakening. Between 2007 and 2015, investigators recruited 18 078 persons [9769 men/8309 women, 59.1 ± 14.3 years of age (mean ± SD)], including 15 764 with hypertension according to ABPM criteria as participants in the prospective randomized chronotherapy trial. The initial evaluation includes 48 h ABPM, detailed medical history and screening laboratory blood and urine tests. The same evaluation procedure is scheduled annually, or more frequently when treatment adjustment is required for proper ambulatory BP control, targeting a median follow-up of >5 years. The primary CVD outcome end point is the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, ischemic stroke and hemorrhagic stroke. The independent Hygia Project Events Committee periodically evaluates blinded clinical reports to ascertain and certify every documented event. Beyond the potential findings resulting from testing the main hypotheses, the Hygia Project has already demonstrated, as proof of concept, that the routine diagnosis of hypertension and individualized assessment of CVD and other risks by ABPM, as currently recommended, is fully viable in the primary care setting, where most people with either hypertension, dyslipidemia, type 2 diabetes or CKD receive routine medical attention. 
27221157	The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. 
27221103	Light is the primary signal that calibrates circadian neural circuits and thus coordinates daily physiological and behavioral rhythms with solar entrainment cues. Drosophila and mammalian circadian circuits consist of diverse populations of cellular oscillators that exhibit a wide range of dynamic light responses, periods, phases, and degrees of synchrony. How heterogeneous circadian circuits can generate robust physiological rhythms while remaining flexible enough to respond to synchronizing stimuli has long remained enigmatic. Cryptochrome is a short-wavelength photoreceptor that is endogenously expressed in approximately half of Drosophila circadian neurons. In a previous study, physiological light response was measured using real-time bioluminescence recordings in Drosophila whole-brain explants, which remain intrinsically light-sensitive. Here we apply analysis of real-time bioluminescence experimental data to show detailed dynamic ensemble representations of whole circadian circuit light entrainment at single neuron resolution. Organotypic whole-brain explants were either maintained in constant darkness (DD) for 6 days or exposed to a phase-advancing light pulse on the second day. We find that stronger circadian oscillators support robust overall circuit rhythmicity in DD, whereas weaker oscillators can be pushed toward transient desynchrony and damped amplitude to facilitate a new state of phase-shifted network synchrony. Additionally, we use mathematical modeling to examine how a network composed of distinct oscillator types can give rise to complex dynamic signatures in DD conditions and in response to simulated light pulses. Simulations suggest that complementary coupling mechanisms and a combination of strong and weak oscillators may enable a robust yet flexible circadian network that promotes both synchrony and entrainment. A more complete understanding of how the properties of oscillators and their signaling mechanisms facilitate their distinct roles in light entrainment may allow us to direct and augment the circadian system to speed recovery from jet lag, shift work, and seasonal affective disorder. 
27221043	Sleep-wake disturbances are highly prevalent following traumatic brain injury (TBI), impeding rehabilitaion and quality of life. However, the mechanisms underlying these sleep disturnbances are unclear, and efficacious treatments are lacking. To investigate possible mechanisms underlying sleep disturbance in TBI, we examined characteristics of the circadian rhythm of melatonin, a hormone involved in sleep-wake regulation. We compared TBI patients reporting sleep disturbance with age- and gender-matched healthy volunteers.We conducted an overnight observational study with salivary melatonin samples collected hourly in 9 patients with severe TBI and 9 controls. Salivary dim light melatonin onset (DLMO) as well as melatonin synthesis onset (SynOn) and offset (SynOff) were used to determine circadian timing. Total overnight salivary melatonin production was calculated as the area under the curve from melatonin synthesis onset to offset.	Compared with healthy individuals, TBI patients showed 42% less melatonin production overnight (d = 0.87; P = .034). The timing of DLMO was delayed by approximately 1.5 hours in patients with TBI compared with controls (d = 1.23; P = .003).	In patients with TBI, melatonin production was attenuated overnight, and the timing of melatonin secretion was delayed. We suggest that disruption to the circadian regulation of melatonin synthesis is a feature of severe TBI, possibly contributing to the sleep difficulties that are commonly reported in this population.	
27216755	The appropriate timing of bolting and flowering is pivotal for reproductive success in Brassicaceae crops including radish (Raphanus sativus L.). Although several flowering regulatory pathways had been described in some plant species, no study on genetic networks of bolting and flowering regulation was performed in radish. In this study, to generate dataset of radish unigene sequences for large-scale gene discovery and functional pathway identification, a cDNA library from mixed radish leaves at different developmental stages was subjected to high-throughput RNA sequencing (RNA-seq).A total of 54.64 million clean reads and 111,167 contigs representing 53,642 unigenes were obtained from the radish leaf transcriptome. Among these, 50,385 unigenes were successfully annotated by BLAST searching against the public protein databases. Functional classification and annotation indicated that 42,903 and 15,382 unique sequences were assigned to 55 GO terms and 25 COG categories, respectively. KEGG pathway analysis revealed that 25,973 unigenes were classified into 128 functional pathways, among which 24 candidate genes related to plant circadian rhythm were identified. Moreover, 142 potential bolting and flowering-related genes involved in various flowering pathways were identified. In addition, seven critical bolting and flowering-related genes were isolated and profiled by T-A cloning and RT-qPCR analysis. Finally, a schematic network model of bolting and flowering regulation and pathways was put forward in radish.	This study is the first report on systematic identification of bolting and flowering-related genes based on transcriptome sequencing and assembly in radish. These results could provide a foundation for further investigating bolting and flowering regulatory networks in radish, and facilitate dissecting molecular genetic mechanisms underlying bolting and flowering in Brassicaceae vegetable crops.	
27216486	Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 (p-ERK) content in fibroblasts from BD patients vs.Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N-terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1.	
27215902	Timing is crucial for social interactions. Animal behavior is synchronized with biotic and abiotic environment variables ensuring that the activity phase of conspecifics occurs during the same period of the day. As biological rhythms are embedded in the complex integrative control of the brain, it is fundamental to explore its interaction with environmental and social factors. This approach will unravel the link between external stimuli carrying information on environmental cycles and the neural commands for behavior, including social behavior, associated with precise phases of those cycles. Arousal in the solitary Gymnotus omarorum and in the gregarious Brachyhypopomus gauderio is characterized by a nocturnal increase in the basal discharge rate of electric behavior, which is mild and transient in G. omarorum and large and persistent in B. gauderio. In this study, we show that the major integrator of social behavior, AVT (arginine vasotocin), is not involved in the nocturnal increase of electric behavior basal rate in isolated animals of either species. On the other hand, endogenous melatonin, the major modulator of the circadian system, is responsible for the nocturnal increase in electric behavior in isolated individuals of both species. 
27213030	Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2'-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm. 
27212595	  It has long been suggested that various aspects of the immune system is affected by the activity of the nervous system. However, how the inputs from the nervous system are converted into the outputs from the immune system had been largely unclear. Studies in the last decade revealed the cellular and molecular basis by which inputs from the autonomic nervous system control the development and functions of immune cells. The principal autonomic neurotransmitters, acetylcholine and noradrenaline, are involved in immune regulation in the context of inflammation through various molecular pathways. Circadian rhythm in the activity of the autonomic nervous system produces fluctuations of immune functions during a day. This review integrates the current knowledge about the autonomic regulation of inflammatory responses and provide therapeutic implications for inflammatory diseases. 
27212038	Subclinical hypercortisolism (SH) is a condition of mild cortisol excess, found in the 5-30% of patients with adrenal incidentalomas, defined as silent adrenal masses diagnosed throughout radiological examinations performed for unrelated diseases. Generally, the diagnosis of SH is supported by the presence of high cortisol levels after a 1-mg dexamethasone suppression test, low adrenocorticotropic hormone levels, altered cortisol circadian rhythm and 24-hour urinary free cortisol levels higher than the upper reference value. Less frequently, diagnosis is made by other tests. Unfortunately, up to now a consensus on SH diagnostic criteria is lacking. Although SH is characterized by the absence of the classical features of Cushing's syndrome by definition, it has been associated with the presence of different metabolic complications (mainly type 2 diabetes mellitus, arterial hypertension, central obesity and dyslipidemia), cardiovascular diseases, osteoporosis and vertebral fractures, altered coagulation parameters, worsening of quality of life, and increased mortality. The management of SH, as well as the improvement of metabolic parameters and other complications after surgical treatment, is still a matter of debate. 
27210490	The aim of the research described here was to compare different methods of body temperature (BT) measurements in dairy cows. It was hypothesised that reticular temperature (RET) values reflect the physiological status of the animals in an equivalent way to rectal (RT) and vaginal (VT) measurements. RT, VT and RET temperatures of twelve lactating Holstein-Friesian cows were measured over five consecutive days in June and October 2013. While RT and VT were manually measured three times a day, RET was automatically recorded at 10 min intervals using a bolus in the reticulum. For comparison with RT and VT, different RET values were used: single values at the respective recording times (RET-SIN), and mean (RET-MEAN) and median (RET-MED) values of 2 h prior to RT and VT measurements. Overall, body temperatures averaged 38·1 ± 0·6, 38·2 ± 0·4, 38·7 ± 0·9, 38·5 ± 0·7 and 38·7 ± 0·5 °C for RT, VT, RET-SIN, RET-MEAN and RET-MED, respectively. RT and VT were lower than all RET measurements, while RET-SIN and RET-MED were higher than RET-MEAN (P < 0·001). RET-MEAN and RET-MED values were higher in the morning, whereas RT and VT were greatest in the evening (P < 0·001). Overall, records of RT and VT were strongly correlated (r = 0·75; P < 0·001). In contrast to RET-SIN and RET-MEAN, RET-MED was higher correlated to RT and VT. In June, coefficients were higher between all methods than in October. Relation of barn T to RT and VT was stronger when compared to RET measurements. RET-SIN was higher correlated to barn T than RET-MEAN or RET-MED. Correlation between VT and barn T was strongest (r = 0·48; P < 0·001). In summary, RET-MED showed highest correlation with VT and RT. However, single RET measurements (influenced by water or feed intake) can lead to extreme variations and differences to single VT and RT values. 
27210069	Circadian rhythms in behaviour and physiology are important for animal health and survival. Studies with individually isolated animals in the laboratory have consistently emphasized the dominant role of light for the entrainment of circadian rhythms to relevant environmental cycles. Although in nature interactions with conspecifics are functionally significant, social signals are typically not considered important time-givers for the animal circadian clock. Our results challenge this view. By studying honeybees in an ecologically relevant context and using a massive data set, we demonstrate that social entrainment can be potent, may act without direct contact with other individuals and does not rely on gating the exposure to light. We show for the first time that social time cues stably entrain the clock, even in animals experiencing conflicting photic and social environmental cycles. These findings add to the growing appreciation for the importance of studying circadian rhythms in ecologically relevant contexts. 
27209182	Male hypogonadism is a common condition, with an increasing body of literature on diagnosis, implications, and management. Given the significant variability in testosterone (T) from a physiologic and assay perspective, a thorough understanding of factors affecting T values and study methodology is essential to interpret reported study outcomes appropriately. However, despite the large number of publications on T, there are no reference materials consolidating all relevant and potentially confounding factors necessary to interpret T studies appropriately.To create a resource document that reviews sources of T variability, free vs total T, assay techniques and questionnaires, and study methodology relevant to interpreting outcomes.	A PubMed search was performed of all the T literature published on T variability, assay techniques, and T-specific questionnaires. Results were summarized in the context of their impact on interpreting T literature outcomes and methodology.	Effect of various factors on T variability and their relevance to study methodology and outcomes.	Several factors affect measured T levels, including aging, circadian rhythms, geography, genetics, lifestyle choices, comorbid conditions, and intraindividual daily variability. The utility of free T over total T is debatable and must be compared using appropriate threshold levels. Among various assay techniques, mass spectrometry and equilibrium dialysis are gold standards. Calculated empirical estimates of free T also are commonly used and accepted. Hypogonadism-specific questionnaires have limited utility in screening for hypogonadism, and their role as objective end points for quantifying symptoms remains unclear. Numerous aspects of study methodology can directly or indirectly affect reported outcomes, including design (randomized, prospective, retrospective), duration, populations studied (age, comorbid conditions), low T threshold, therapeutic agent used, objective measurements and end points selected, and statistical interpretation.	Critical appraisal of the T literature requires an understanding of numerous factors resulting in T variability, study design and methodology, and limitations of assay techniques and objective measurement scales.	
27208616	The intergeniculate leaflet (IGL) is a flat retinorecipient thalamic structure implicated in orchestrating circadian rhythm, historically considered to be a subdivision of the neighboring ventrolateral geniculate nucleus (VLG). IGL consists of two main neuronal subpopulations: enkephalinergic and neuropeptide Y (NPY)-synthesizing cells. These cell types have different functions, connectivity and firing pattern in vivo, which suggest that they have different membrane currents to support their functional differences. We therefore performed patch-clamp experiments combined with immunohistochemical staining to clarify possible differences in the subthreshold currents of IGL neurons. Our results suggest that IGL neurons can be divided into two subpopulations based on two ionic currents. A T-type calcium current (IT) was identified in neurons that do not synthesise NPY, whereas all NPY-positive neurons were found to express a marked A-type potassium current (IA). Due to the fact that the clear electrophysiological discriminants between IGL and VLG are lacking, we decided to compare the amplitudes of the identified currents between those two structures. Our data suggest that VLG neurons can be characterized by a high amplitude IT and a low IA. Finally, we compared both currents with WAG/Rij rats, a well-established model of absence epilepsy, with co-occurring retinal pathologies, sleep-onset disturbances, and seizures exhibiting circadian rhythmicity. Data presented in this study uncovered pathologies in the IT exhibiting neurons of the IGL and VLG. In conclusion, the data presented here suggest that different subthreshold current expression supports the functional differences of thalamic nuclei. Those differences are promising for possible pharmacological manipulations of specified cell types in pathophysiologies including absence epilepsy. 
27208227	The circadian clock synchronizes a wide range of biological processes with the day/night cycle, and correct circadian regulation is essential for photosynthetic activity and plant growth. We describe here a mechanism where a plastid signal converges with the circadian clock to fine-tune the regulation of nuclear gene expression in Arabidopsis (Arabidopsis thaliana). Diurnal oscillations of tetrapyrrole levels in the chloroplasts contribute to the regulation of the nucleus-encoded transcription factors C-REPEAT BINDING FACTORS (CBFs). The plastid signal triggered by tetrapyrrole accumulation inhibits the activity of cytosolic HEAT SHOCK PROTEIN90 and, as a consequence, the maturation and stability of the clock component ZEITLUPE (ZTL). ZTL negatively regulates the transcription factor LONG HYPOCOTYL5 (HY5) and PSEUDO-RESPONSE REGULATOR5 (PRR5). Thus, low levels of ZTL result in a HY5- and PRR5-mediated repression of CBF3 and PRR5-mediated repression of CBF1 and CBF2 expression. The plastid signal thereby contributes to the rhythm of CBF expression and the downstream COLD RESPONSIVE expression during day/night cycles. These findings provide insight into how plastid signals converge with, and impact upon, the activity of well-defined clock components involved in circadian regulation. 
27207944	Biological rhythms, such as rhythms in gene expression controlled by the cell cycle or the circadian clock, are important in cell physiology. A common type of experiment compares rhythmicity in tissues or cells either kept under different conditions or having different genotypes. Such investigations provide insights into underlying mechanisms as well as functions of rhythms.We present and benchmark a set of statistical and computational methods for this type of analysis, here termed differential rhythmicity analysis. The methods detect alterations in rhythm amplitude, phase and signal to noise ratio in one set of measurements compared to another. Using these methods, we compared circadian rhythms in liver mRNA expression in mice held under two different lighting conditions: constant darkness and light-dark cycles, respectively. This analysis revealed widespread and reproducible amplitude increases in mice kept in light-dark cycles. Further analysis of the subset of differentially rhythmic transcripts implied the immune system in mediating ambient light-dark cycles to rhythmic transcriptional activities. The methods are suitable for genome- or proteome-wide studies, and provide rigorous P values against well-defined null hypotheses.	The methods were implemented as the accompanying R software package DODR, available on CRAN.	pal-olof.westermark@charite.de	Supplementary data are available at Bioinformatics online.	
27206813	Circulating lipid components were studied under near-normal tropical conditions (around Lucknow) in 162 healthy volunteers - mostly medical students, staff members and members of their families (103 males and 59 females; 7 to 75y), subdivided into 4 age groups: A (7-20y; N=42), B (21-40y; N=60), C (41-60y; N=35) and D (61-75y; N=25).Blood samples were collected from each subject every 6h for 24h (4 samples). Plasma was separated and total cholesterol, high-density-lipoprotein (HDL) cholesterol, phospholipids and total lipids were measured spectrophotometrically. Data from each subject were analyzed by cosinor. We examined by multiple-analysis of variance how the MESOR (Midline Estimating Statistic Of Rhythm, a rhythm-adjusted mean) and the circadian amplitude of these variables is affected by gender, age, diet (vegetarian vs. omnivore), and smoking status.	In addition to effects of gender and age, diet and smoking were found to affect the MESOR of circulating plasma lipid components in healthy Indians residing in northern India. Age also affected the circadian amplitude of these variables.	These results indicate the possibility of using non-pharmacological interventions to improve a patient's metabolic profile before prescribing medication under near normal tropical conditions. They also add information that may help refine cut-off values in the light of factors shown here to affect blood lipids.	
27203369	Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our May 2016 selection includes a new method for labeling and visualizing nonprotein biomolecules using electron microscopy; a small molecule, originally found in tangerine peel, that regulates our circadian clock and helps with some of the metabolic pathologies associated with circadian rhythms; and a finding that asparagine is used as an amino acid exchanger in tumor cells. 
27199894	In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic-pituitary-adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors - glucocorticoids - released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both the HPA axis and the immune system, and discusses their interactions. 
27198945	This epidemiological study evaluated the impact of school time on sleep parameters of children and adolescents.This cross-sectional study involved 639 elementary and high school students (mean age 13.03 years, range 8-18, 58.5% female) from the south of Brazil. Participants answered the Morningness-Eveningness Questionnaire (MEQ), and were asked about their sleeping habits on weekdays and weekends. Sleep deficit was defined as the difference between sleep duration on weekdays and weekends.	The morning-school-time students presented significantly higher age, bedtime and wake up differences, sleep deficits, and social jetlag. The sleep deficit presented by girls was greater than that observed in boys of the same age. The difference between weekday and weekend waking times was also significantly greater in girls than in boys aged 13-18 years. Sleep deficit was significantly positively correlated with age and differences in wake up times, and significantly negatively correlated with MEQ scores, social jetlag, difference between weekday and weekend bedtimes, midpoint of sleep on weekends, and midpoint of sleep on weekends corrected for sleep deficit. A step-by-step multivariate logistic regression identified social jetlag, the difference between waking times on weekdays and weekends, and the midpoint of sleep on weekends as significant predictors of sleep deficit (Adjusted R(2) = 0.95; F = 1606.87; p <0.001).	The results showed that school time influences the sleep parameters. The association of school schedules and physiological factors influence the sleep/wake cycle.	
27198898	To explore Canadian mothers' experiences with infant sleep safety.Parents decide when, how and where to place their infants to sleep. It is anticipated that they will follow international Sudden Infant Death Syndrome prevention sleep safety guidelines. Limited evidence is available for how parents take up guidelines; no studies have explored Canadian mothers' experiences regarding infant sleep safety.	An inductive qualitative descriptive study using some elements of grounded theory, including concurrent data collection and analysis and memoing.	Semi-structured interviews and constant comparative analysis were employed to explore infant sleep safety experiences of 14 Canadian mothers residing in Metro Vancouver. Data collection commenced in December 2012 and ended in July 2013.	The core theme, Infant Sleep Safety Cycle, represents a cyclical process encompassing sleep safety from the prenatal period to the first six months of infants' lives. The cyclical process includes five segments: mothers' expectations of sleep safety, their struggles with reality as opposed to maternal visions, modifications of expectations, provision of rationale for choices and shifts in mothers' views of infants' developmental capabilities. Mothers' experiences were influenced by four factors: perceptions of everyone's needs, familial influences, attitudes and judgments from outsiders and resource availability and accessibility.	To manage infants' sleep, mothers reframed sleep safety guidelines and downplayed the risk of Sudden Infant Death Syndrome for all forms of sleep at all times. Healthcare providers can support mothers' efforts to manage their infants' sleep challenges. During prenatal and postpartum periods, providers' interventions can influence mothers' efforts to adhere to sleep safety principles.	The study findings support healthcare providers' efforts to assist mothers to modify expectations and develop strategies to support sleep safety principles while acknowledging their challenges.	
27197764	A circadian rhythm of the dinoflagellate Peridinium quadridentatum was studied at a time-series station in the southwestern Gulf of Mexico, in May 2007. Different substrates (water column, the seagrass Thalassia testudinum, macroalgae, coral rubble and sandy sediment surface) were sampled at the site at 1.5-3.5m depth. In the samples of coral rubble, P. quadridentatum was scarce. In the water column, the species showed an abundance peak at 15:00. The cell abundance of P. quadridentatum in Thalassia samples increased from 15:00 until 18:00 (1.81×10(4)cells/gsubstratewet weight), and then continuously decreased until 06:00. Changes in P. quadridentatum cell abundance on macroalgae followed the same trend as on Thalassia, with the maximal value at 18:00. The higher abundance of P. quadridentatum (up to 1.40×10(4)cells/gSWW) in macroalgae samples showed the preference for seaweeds. P. quadridentatum has a neritic tropical-boreal distribution. A new combination is proposed: Peridinium quadridentatum var. trispiniferum. 
27197349	The pilot study discussed in this article assessed formaldehyde levels in portable classrooms (PCs) and traditional classrooms the authors evaluated formaldehyde levels in day and overnight indoor air (TCs) and explored factors influencing indoor air quality (e.g., carbon dioxide, temperature, and relative humidity). In a cross-sectional design, samples from nine PCs renovated within three years previously and three TCs in a school district in metropolitan Atlanta, Georgia. Formaldehyde levels ranged from 0.0068 to 0.038 parts per million (ppm). In both types of classroom, overnight formaldehyde median levels (PCs = 0.018 ppm; TCs = 0.019 ppm) were higher than day formaldehyde median levels (PCs = 0.011 ppm; TCs = 0.016 ppm). Carbon dioxide levels measured 470-790 ppm at 7:00 a.m. and 470-1800 ppm at 4:00 p.m. Afternoon medians were higher in TCs (1,400 ppm) than in PCs (780 ppm). Consistent with previous studies, formaldehyde levels were similar among PCs and TCs. Reducing carbon dioxide levels by improving ventilation is recommended for classrooms.
27195315	Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. 
27194331	Circadian rhythms regulate bodily functions within 24 h and long-term disruptions in these rhythms can cause various diseases. Recently, the peripheral auditory organ, the cochlea, has been shown to contain a self-sustained circadian clock that regulates differential sensitivity to noise exposure throughout the day. Animals exposed to noise during the night are more vulnerable than when exposed during the day. However, whether other structures throughout the auditory pathway also possess a circadian clock remains unknown. Here, we focus on the inferior colliculus (IC), which plays an important role in noise-induced pathologies such as tinnitus, hyperacusis, and audiogenic seizures. Using PER2::LUC transgenic mice and real-time bioluminescence recordings, we revealed circadian oscillations of Period 2 protein in IC explants for up to 1 week. Clock genes (Cry1, Bmal1, Per1, Per2, Rev-erbα, and Dbp) displayed circadian molecular oscillations in the IC. Averaged expression levels of early-induced genes and clock genes during 24 h revealed differential responses to day or night noise exposure. Rev-erbα and Dbp genes were affected only by day noise exposure, whereas Per1 and Per2 were affected only by night noise exposure. However, the expression of Bdnf was affected by both day and night noise exposure, suggesting that plastic changes are unlikely to be involved in the differences in day or night noise sensitivity in the IC. These novel findings highlight the importance of circadian responses in the IC and emphasize the importance of circadian mechanisms for understanding central auditory function and disorders.Recent findings identified the presence of a circadian clock in the inner ear. Here, we present novel findings that neurons in the inferior colliculus (IC), a central auditory relay structure involved in sound processing, express a circadian clock as evidenced at both the mRNA and protein levels. Using a reporter mouse that expresses a luciferase protein coupled to the core clock protein PERIOD2 (PER2::LUC), we could observe spontaneous circadian oscillations in culture. Furthermore, we reveal that the mRNA profile of clock-related genes in the IC is altered differentially by day or night noise exposure. The identification of a clock in the IC is relevant for understanding the mechanisms underlying dysfunctions of the IC such as tinnitus, hyperacusis, or audiogenic seizures.	
27192999	Illumination of nocturnal environments is increasing steadily worldwide. While there are some benefits for mankind, light at night affects animals, plants, and human health by blurring the natural distinction between day and night. International regulations exist to protect the environment for the maintenance of human health but nocturnal darkness is not considered. In Germany, cities and communities labeled as Climatic Health Resorts provide for high standards in air quality. However, their degree of nocturnal darkness is unexplored so far. In our study, we examined the degree of nocturnal darkness in German Climatic Health Resorts by two datasets based on georeferenced remote sensing data. The majority of Climatic Health Resorts (93.1 %) are able to offer a relative respite (≥ 20 mag/arcsec2) from a degraded nocturnal environment, while only 3.4 % are able to offer a dark, if by no means pristine, night environment (≥ 21 mag/arcsec2). Climatic Health Resorts emit less light as well as are less affected by night sky brightness compared to the average of non-classified communities. In combination with daytime requirements, the resorts provide conditions for a more distinct day-and-night-cycle than non-classified communities.
27191847	In older people, less diurnal variability in cortisol levels has been consistently related to worse physical performance, especially to slower walking speed (WS). The cortisol awakening response (CAR) is a discrete component of the hypothalamic-pituitary-adrenal axis that has been related to several health problems, such as cardiovascular disease and/or worse performance on executive function and memory. The relationship between the CAR and physical performance in older people is poorly understood. In this study, in 86 older people (mean age = 64.42, SD = 3.93), we investigated the relationship between the CAR and WS, a commonly used measure of physical performance in the older population that has also been related to health problems, such as cardiovascular disease and executive function performance in older people. Additionally, we studied whether the relationship between the CAR and WS was independent from cortisol levels on awakening and several possible confounders. Results showed that a CAR of reduced magnitude (measured with 3 samples each day, for two consecutive days, and calculated as the area under the curve with respect to the increase), but not cortisol levels on awakening, was related to slower WS. In addition, this relationship was independent from cortisol levels on awakening. It is possible that a CAR of reduced magnitude would contribute to less diurnal cortisol variability, affecting physical performance. Additionally, it is possible that a CAR of reduced magnitude affects WS through a possible negative effect on executive function, or that the association between the CAR and WS is due to the fact that both are related to similar health problems and to changes in cognitive performance in older people.
27191691	Ammar, A, Chtourou, H, and Souissi, N. Effect of time-of-day on biochemical markers in response to physical exercise. J Strength Cond Res 31(1): 272-282, 2017-It is well established that many physiological functions are time-of-day (TOD) dependent, and their circadian rhythms are well documented in healthy populations at resting state. In fact, greater rate of oxidative stress, white blood cell, homocysteine, and muscle damage markers were shown in the early evening (≈18:00 hours), and more efficient antioxidant activity was observed in the early morning (≈06:00 hours). During physical tasks, the majority of the above-mentioned physiological functions increase from pre to post physical exercise with different rates of increases from morning to evening. These different rates of increases are suggested to alter the physiological resting diurnal variation. In this context, given the possible significant interaction "TOD × physical exercise," circadian rhythms of the physiological responses during physical activity are still not well established in trained subjects. Otherwise, it was suggested that the diurnal variation of these biochemical parameters could, in part, explain the typical diurnal fluctuation of physical performance. Therefore, the aim of this review was to summarize the currently available studies investigating the circadian rhythms of physiological functions at rest and after physical exercise and to establish their possible effect on the diurnal variation of sport performance. Although studies in this field are limited, the available information shows that compared with sedentary subjects, trained population maintained similar diurnal variations of hematological parameters, homocysteine, and some biochemical markers at rest and even after physical exercise. However, after strength exercises, the circadian rhythms for the majority of oxidative stress and muscle damage markers were altered because of the higher rate of increased pre-post exercises registered in the morning compared with the afternoon and evening. The available studies reveal that the significant circadian variation observed for sport performances could be more likely explained by the alteration of ionic movement and the diurnal fluctuation of homocysteine, lactate, muscle damage, and antioxidant markers.
27191204	Affective instability, the tendency to experience emotions that fluctuate frequently and intensively over time, is a core feature of several mental disorders including borderline personality disorder. Currently, affect is often measured with Ecological Momentary Assessment protocols, which yield the possibility to quantify the instability of affect over time. A number of linear mixed models are proposed to examine (diagnostic) group differences in affective instability. The models contribute to the existing literature by estimating simultaneously both the variance and serial dependency component of affective instability when observations are unequally spaced in time with the serial autocorrelation (or emotional inertia) declining as a function of the time interval between observations. In addition, the models can eliminate systematic trends, take between subject differences into account and test for (diagnostic) group differences in serial autocorrelation, short-term as well as long-term affective variability. The usefulness of the models is illustrated in a study on diagnostic group differences in affective instability in the domain of eating disorders. Limitations of the model are that they pertain to group (and not individual) differences and do not focus explicitly on circadian rhythms or cycles in affect. 
27190207	Elevated cortisol levels with aging have been associated with atrophy of the hippocampus and prefrontal cortex (PFC), as well as with impaired cognitive functions in men. However, coexisting diseases have confounded many studies examining these relationships. Studies in women are lacking. Our objective was to test whether salivary cortisol levels were related to morphology of the hippocampus and the PFC, and to cognitive performance.A cross-sectional study including 200 elderly (55-80 years old) men and women.	We used magnetic resonance imaging, tests of episodic-, semantic-, and working memory, visuospatial ability, and cortisol levels in four saliva samples collected during 1 day.	Area under the curve (AUC) for cortisol levels was negatively related to cortical surface area of the left anterior cingulate gyrus (caudal P<0.001; rostral P=0.006), right lateral orbitofrontal cortex (P=0.004), and right rostral middle frontal gyrus (P=0.003). In women, there was also a negative relationship with cortical surface area in the left rostral middle frontal gyrus (P=0.006). No relationship was found between cortisol levels and hippocampal volume.	This study suggests that the structure of the medial PFC is related to cortisol levels in both elderly women and men.	
27189909	Caloric sweeteners such as sugar and honey are replaced in thousands of food products by noncaloric artificial sweeteners (NASs). The aim of the present study was to determine the effects of chronic NAS intake on circadian sleep regulation.Circadian rhythms of sleep and locomotor activity were evaluated in mice after consumption of drinking water containing 0.1% (w/v) saccharin for 2 wk.	The intake of saccharin ad libitum significantly reduced wakefulness and increased non-rapid eye movement sleep during the first half of the active (dark) phase, whereas wakefulness was significantly increased at the start of the sleep phase. Saccharin consumption obviously reduced spontaneous activity during the first half of the dark period.	The findings suggest that NASs disturb the circadian sleep-wake cycle and cause behavioral inactivity in mice.	
27188906	Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet-induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8hours during the dark cycle was initiated when high-fat diet-fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet-induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance. 
27188189	Communication breakdowns between members of the health care team compromise patient safety and experience. Communication breakdowns with parents, an important but often overlooked part of the health care team, are understudied. Parents may play a particularly important role in nighttime care given decreased staffing and inadequate transitions of care at night. We studied communication breakdowns evidenced by lack of shared understanding between parents and night-team residents about the reason for admission and care plan.We conducted a prospective cohort study of parents (n = 286) and night-team senior residents (n = 34) from May 1, 2013 to October 31, 2013. Parents and residents rated communication and described patients' reason for admission, overall plan, and overnight plan. Two physician investigators independently reviewed (κ = 0.63) resident-parent dyads, assigned subsequently dichotomized 4-point overall agreement scores, and rated plan complexity. Using clustered logistic regression, we evaluated relationships among demographics, plan complexity, and shared understanding. We also examined resident and parent perceptions of shared understanding.	We analyzed data from 257 parent-resident dyads. Among these, 45.1% were rated as lacking shared understanding (agreement score = 1 or 2). In multivariate analysis, higher plan complexity (P < .001) and length of stay (P = .002) were associated with lack of shared understanding; lower parental education was a borderline predictor (P = .05). When surveyed, parents and residents reported that they shared an understanding with one another about care plans in 86.0% and 73.1% of cases, respectively.	Parents and night-team residents frequently lack shared understanding. Family-centered care initiatives to improve parent-provider communication and shared understanding may help empower parents as partners in safe and high-quality nighttime care.	
27186359	Circadian expression of clock genes in peripheral tissues is critical to the coordinated regulation of intestinal digestive and absorptive functions, insulin secretion, and peripheral tissue nutrient deposition during periods of nutrient ingestion, thereby preventing metabolic dysregulation. As glucagon-like peptide-1 is a key incretin hormone that regulates glucose-dependent insulin secretion, we hypothesized that this intestinal hormone is a player in the peripheral metabolic clock, linking nutrient ingestion to insulin secretion. We have now established that secretion of glucagon-like peptide-1 from the intestinal L cell shows a rhythmic pattern in rats and humans in vivo that is altered by circadian disruptors, such as constant light exposure, consumption of a Western diet and feeding at inappropriate times (i.e., during the light period in rodents). Interestingly, the alterations in the rhythm of the glucagon-like peptide-1 secretory responses were found to parallel the changes in the pattern of insulin responses in association with significant impairments in glucose tolerance. Furthermore, we have detected circadian clock gene expression, and showed circadian secretion of glucagon-like peptide-1 from both the murine and human L cell in vitro. These findings demonstrate that glucagon-like peptide-1 is a functional component of the peripheral metabolic clock, and suggest that altered release of glucagon-like peptide-1 might play a role in the metabolic perturbations that result from circadian disruption. 
27186326	The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to estimate odds ratios (ORs). The combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score. We examined independent and joint associations of wGRS derived from placental and maternal genomes with PA. Seven SNPs in five genes (ARNTL2, CRY2, DEC1, PER3 and RORA), in the placental genome, were associated with PA risk. Each copy of the minor allele (G) of a SNP in the RORA gene (rs2899663) was associated with a 30% reduced odds of PA (95% CI 0.52-0.95). The odds of PA increased with increasing placental-wGRS (Ptrend<0.001). The ORs were 1.00, 2.16, 3.24 and 4.48 across quartiles. Associations persisted after the maternal-wGRS was included in the model. There was evidence of an additive contribution of placental and maternal genetic contributions to PA risk. Participants with placental- and maternal-wGRS in the highest quartile, compared with those in the lowest quartile, had a 15.57-fold (95% CI 3.34-72.60) increased odds of PA. Placental variants in circadian clock-related genes are associated with PA risk; and the association persists after control of genetic variants in the maternal genome. 
27184153	The aim of this investigation was (1) to evaluate the reliability of laser Doppler flowmetry (LDF) taking into consideration the use of a silicone splint and the inclination of the probe towards the buccal surface of a human tooth and (2) to determine whether diurnal variations of pulpal blood flow can be registered by means of LDF. Forty-one splints were made by one and the same principal investigator for the registration of pulpal blood flow in vivo in a maxillary right central incisor. Thirty dentists, without experience in LDF recording, were then asked to drill a right-angled shaft in a pre-manufactured splint with a referral point at 2 mm from the enamel-cement border central on the buccal surface of the right central upper incisor. The remaining 11 splints were handled by the principal investigator. The shafts in the 30 splints were analysed using Cone Beam CT imaging of the axial and sagittal angles and compared these to the 11 shafts prepared by the trained principal investigator. LDF was recorded for 90 s in each splint and statistically analysed. LDF values without the use of a splint were statistically significantly different (p < 0.05) and the variance was greater, indicating the superiority of splint use. Significant diurnal variations on LDF values were observed, indicating that special attention should be paid to registration during the day, especially when multiple measurements are to be compared. 
27181907	The critical role of metabolic abnormality in hypertension is increasingly recognized, but its biomarkers are not clearly identified. In this study, 47 chemical compounds recorded by literature were employed as target metabolites of essential hypertension (EH). We detected their content in the plasma of EH patients and healthy subjects by using the Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS). After screening the most altered compounds, acupuncture was used to treat patients for 3 months and these plasma metabolites were tested again. The results showed that oleic acid (OA) and myoinositol (MI) were the most important differential metabolites between the hypertensive plasma and the healthy plasma. They were also closely correlated with 24-hour blood pressure and nocturnal dipping. Moreover, plasma OA and MI could be restored to normal levels by acupuncture, accompanying with reduction of 24-hour systolic and diastolic blood pressure [from 145.10 ± 9.28 mm Hg to 140.70 ± 9.59 mm Hg (P < 0.0001), and 88.35 ± 7.92 mm Hg to 85.86 ± 7.95 mm Hg (P = 0.0024), respectively] and improvement of circadian blood pressure rhythm. This study demonstrated that plasma OA and MI were potential hypertension biomarkers and they could be used to preliminarily assess the treating effects such as acupuncture. 
27180068	In patients with neurodegenerative diseases, sleep disorders are common; they impair the quality of life for patients and caregivers and are associated with poorer clinical outcomes. Melatonin has circadian, hypnotic, and free radical-scavenging effects, and preclinical data suggest benefits of melatonin on neurodegeneration. However, randomized, controlled trials of melatonin in patients with neurodegenerative diseases have not shown strong effects. Trials in Alzheimer's patients demonstrate a lack of benefit on sleep quantity. Subjective measures of sleep quality are mixed, with possible symptomatic improvements seen only on some measures or at some time points. Benefits on cognition have not been observed across several studies. In Parkinson's patients, there may be minimal benefit on objective sleep measures, but a suggestion of subjective benefit in few, small studies. Effective treatments for the sleep disorders associated with neurodegenerative diseases are urgently needed, but current data are insufficient to establish melatonin as such a treatment. 
27179881	The present study on zebrafish (Danio rerio) is the first attempt to demonstrate the circadian mRNA expression of melatonin biosynthesizing enzyme genes (Tph1a, Aanat1, Aanat2 and Hiomt) and clock associated genes (Bmal1a, Clock1a, Per1b, Per2 and Cry2a) in the ovary with a comparison to whole brain in normal (LD=12h L:12h D) and altered photic conditions (continuous dark, DD; continuous light, LL). Moreover, the present study also confirmed the ability of zebrafish ovary to biosynthesize melatonin both in vivo and in vitro with a significant difference at day and night. qRT-PCR analysis of genes revealed a dark acrophase of Aanat2 in both organs while Tph1 is in whole brain in LD condition. On the contrary, Bmal1a and Clock1a giving their peak in light, thereby showing a negative correlation with Tph1a and Aanat2. In LD-ovary, the acrophase of Tph1a, Bmal1a and Clock1a is in light and thus display a positive correlation. This trend of relationship in respect to Tph1a is not changing in altered photic conditions in both organs (except in DD-ovary). On the other hand this association for Aanat2 is varying in ovary under altered photic conditions but only in DD-whole brain. Both in LD and LL the expression of Aanat2 in brain presenting an opposite acrophase with both Bmal1a and Clock1a of ovary and consequently displaying a strong negative correlation among them. Interestingly, all ovarian clock associated genes become totally arrhythmic in DD, representing a loss of correlation between the melatonin synthesizing genes in brain and clock associated genes in ovary. The result is also indicating the formation of two heterodimers namely Clock1a:Bmal1a and Per2:Cry2a in the functioning of clock genes in both organs, irrespective of photic conditions, as they are exhibiting a strong significant positive correlation. Collectively, our data suggest that ovary of zebrafish is working as peripheral oscillator having its own melatonin biosynthesizing machinery and signifying a possible correlation with central oscillating system in various photic conditions. 
27179657	Cushing's syndrome (CS) is associated with cardiovascular disease. The impact of the hemodynamic load on left ventricular mass (LVM) in patients with CS is not well known. In fact, the effects of 24-h blood pressure (BP) load and BP circadian rhythm on cardiac structure and function have not been studied. Aim of the present study has thus been to assess the presence of cardiac remodeling in patients with newly diagnosed CS, combining evaluation of cardiac remodeling and assessment of BP burden derived by 24-h ambulatory blood pressure monitoring (ABPM). 25 patients (4 M, 21 F) with CS underwent echocardiography in order to assess cardiac morphology and geometry (relative wall thickness-RWT). As controls, 25 subjects similar for demographic characteristics and 24-h BP were used. CS Patients were similar to controls by age, sex, mean 24-h BP, and body mass index. There was a significant increase in left ventricular mass (LVM; 44.4 ± 14.7 vs. 36.9 ± 10 g/m2.7, p = 0.03) and a significant increase in RWT (0.46 ± 0.07 vs. 0.41 ± 0.08, p = 0.02) in CS patients compared to controls. The prevalence of CS patients with pressure non-dipping profile was greater than that of controls (56 vs. 16 %, p < 0.05), with no significant association with LVM or geometry. 24-h urinary cortisol was not associated with LVM (r = 0.1, p = 0.5) or RWT (r = 0.02, p = 0.89) in the CS group. In conclusion, LVM and the concentric pattern of the left ventricle are relatively independent from 24-h BP load and profile (dipping/non-dipping) in CS patients.
27179365	The apnoea-hypopnoea index (AHI) is the primary measurement used to characterize the obstructive sleep apnoea-hypopnoea syndrome (OSAHS). Despite its popularity, there are limiting factors to its application such as night-to-night variability.To evaluate the variability of AHI in the OSAHS.	A prospective study was designed in our university hospital's sleep unit. Adults with clinical suspicion of OSAHS underwent 2 consecutive nights of polysomnographic recording. The population was divided in two groups according to an AHI>or<10. Patients with psychiatric disorders or professions that might result in sleep deprivation or an altered sleep/wake cycle were excluded.	Twenty patients were enrolled. The mean age was 50.6±9.3 years. OSAHS was mild in 4 cases, moderate in 6 cases and severe in 8 cases. AHI was less than 5 in two cases. AHI values were not significantly altered throughout both recording nights (33.2 vs. 31.8 events/h). A significant positive correlation was found between AHI measured on the first and the second night. However, a significant individual variability was noted. Comparison between both patient's groups showed a correlation between AHI and the body mass index.	This study demonstrates that the AHI in OSAHS patients is well correlated between two consecutive nights. However, a significant individual variability should be taken into consideration, especially when AHI is used in the classification of OSAHS or as a criterion of therapeutic success.	
27179025	The modular architecture of aureochrome blue light receptors, found in several algal groups including diatoms, is unique by having the LOV-type photoreceptor domain fused to the C-terminus of its putative effector, an N-terminal DNA-binding bZIP module. The structural and functional understanding of aureochromes' light-dependent signaling mechanism is limited, despite their promise as an optogenetic tool. We show that class I aureochromes 1a and 1c from the diatom Phaeodactylum tricornutum are regulated in a light-independent circadian rhythm. These aureochromes are capable to form functional homo- and heterodimers, which recognize the ACGT core sequence within the canonical 'aureo box', TGACGT, in a light-independent manner. The bZIP domain holds a more folded and less flexible but extended conformation in the duplex DNA-bound state. FT-IR spectroscopy in the absence and the presence of DNA shows light-dependent helix unfolding in the LOV domain, which leads to conformational changes in the bZIP region. The solution structure of DNA bound to aureochrome points to a tilted orientation that was further validated by molecular dynamics simulations. We propose that aureochrome signaling relies on an allosteric pathway from LOV to bZIP that results in conformational changes near the bZIP-DNA interface without major effects on the binding affinity. 
27177043	A person with a drop of more than 10% in nocturnal arterial blood pressure during the circadian rhythm is referred to as a dipper and one with a smaller decrease is referred to as a non-dipper. In our study, we aimed to compare the thrombolysis in myocardial infarction (TIMI) frame count in non-dipper and dipper hypertensive patient groups who had normal coronary artery angiography.Patients with normal coronary arteries and with ambulatory blood pressure monitoring follow ups were retrospectively investigated and 60 patients (35%, female) were included in our study. The patients were grouped as dipper (n = 30) and non-dipper (n = 30) hypertensives.	The TIMI frame counts in all three coronary arteries and the mean TIMI frame count in the dipper hypertensive patient group were significantly lower than those of the non-dipper hypertensives (right coronary artery TIMI frame count: 16.83 ± 3.70; 21.63 ± 3.44, p < 0.001; circumflex artery TIMI frame count: 21.28 ± 3.52; 25.65 ± 3.61, p < 0.001; left anterior descending artery TIMI frame count: 34.20 ± 2.80; 37.05 ± 3.30, p = 0.001; corrected left anterior descending artery TIMI frame count: 20.05 ± 1.63; 21.74 ± 1.95, p = 0.001; mean TIMI frame count: 19.31 ± 2.3; 22.94 ± 2.61, p < 0.001). The body mass index (BMI) was 23.79 ± 2.81 kg/m2 in the dipper patient group, while it was 25.47 ± 2.92 in the non-dippers. BMI was found to be significantly higher in the non-dipper group than in the dipper group (p = 0.027).	In this study, TIMI frame count, which is a simple, productive, objective and reproducible method for determination of microvascular changes, was found to be higher in non-dipper hypertensive patients than in the dipper patients.	
27173360	Commercial motor vehicle (CMV) drivers in the US may start a new duty cycle after taking a 34-h restart break. A restart break provides an opportunity for sleep recuperation to help prevent the build-up of fatigue across duty cycles. However, the effectiveness of a restart break may depend on its timing, and on how many nighttime opportunities for sleep it contains. For daytime drivers, a 34-h restart break automatically includes two nighttime periods. For nighttime drivers, who are arguably at increased risk of fatigue, a 34-h restart break contains only one nighttime period. To what extent this is relevant for fatigue depends in part on whether nighttime drivers revert back to a nighttime-oriented sleep schedule during the restart break. We conducted a naturalistic field study with 106 CMV drivers working their normal schedules and performing their normal duties. These drivers were studied during two duty cycles and during the intervening restart break. They provided a total of 1260days of data and drove a total of 414,937 miles during the study. Their duty logs were used to identify the periods when they were on duty and when they were driving and to determine their duty cycles and restart breaks. Sleep/wake patterns were measured continuously by means of wrist actigraphy. Fatigue was assessed three times per day by means of a brief psychomotor vigilance test (PVT-B) and a subjective sleepiness scale. Data from a truck-based lane tracking and data acquisition system were used to compute lane deviation (variability in lateral lane position). Statistical analyses focused on 24-h patterns of duty, driving, sleep, PVT-B performance, subjective sleepiness, and lane deviation. Duty cycles preceded by a restart break containing only one nighttime period (defined as 01:00-05:00) were compared with duty cycles preceded by a restart break containing more than one nighttime period. During duty cycles preceded by a restart break with only one nighttime period, drivers showed more nighttime-oriented duty and driving patterns and more daytime-oriented sleep patterns than during duty cycles preceded by a restart break with more than one nighttime period. During duty cycles preceded by a restart break with only one nighttime period, drivers also experienced more lapses of attention on the PVT-B and increased lane deviation at night, and they reported greater subjective sleepiness. Importantly, drivers exhibited a predominantly nighttime-oriented sleep schedule during the restart break, regardless of whether the restart break contained only one or more than one nighttime period. Consistent with findings in laboratory-based studies of the restart break, the results of this naturalistic field study indicate that having at least two nighttime periods in the restart break provides greater opportunity for sleep recuperation and helps to mitigate fatigue. 
27172729	Even though unhealthy consequences of night work for women have been evidenced by international scientific literature only in recent years, they were well acknowledged from ancient times. This essay traces the historical evolution of women's health conditions at work, focusing specifically on nocturnal work. Using the legendary web of Penelope of ancient Greek myths as a metaphor, the paper analyses the early limitations of night-work for women in pre-industrial era and the development of a modern international legislation on this issue, aimed at protecting women's health at the beginning of the twentieth century. The reform of national legislations in a gender-neutral manner has recently abolished gender disparities in night-work, but it seems it also reduced women's protection at work.
27172718	The authors discuss the results of application of melatonin in patients with hypertensive disease. Treatment with melatonin facilitated normalization of arterial pressure and cerebral hemodynamics at night time.
27171500	Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. The mechanisms underlying circadian regulation of autophagy, however, are still unclear. Here, we observed that numbers of autophagosomes and autolysosomes exhibit daily rhythms in the zebrafish liver, and cebpb/(c/ebpβ) and various autophagy genes are rhythmically expressed in zebrafish larvae but significantly upregulated in per1b and TALEN-generated nr1d1/rev-erbα mutant fish, indicating that both Per1b and Nr1d1 play critical roles in autophagy rhythms. Luciferase reporter and ChIP assays show that the circadian clock directly regulates autophagy genes through Nr1d1, and also regulates transcription of cebpb through Per1b. We also found that fasting leads to altered expression of both circadian clock genes and autophagy genes in zebrafish adult peripheral organs. Further, transcriptome analysis reveals multiple functions of Nr1d1 in zebrafish. Taken together, these findings provide evidence for how the circadian clock regulates autophagy, imply that nutritional signaling affects both circadian regulation and autophagy activities in peripheral organs, and shed light on how circadian gene mutations act through autophagy to contribute to common metabolic diseases such as obesity. 
27170536	Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources. 
27170300	Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL. 
27170092	The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes. 
27169989	Summaryplantcell;28/4/tpc.116.tt0416/FIG1F1fig1This teaching tool explores circadian rhythms in plants. The topic is presented as a series of concepts illustrated by examples, including the architecture of circadian clocks and the connections between the oscillator and circadian-regulated processes such as metabolism and flowering. The Teaching Tool introduces some of the techniques used to investigate circadian biology and explores how understanding circadian rhythms could lead to crop improvement. 
27169471	Huanglongbing (HLB) and tristeza, are diseases of citrus caused by a member of the α-proteobacteria, 'Candidatus Liberibacter asiaticus' (CaLas), and Citrus tristeza virus (CTV) respectively. HLB is a devastating disease, but CTV strains vary from very severe to very mild. Both CaLas and CTV are phloem-restricted. The CaLas-B232 strain and CTV-B6 cause a wide range of severe and similar symptoms. The mild strain CTV-B2 doesn't induce significant symptoms or damage to plants.Transcriptome profiles obtained through RNA-seq revealed 611, 404 and 285 differentially expressed transcripts (DETs) after infection with CaLas-B232, CTV-B6 and CTV-B2. These DETs were components of a wide range of pathways involved in circadian rhythm, cell wall modification and cell organization, as well as transcription factors, transport, hormone response and secondary metabolism, signaling and stress response. The number of transcripts that responded to both CTV-B6 and CaLas-B232 was much larger than the number of transcripts that responded to both strains of CTV or to both CTV-B2 and CaLas-B232. A total of 38 genes were assayed by RT-qPCR and the correlation coefficients between Gfold and RT-qPCR were 0.82, 0.69, 0.81 for sweet orange plants infected with CTV-B2, CTV-B6 and CaLas-B232, respectively.	The number and composition of DETs reflected the complexity of symptoms caused by the pathogens in established infections, although the leaf tissues sampled were asymptomatic. There were greater similarities between the sweet orange in response to CTV-B6 and CaLas-B232 than between the two CTV strains, reflecting the similar physiological changes caused by both CTV-B6 and CaLas-B232. The circadian rhythm system of plants was perturbed by all three pathogens, especially by CTV-B6, and the ion balance was also disrupted by all three pathogens, especially by CaLas-B232. Defense responses related to cell wall modification, transcriptional regulation, hormones, secondary metabolites, kinases and stress were activated by all three pathogens but with different patterns. The transcriptome profiles of Citrus sinensis identified host genes whose expression is affected by the presence of a pathogen in the phloem without producing symptoms (CTV-B2), and host genes whose expression leads to induction of symptoms in the plant (CTV-B6, CaLas-B232).	
27168152	The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1) was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS) whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration. These results suggest that pro-inflammatory stimuli can disrupt circadian rhythms in macrophages and that impaired circadian rhythms may contribute to cardiovascular diseases by altering macrophage behavior. 
27167607	The role of melatonin in maintaining proper function of the circadian system has been proposed but very little evidence for such an effect has been provided. To ascertain the role, the aim of the study was to investigate impact of long-term melatonin absence on regulation of circadian system. The parameters of behavior and circadian clocks of rats which were devoid of the melatonin signal due to pinealectomy (PINX) for more than one year were compared with those of intact age-matched controls. PINX led to a decrease in spontaneous locomotor activity and a shortening of the free-running period of the activity rhythm driven by the central clock in the suprachiasmatic nuclei (SCN) in constant darkness. However, the SCN-driven rhythms in activity and feeding were not affected and remained well entrained in the light/dark cycle. In contrast, in these conditions PINX had a significant effect on amplitudes of the clock gene expression rhythms in the duodenum and also partially in the liver. These results demonstrate the significant impact of long-term melatonin absence on period of the central clock in the SCN and the amplitudes of the peripheral clocks in duodenum and liver and suggest that melatonin might be a redundant but effective endocrine signal for these clocks. 
27167478	The prevalence of the insomnia syndrome and the effects of caffeine on sleep are in part genetically determined. Pharmacogenetic studies in humans demonstrate that functional polymorphisms of the genes encoding adenosine A2A receptors and dopamine transporters contribute to individual differences in impaired sleep quality by caffeine. The A2A receptor and dopamine transporter are preferentially expressed in the striatum. Together, these observations suggest that the striatum plays an important role in sleep-wake regulation. Individual caffeine sensitivity and A2A receptor genotype should be taken into account in the development of possible novel adenosine-based pharmacotherapies of sleep-wake disorders and neurodegenerative disorders such as Parkinson's disease. This may permit the prediction of individual drug effects and improve the reliability of clinical trials.
27166084	Crohn's disease (CD) and ulcerative colitis (UC) are the main representatives of inflammatory bowel diseases (IBD), a group of chronic, immune system-mediated inflammatory diseases of the gastrointestinal (GI) tract. The pathogenesis of the intestinal lesions in IBD is not entirely identified and understood: excessive activation of the immune system may come as a result of the interaction of various environmental and infectious factors, genetic predisposition, and the mediation of abnormal intestinal flora. The main objective of the current study is to further identify the risk factors for the development of IBD. Currently, there is very little knowledge about circadian rhythm and IBD and there are only a few studies on the relationship between sleep disturbances and the course of the disease, as well as pro- and anti-inflammatory cytokine profile and general immune system functioning. Furthermore, the relationship between the expression of circadian rhythm genes and severe course of IBD is still unknown. The aim of this review is to show the current state of knowledge about the relationship between circadian rhythm disorders, sleep disturbance and inflammation in the GI tract and to analyze the possibility of employing this knowledge in diagnosis and treatment of IBD. 
27165820	The kidney is influenced by circadian rhythms and is entrained to the sleep-wake cycle allowing anticipation of the metabolic and physiological demands of the kidney throughout a 24-hour cycle. Although sleep disruption has been studied extensively in cardiovascular and metabolic disease, its association with chronic kidney disease has not been shown. We examined this in a prospective cohort study of 4238 participants from the Nurses' Health Study and analyzed the association of self-reported sleep duration with decline in renal function over an 11-year period (1989 to 2000). Individuals who reported shorter sleep duration were more likely to experience a rapid decline in estimated glomerular filtration rate (30% or more). Compared with sleeping 7 to 8 hours per night, the adjusted odds ratios for a rapid decline in renal function were a significant 1.79 (95% CI, 1.06-3.03) for 5 hours or less sleep per night, a significant 1.31 (95% CI, 1.01-1.71) for 6 hours sleep per night, but an insignificant 0.88 (95% CI, 0.50-1.57) for 9 or more hours sleep per night. Similarly, there was a significant trend in the adjusted annualized decline in estimated glomerular filtration rate of 1.2 ml/min/1.73 m(2)/year, 0.9 ml/min/1.73 m(2)/year, 0.8 ml/min/1.73 m(2)/year, and 0.8 ml/min/1.73 m(2)/year for individuals sleeping 5 hours or less per night, 6 hours per night, 7 to 8 hours per night, and 9 hours or more per night, respectively. Thus, shorter sleep duration is prospectively and independently associated with faster decline in renal function. 
27165273	The metabolic syndrome (MS) is a collection of risk factors for cardiovascular disease, including obesity, hypertension, hyperinsulinemia, glucose intolerance and dyslipidemia. MS is associated with low-grade inflammation of the white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance and diabetes. Adipocytes secrete proinflammatory cytokines as well as leptin and trigger a vicious circle which leads to additional weight gain largely as fat. The imbalance between inflammatory and anti-inflammatory signals is crucial to aging. Healthy aging can benefit from melatonin, a compound known to possess direct and indirect antioxidant properties, to have a significant protective effect on mitochondrial function, to enhance circadian rhythm amplitudes, to modulate the immune system and to exhibit neuroprotective actions. Melatonin levels decrease in the course of senescence and are more strongly reduced in diseases related to insulin resistance. This short review article analyzes the multiple protective actions of melatonin that are relevant to the attenuation of inflammatory responses and progression of inflammaging and how melatonin is effective to curtail MS in animal models of hyperadiposity. The clinical data supporting the possible therapeutic use of melatonin in human MS are also reviewed. Since attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, piromelatine) and in clinical trials these analogs were administered in doses considerably higher than those usually employed for melatonin, clinical trials on melatonin in the range of 50-100 mg/day are needed to further assess its therapeutic value in MS.
27165169	The hemodynamics of 17β-estradiol (E2) synthesized and secreted from the stomach has been revealed gradually. This study aimed to clarify the circadian rhythm of E2 synthesis and secretion in the stomach, and the relationship between the expression of hepatic estrogen receptor (ER) α and serum E2 levels in systemic circulation. Wistar male rats were maintained in a room with a 12-h light and 12-h dark cycle (lights on from 0700 to 1900 h), and were sacrificed at every 4-hour interval starting at 0800 h. The results showed that the expression of gastric Cyp19a1 was higher in nighttime than in daytime, and that the portal venous E2 level was 2.2 times higher at 2400 h than that at 1200 h. The arterial E2 level was also the highest at 2400 h, and showed an apparent circadian rhythm positively correlated with portal venous E2 levels. Conversely, the expression of liver Esr1 peaked at 1200 h and turned to decrement at 2400 h. The population of immunoreactive nuclei with ERα antibody decreased at 2400 h compared with that at 1200 h. The regression analysis showed that the liver Esr1 mRNA was negatively correlated to portal venous and arterial E2 levels. It could be concluded that the circadian rhythm of the systemic E2 level depended both on the amounts of gastric E2 in the portal vein and on the Esr1 expression in the liver. 
27164924	In the absence of a comprehensive neural model to explain the underlying mechanisms of disturbed circadian function in bipolar disorder, mathematical modeling is a helpful tool. Here, circadian activity as a response to exogenous daily cycles is proposed to be the product of interactions between neuronal networks in cortical (cognitive processing) and subcortical (pacemaker) areas of the brain.To investigate the dynamical aspects of the link between disturbed circadian activity rhythms and abnormalities of neurotransmitter functioning in frontal areas of the brain, we developed a novel mathematical model of a chaotic system which represents fluctuations in circadian activity in bipolar disorder as changes in the model's parameters.	A novel map-based chaotic system was developed to capture disturbances in circadian activity across the two extreme mood states of bipolar disorder. The model uses chaos theory to characterize interplay between neurotransmitter functions and rhythm generation; it aims to illuminate key activity phenomenology in bipolar disorder, including prolonged sleep intervals, decreased total activity and attenuated amplitude of the diurnal activity rhythm. To test our new cortical-circadian mathematical model of bipolar disorder, we utilized previously collected locomotor activity data recorded from normal subjects and bipolar patients by wrist-worn actigraphs.	All control parameters in the proposed model have an important role in replicating the different aspects of circadian activity rhythm generation in the brain. The model can successfully replicate deviations in sleep/wake time intervals corresponding to manic and depressive episodes of bipolar disorder, in which one of the excitatory or inhibitory pathways is abnormally dominant.	Although neuroimaging research has strongly implicated a reciprocal interaction between cortical and subcortical regions as pathogenic in bipolar disorder, this is the first model to mathematically represent this multilevel explanation of the phenomena of bipolar disorder.	
27162542	Ovarian cancer is the third most common gynaecological malignancy. Changes in circadian rhythms such as bright light exposure may affect female reproductive physiology. Night shift work is associated with higher risks of developing gynaecological cancers. In addition, the season of birth is also suggested as an important environmental risk factor for developing gynaecological cancers. Melatonin may play an important role in this association as a marker of circadian rhythms. Serum from 96 women with ovarian cancer and 40 healthy women were collected and the level of melatonin was measured. In addition 277 women with ovarian cancer and 1076 controls were retrospectively collected for season of birth analysis over seven years. The serum levels of melatonin were significantly lower in women with ovarian cancer compared with healthy women (p<0.05). However there was no difference in melatonin levels in perimenopausal and postmenopausal patients. In addition, there is no statistically significant difference in seasonal distribution of birth between ovarian cancer patients and the control group. The melatonin levels in ovarian cancer patients and controls were not associated with the season of birth. Our results demonstrate the lower serum levels of melatonin in ovarian cancer patients which may contribute to the pathogenesis of ovarian cancer. The incidence of ovarian cancer was not associated with the season of birth. The serum levels of melatonin do not appear to be associated with season of birth in ovarian cancer patients. 
27162360	Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light-dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir-276a-binding site in the tim 3' UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions.
27161966	Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL.We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters.	Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters.	Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.	
27161955	The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, we explored between-subject variability (BSV) and circadian rhythmicity in DPD and TS activity in human volunteers.The BSVs in DPD activity (n = 20) in peripheral blood mononuclear cells (PBMCs) and in plasma, measured by means of the dihydrouracil (DHU) and uracil (U) plasma levels and DHU : U ratio (n = 40), and TS activity in PBMCs (n = 19), were examined. Samples were collected every 4 h throughout 1 day for assessment of circadian rhythmicity in DPD and TS activity in PBMCs (n = 12) and DHU : U plasma ratios (n = 23). In addition, the effects of genetic polymorphisms and gene expression on DPD and TS activity were explored.	Population mean (± standard deviation) DPD activity in PBMCs and DHU : U plasma ratio were 9.2 (±2.1) nmol mg(-1) h(-1) and 10.6 (±2.4), respectively. Individual TS activity in PBMCs ranged from 0.024 nmol mg(-1) h(-1) to 0.596 nmol mg(-1) h(-1) . Circadian rhythmicity was demonstrated for all phenotype markers. Between 00:30 h and 02:00 h, DPD activity in PBMCs peaked, while the DHU : U plasma ratio and TS activity in PBMCs showed trough activity. Peak-to-trough ratios for DPD and TS activity in PBMCs were 1.69 and 1.62, respectively. For the DHU : U plasma ratio, the peak-to-trough ratio was 1.43.	BSV and circadian variability in DPD and TS activity were demonstrated. Circadian rhythmicity in DPD might be tissue dependent. The results suggested an influence of circadian rhythms on phenotype-guided fluoropyrimidine dosing and supported implications for chronotherapy with high-dose fluoropyrimidine administration during the night.	
27161526	The neuropeptide PDF promotes the normal sequencing of circadian behavioral rhythms in Drosophila, but its signaling mechanisms are not well understood. We report daily rhythmicity in responsiveness to PDF in critical pacemakers called small LNvs. There is a daily change in potency, as great as 10-fold higher, around dawn. The rhythm persists in constant darkness and does not require endogenous ligand (PDF) signaling or rhythmic receptor gene transcription. Furthermore, rhythmic responsiveness reflects the properties of the pacemaker cell type, not the receptor. Dopamine responsiveness also cycles, in phase with that of PDF, in the same pacemakers, but does not cycle in large LNv. The activity of RalA GTPase in s-LNv regulates PDF responsiveness and behavioral locomotor rhythms. Additionally, cell-autonomous PDF signaling reversed the circadian behavioral effects of lowered RalA activity. Thus, RalA activity confers high PDF responsiveness, providing a daily gate around the dawn hours to promote functional PDF signaling. 
27161048	Sleep disorders are common are common following traumatic brain injury.In this article we review the spectrum and proposed mechanisms of traumatic brain injury associated sleep disorders and discuss the clinical approach to diagnosis and management of these disorders.	Disordered sleep and wakefulness after traumatic brain injury is common. Sleep disruption contributes to morbidity, such as the development of neurocognitive and neurobehavioral deficits, and prolongs the recovery phase after injury. Early recognition and correction of these problems may limit the secondary effects of traumatic brain injury and improve patient outcomes.	Evaluating sleep disorders in traumatic brain injury should be an important component of post-traumatic brain injury assessment and management.	
27160717	Endogenous Cushing's syndrome (CS) is a rare disease, and usually characterized by hypertension, diabetes, obesity, osteoporosis, facial rounding, dorsocervical fat pad, thin skin, purple striae, hirsutism, and mood disorders. Efficient diagnostic and screening strategies lead to the diagnosis of a significantly higher number of cases of CS. As a screening test for CS, the Endocrine Society's Clinical Practice Guidelines recommend a single test with a high diagnostic accuracy, among the 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and 24 h urinary free cortisol (UFC). In normal subjects, administering a higher than physiological dose of glucocorticoids prompts the suppression of cortisol secretion. The 1-mg DST explores this normal feedback reaction from the hypothalamic-pituitary-adrenal axis (HPA). It is a simple dynamic test, usually performed in outpatients. A morning serum cortisol level <50 nmol/L suffices to exclude CS, unless there is a strong clinical suspicion to suggest otherwise. The HPA axis reaches a nadir just after a person has fallen asleep, but its circadian rhythm is impaired in CS patients, who feature higher cortisol values at night, which are easy to measure in saliva (the LNSC assay). Saliva collection is also suitable for outpatients since cortisol is stable at room temperature and the collection device can be mailed to the laboratory for analysis. UFC levels reflect the integrated tissue exposure to free cortisol over 24 h, and thus provide a particular picture of endogenous hypercortisolism. In most cases, high UFC levels coincide with severe hypercortisolism. UFC is used not only to diagnose CS, but also to monitor its response to medical treatment. All screening tests have procedural snares: some drugs can interfere with the DST; false-positive or false-negative LNSC results may be due to an inadequate soaking of the device or to cyclic CS; and in the case of UFC it is important to ensure that patients provide complete urine collections with appropriate total volumes. Measuring cortisol with antibody-based immunoassays can also generate false-positive results due to cross-reactivity between cortisol, cortisone and other metabolites. Structurally-based assays, such as liquid chromatography with tandem mass spectrometry, only measure cortisol and have only recently become available for use in routine clinical practice. This review summarizes the recent literature on the clinical and biochemical aspects of CS diagnostics with a view to helping physicians choose the best screening test for diagnosing endogenous hypercortisolism. 
27160587	Whether temporal differences alter the clinical outcomes of patients with out-of-hospital cardiac arrest (OHCA) remains inconclusive. Furthermore, the relationship between time of day and resuscitation efforts is unknown.We studied adult OHCA patients in the Survey of Survivors after Out-of-Hospital Cardiac Arrest in the Kanto Region (SOS-KANTO) 2012 study from January 2012 to March 2013 in Japan. The primary variable was 1-month survival. The secondary outcome variables were prehospital and in-hospital resuscitation efforts by bystanders, emergency medical services personnel, and in-hospital healthcare providers. Daytime was defined as 0701 to 1500 h, evening was defined as 1501 to 2300 h, and night was defined as 2301 to 0700 h.	During the study period, 13,780 patients were included in the analysis. The patients with night OHCA had significantly lower 1-month survival compared to the patients with daytime OHCA (night vs. daytime, adjusted odds ratio (OR) 1.66; 95 % confidence interval (CI), 1.34-2.07; P < 0.0001). The nighttime OHCA patients had significantly shorter call-response intervals, bystander CPR, in-hospital intubation, and in-hospital blood gas analyses compared to the daytime and evening OHCA patients (call-response interval: OR 0.95 and 95 % CI 0.93-0.96; bystander CPR: OR 0.85 and 95 % CI 0.78-0.93; in-hospital intubation: OR 0.85 and 95 % CI 0.74-0.97; and in-hospital blood gas analysis: OR 0.86 and 95 % CI 0.75-0.98).	There was a significant temporal difference in 1-month survival after OHCA. The nighttime OHCA patients had significantly decreased resuscitation efforts by bystanders and in-hospital healthcare providers compared to those with evening and daytime OHCA.	
27159553	Animal migrations are costly and are often characterized by high predation risk for individuals. Three of the most oft-assumed mechanisms for reducing risk for migrants are swamping predators with high densities, specific timing of migrations and increased body size. Assessing the relative importance of these mechanisms in reducing predation risk particularly for migrants is generally lacking due to the difficulties in tracking the fate of individuals and population-level characteristics simultaneously. We used acoustic telemetry to track migration behaviour and survival of juvenile sockeye salmon (Oncorhynchus nerka) smolts released over a wide range of conspecific outmigration densities in a river associated with poor survival. The landscape was indeed high risk; smolt survival was poor (˜68%) over 13·5 km of river examined even though migration was rapid (generally <48 h). Our results demonstrate that smolts largely employ swamping of predators to reduce predation risk. Increased densities of co-migrant conspecifics dramatically improved survival of smolts. The strong propensity for nocturnal migration resulted in smolts pausing downstream movements until the next nightfall, greatly increasing relative migration durations for smolts that could not traverse the study area in a single night. Smolt size did not appear to impact predation risk, potentially due to unique characteristics of the system or our inability to tag the entire size range of outmigrants. Movement behaviours were important in traversing this high-risk landscape and provide rare evidence for swamping to effectively reduce individual predation risk.
27159443	We investigated whether 24-hour monitoring of corneoscleral limbus area (CSLA) with the Sensimed Triggerfish contact lens sensor (CLS) can be used clinically to assess midterm efficacy of canaloplasty and to assess the relationships of CSLA changes with the heart rhythm.Ten eyes of 10 patients, with POAG, which were qualified either to canaloplasty or canaloplasty and phacoemulsification, were included in this study. Eyes were washed out before the surgery and control visits were done at days 1, 7, and 3, 6, 12 months postoperatively, at which subjects were examined. We performed 24-hour monitoring of CSLA changes and Holter ECG at washout, and at 3- and 12-month postop visits. Raw CLS signals were processed to lead two parameters describing short-term 24-hour variability of CSLA (VAR, â). Heart activity parameters from CLS were compared to those acquired from Holter ECG.	Mean post washout IOP was 20.6 ± 4.7 and decreased to 14.2 ± 3.0 mm Hg 1 year after surgery (P < 0.01). A decreasing trend in VAR and â parameters were noted. Statistically significant differences were found between the washout and 3-month postop visit for VAR and â (P = 0.014 and P = 0.027, respectively) as well as between the washout and 12-month postop result for the parameter â (P = 0.031). No statistically significant differences were found between the 3- and 12-month postop results for both considered parameters.	Canaloplasty alone or combined with cataract surgery is a successful surgical method of lowering IOP in glaucoma patients. Canaloplasty decreases 24-hour CSLA fluctuation pattern measured with CLS.	
27159160	We analyzed the association between change in work schedule and modifications in nutritional status. We performed a panel study with nursing professionals based on two surveys seven year apart (n = 372). Groups with no change in work schedule, change from daytime to night shift, and change from night to daytime shift were analyzed. Outcomes were weight gain and body mass index (BMI) category increase. Participants who changed from daytime to night shift showed about twice increase in odds of more than 5 kg weight gain and BMI category increase. Changing from daytime to night work seems to influence weight and BMI. 
27157688	The purpose of this study was to investigate the acute physiological stress response to an emergency alarm and mobilization during the day and at night. Sixteen healthy males aged 25 ± 4 years (mean ± SD) spent four consecutive days and nights in a sleep laboratory. This research used a within-participants design with repeated measures for time, alarm condition (alarm or control), and trial (day or night). When an alarm sounded, participants were required to mobilize immediately. Saliva samples for cortisol analysis were collected 0 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after mobilization, and at corresponding times in control conditions. Heart rate was measured continuously throughout the study. Heart rate was higher in the day (F(20,442) = 9.140, P < 0.001) and night (F(23,459) = 8.356, P < 0.001) alarm conditions compared to the respective control conditions. There was no difference in saliva cortisol between day alarm and day control conditions. Cortisol was higher (F(6,183) = 2.450, P < 0.001) following the night alarm and mobilization compared to the night control condition. The magnitude of difference in cortisol between night control and night alarm conditions was greater (F(6,174) = 4.071, P < 0.001) than the magnitude of difference between the day control and day alarm conditions. The augmented heart rate response to the day and night alarms supports previous observations in field settings. Variations in the cortisol responses between conditions across the day and night may relate to differences in participants' ability to interpret the alarm when sleeping versus when awake.
27156901	Hypertension may be the most modifiable risk factor for post-stroke cognitive impairment (PSCI). We investigated how home blood pressure (HBP) can predict PSCI as well as stroke recurrence.We studied 249 consecutive patients with noncardioembolic minor ischemic stroke including single lacunar infarct (sLI), multiple lacunae (mLI), and atherothrombotic infarction, which were tracked at our outpatient clinic. HBP was measured in the early morning (m-HBP) and just before going to bed (b-HBP). HBP categories based on systolic blood pressure were created as follows: HB1, both m-HBP and b-HBP less than 135 (mmHg); HB2, m-HBP less than or equal to135 and b-HBP less than 135; HB3, m-HBP less than 135 and b-HBP less than or equal to 135; HB4, both m-HBP and b-HBP less than or equal to 135. After 4.1 years of tracking, the patients were divided into 4 groups: Group 1, good outcome (n = 188); Group 2, the development of silent infarcts (n = 16); Group 3, the development of PSCI (n = 33); and Group 4, stroke recurrence (n = 15).	HB2 and HB4 (versus HB1) (hazard ratio [HR]: 6.5, P = .0068 and HR: 9.5, P = .0008, respectively) and mLI (versus sLI) (HR: 4.0, P = .021) were independently associated with Group 2. HB3 and HB4 (HR: 4.2, P = .037; HR: 5.4, P < .0001) and mLI (HR: 6.4, P < .0001) were significantly associated with Group 3. HB4 (HR: 8.1, P = .0002) and mLI (HR: 10.2, P = .0003) were significantly associated with Group 4. Clinic blood pressure (BP) was not significantly associated with any adverse groups.	High HBP and mLI were strongly associated with PSCI as well as stroke recurrence. BP should be monitored based on HBP, especially bedtime HBP, for the prevention of PSCI.	
27155052	The role of light and feeding cycles in synchronizing self-feeding and locomotor activity rhythms was studied in white shrimps using a new self-feeding system activated by photocell trigger. In experiment 1, shrimps maintained under a 12:12h light/dark (LD) photoperiod were allowed to self-feed using feeders connected to a photoelectric cell, while locomotor activity was recorded with a second photocell. On day 30, animals were subjected to constant darkness (DD) for 12days to check the existence of endogenous circadian rhythms. In the experiment 2, shrimps were exposed to both a 12:12h LD photoperiod and a fixed meal schedule in the middle of the dark period (MD, 01:00h). On day 20, shrimps were exposed to DD conditions and the same fixed feeding. On day 30, they were maintained under DD and fasted for 7days. The results revealed that under LD, shrimps showed a clear nocturnal feeding pattern and locomotor activity (81.9% and 67.7% of total daily food-demands and locomotor activity, respectively, at nighttime). Both feeding and locomotor rhythms were endogenously driven and persisted under DD with an average period length (τ) close to 24h (circadian) (τ=24.18±0.13 and 23.87±0.14h for locomotor and feeding, respectively). Moreover, Shrimp showed a daily food intake under LD condition (1.1±0.2gday(-1) in the night phase vs. 0.2±0.1gday(-1) in the light phase). Our findings might be relevant for some important shrimp aquaculture aspects, such as developing suitable feeding management on shrimp farms. 
27154468	Male vocal displays play an important role in sexual selection in many species. If there are costs or constraints, calls may convey honest information about the caller. We studied the loud calls of male simakobu (Simias concolor), a sexually dimorphic primate that resides in one-male groups, on Siberut Island, Indonesia.We combined behavioral and ecological data with acoustic analysis to determine the influence of energy costs and status on calling effort. Based on all-day follows (n = 107) and loud-call recordings (n = 186), we determined how calling rates and durations varied in relation to short-term (time of day, temperature, travel distance) and long-term (fruit availability, physical condition) measures of energy availability and expenditure.	We found that males avoided calling at the hottest times of the day, and produced shorter calls at higher temperatures, supporting the hypothesis that calls are influenced by thermoregulation costs. A peak of longer duration calls just before sunrise, however, could not be explained by energy constraints, but we hypothesize that this pattern is related to the fact that dawn calls occur in choruses, motivating males to call longer than their neighbors. Contrary to predictions, calling rates increased with decreasing fruit availability and did not appear to be energetically costly.	We hypothesize that calling rates instead reflect strategies involving feeding and/or mate competition, signaling the motivation, rather than fighting ability, of the caller. Overall, results only weakly support the hypothesis that the timing and duration-but not rate-of simakobu loud calls are influenced by energy costs. Am J Phys Anthropol 161:44-52, 2016. © 2016 Wiley Periodicals, Inc.	
27154335	The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the master circadian clock that coordinates daily rhythms in behavior and physiology in mammals. Like other hypothalamic nuclei, the SCN displays an impressive array of distinct cell types characterized by differences in neurotransmitter and neuropeptide expression. Individual SCN neurons and glia are able to display self-sustained circadian rhythms in cellular function that are regulated at the molecular level by a 24h transcriptional-translational feedback loop. Remarkably, SCN cells are able to harmonize with one another to sustain coherent rhythms at the tissue level. Mechanisms of cellular communication in the SCN network are not completely understood, but recent progress has provided insight into the functional roles of several SCN signaling factors. This review discusses SCN organization, how intercellular communication is critical for maintaining network function, and the signaling mechanisms that play a role in this process. Despite recent progress, our understanding of SCN circuitry and coupling is far from complete. Further work is needed to map SCN circuitry fully and define the signaling mechanisms that allow for collective timekeeping in the SCN network. 
27154303	The Arabian oryx inhabits an environment where summer ambient temperatures can exceed 40 °C for extended periods of time. While the oryx uses a suite of adaptations that aid survival, the effects of this extreme environment on inactivity are unknown. To determine how the oryx manages inactivity seasonally, we measured the daily rhythm of body temperature and used fine-grain actigraphy, in 10 animals, to reveal when the animals were inactive in relation to ambient temperature and photoperiod. We demonstrate that during the cooler winter months, the oryx was inactive during the cooler parts of the 24-h day (predawn hours), showing a nighttime (nocturnal) inactivity pattern. In contrast, in the warmer summer months, the oryx displayed a bimodal inactivity pattern, with major inactivity bouts (those greater than 1 h) occurring equally during both the coolest part of the night (predawn hours) and the warmest part of the day (afternoon hours). Of note, the timing of the daily rhythm of body temperature did not vary seasonally, although the amplitude did change, leading to a seasonal alteration in the phase relationship between inactivity and the body temperature rhythm. Because during periods of inactivity the oryx were presumably asleep for much of the time, we speculate that the daytime shift in inactivity may allow the oryx to take advantage of the thermoregulatory physiology of sleep, which likely occurs when the animal is inactive for more than 1 h, to mitigate environmentally induced increases in body temperature. 
27153809	Recent evidence indicates that histamine, acting on histamine 1 receptor (H1R), resets the circadian clock in the mouse suprachiasmatic nucleus (SCN) by increasing intracellular Ca(2+) concentration ([Ca(2+)]i) through the activation of CaV1.3 L-type Ca(2+) channels and Ca(2+)-induced Ca(2+) release from ryanodine receptor-mediated internal stores.In the current study, we explored the underlying mechanisms with various techniques including Ca(2+)- and Cl(-)-imaging and extracellular single-unit recording. Our hypothesis was that histamine causes Cl(-) efflux through cystic fibrosis transmembrane conductance regulator (CFTR) to elicit membrane depolarization needed for the activation of CaV1.3 Ca(2+) channels in SCN neurons. We found that histamine elicited Cl(-) efflux and increased [Ca(2+)]i in dissociated mouse SCN cells. Both of these events were suppressed by bumetanide [Na(+)-K(+)-2Cl(-) cotransporter isotype 1 (NKCC1) blocker], CFTRinh-172 (CFTR inhibitor), gallein (Gβγ protein inhibitor) and H89 [protein kinase A (PKA) inhibitor]. By itself, H1R activation with 2-pyridylethylamine increased the level of cAMP in the SCN and this regulation was prevented by gallein. Finally, histamine-evoked phase shifts of the circadian neural activity rhythm in the mouse SCN slice were blocked by bumetanide, CFTRinh-172, gallein or H89 and were not observed in NKCC1 or CFTR KO mice.	Taken together, these results indicate that histamine recruits the H1R-Gβγ-cAMP/PKA pathway in the SCN neurons to activate CaV1.3 channels through CFTR-mediated Cl(-) efflux and ultimately to phase-shift the circadian clock. This pathway and NKCC1 may well be potential targets for agents designed to treat problems resulting from the disturbance of the circadian system.	
27153131	We examined whether hypothalamic-pituitary-adrenal axis activity in the nestlings of a semialtricial raptor, the black kite (Milvus migrans), varied with advancing age, throughout the day, and in response to a number of socioecological factors presumed to affect allostatic load. Both baseline corticosterone (CORT) titers and maximum CORT levels during 30 min of handling and restraint augmented across all sampled ages, suggesting that nestlings' energetic demands and capacity to respond to perturbations increase progressively throughout development. CORT secretion also peaked in the early morning, reached minimum levels in the central hours of the day, and increased again before dusk, suggesting a possible role of CORT in the regulation of activity-inactivity patterns. Finally, nestlings raised in a year of low marsh inundation, implying lower food availability and heightened allostatic loads, exhibited higher adrenocortical responsiveness to stress than nestlings raised in years of intermediate or high flooding. The nondetectable effect of other socioecological variables, such as territory quality, temperature, or brood order, suggests that parents may be able to buffer their nestlings from adverse environmental conditions or that the effect of such factors may have been obscured by selective mortality operating before sampling. We propose that future studies increase the simultaneous use of complementary techniques (fecal sampling, feather analysis) to reach firmer and more comprehensive conclusions, especially for planning the management and conservation of sensitive species.
27152260	Sleep disorders have a profound and well-documented impact on overall health and quality of life in the general population. In patients with chronic disease, sleep disorders are more prevalent, with an additional morbidity and mortality burden. The complex and dynamic relationship between sleep disorders and chronic kidney disease (CKD) remain relatively little investigated. This article presents an overview of sleep disorders in patients with CKD, with emphasis on relevant pathophysiologic underpinnings and clinical presentations. Evidence-based interventions will be discussed, in the context of individual sleep disorders, namely sleep apnea, insomnia, restless leg syndrome and excessive daytime sleepiness. Limitations of the current knowledge as well as future research directions will be highlighted, with a final discussion of different conceptual frameworks of the relationship between sleep disorders and CKD. 
27151213	Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle. Analysis of hGH1 promoter sequences revealed an enhancer motif (E-box) element that binds the circadian transcriptional machinery (Bmal1 and Clock). Furthermore, Bmal1/Clock were able to transactivate the hGH1 promoter, and mutation of this E-box element adversely affected basal activity after gene transfer. The ability of Bmal1 to bind the hGH1 promoter region containing the E-box element was confirmed in the hGH1 transgenic mouse pituitary in situ Occupancy was reduced in mice fed a high fat diet during the light (inactive) stage of the daily cycle in mice and corresponded to a decrease in hGH1 RNA levels. The decreases in occupancy and RNA levels were not seen, however, during the dark (active) stage. A chromatin loop required for efficient postnatal hGH1 expression was negatively affected by the high fat diet in the light but not dark stage similar to the pattern observed with Bmal1 association with the promoter region. This is the first evidence that hGH synthesis follows a diurnal rhythm and of dynamic associations of the circadian machinery with a component of a chromosomal structure of the hGH1 locus that is essential for efficient expression.
27151044	The aim of this work is the investigation of measures of ambulatory brachial and aortic blood pressure and indices of arterial stiffness and aortic wave reflection in Marfan patients.A case-control study was conducted including patients with diagnosed Marfan syndrome following Ghent2 nosology and healthy controls matched for sex, age and daytime brachial systolic blood pressure. For each subject a 24 h ambulatory blood pressure and 24 h pulse wave analysis measurement was performed.	All parameters showed a circadian pattern whereby pressure dipping was more pronounced in Marfan patients. During daytime only Marfan patients with aortic root surgery showed increased pulse wave velocity. In contrast, various nighttime measurements, wave reflection determinants and circadian patterns showed a significant difference.	The findings of our study provide evidence that ambulatory measurement of arterial stiffness parameters is feasible and that these determinants are significantly different in Marfan syndrome patients compared to controls in particular at nighttime. Further investigation is therefore indicated.	
27150337	The pineal gland, as part of the human epithalamus, is the main production site of peripheral melatonin, which promotes the modulation of sleep patterns, circadian rhythms and circadian preferences (morningness vs. eveningness). The present study analyses the pineal gland volume (PGV) and its association with circadian preferences and symptom severity in adult ADHD patients compared to healthy controls. PGV was determined manually using high-resolution 3T MRI (T1-magnetization prepared rapid gradient echo) in medication free adult ADHD patients (N=74) compared to healthy controls (N=86). Moreover, the Morningness-Eveningness Questionnaire (MEQ), the ADHD Diagnostic Checklist and the Wender-Utah Rating Scale were conducted. PGV differed between both groups (patients: 59.9±33.8mm(3); healthy controls: 71.4±27.2mm(3), P=0.04). In ADHD patients, more eveningness types were revealed (patients: 29%; healthy controls: 17%; P=0.05) and sum scores of the MEQ were lower (patients: 45.8±11.5; healthy controls 67.2±10.1; P<0.001). Multiple regression analyses indicated a positive correlation of PGV and MEQ scores in ADHD (β=0.856, P=0.003) but not in healthy controls (β=0.054, P=0.688). Patients' MEQ scores (β=-0.473, P=0.003) were negatively correlated to ADHD symptoms. The present results suggest a linkage between the PGV and circadian preference in adults with ADHD and an association of the circadian preference to symptom severity. This may facilitate the development of new chronobiological treatment approaches for the add-on treatment in ADHD. 
27149678	Immunoglobulin A (IgA) is the primary antibody responsible for mucosal defense in mammals and has been used as a marker for chronic stress and immune status. Therefore, this antibody may provide a more reliable indicator of an individual's immunocompetence than is currently available through other methods. Immunoglobulin A has never before been quantified in a wild population of non-human primates using non-invasive sample collection techniques. In this study, we present methodology for non-invasive IgA extraction in the field and provide quantification of mean fecal IgA concentrations in wild chimpanzees (Pan troglodytes schweinfurthii). During the study period (November 2009-October 2010), we collected fecal samples (N = 1463) from 59 individuals at Gombe National Park, Tanzania. We modified a field extraction technique for steroidal hormones to extract IgA from the fecal samples and then quantified mean IgA concentrations (ng/g) using a commercial human IgA enzyme immunoassay. Mean IgA concentration varied among individuals but not by sex or reproductive status. Mature animals tended toward higher mean IgA concentration than immature. Mean IgA concentration differed by quartile season, following a similar pattern previously observed for respiratory illness rates in this population, with the late dry season having significantly higher averages than the late wet. A circadian rhythm was also evident with mean IgA concentrations higher in samples collected in the latter half of the day. These demographic and temporal patterns of IgA concentration provide baseline values necessary to interpret future results, which may be combined with other health values to better understand the role of health and long-term stress in wild great ape populations. Am. J. Primatol. © 2016 Wiley Periodicals, Inc.
27148829	Dopamine has been implicated in the regulation of sleep-wake states and the circadian rhythm. However, there is no consensus on the impact of two established dopaminergic gene variants: the catechol-O-methyltransferase Val158Met (COMT Val158Met; rs4680) and the dopamine D4 receptor Exon III variable-number-of-tandem-repeat polymorphism (DRD4 VNTR). Pursuing a multi-method approach, we examined their potential effects on circadian preferences, arousal regulation and sleep. Subjects underwent a 7-day actigraphy assessment (SenseWear Pro3), a 20-minute resting EEG (analyzed using VIGALL 2.0) and a body mass index (BMI) assessment. Further, they completed the Morningness-Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). The sample comprised 4625 subjects (19-82 years) genotyped for COMT Val158Met, and 689 elderly subjects (64-82 years) genotyped for DRD4 VNTR. The number of subjects varied across phenotypes. Power calculations revealed a minimum required phenotypic variance explained by genotype ranging between 0.5% and 1.5% for COMT Val158Met and between 3.3% and 6.0% for DRD4 VNTR. Analyses did not reveal significant genotype effects on MEQ, ESS, PSQI, BMI, actigraphy and EEG variables. Additionally, we found no compelling evidence in sex- and age-stratified subsamples. Few associations surpassed the threshold of nominal significance (p < .05), providing some indication for a link between DRD4 VNTR and daytime sleepiness. Taken together, in light of the statistical power obtained in the present study, our data particularly suggest no impact of the COMT Val158Met polymorphism on circadian preferences, arousal regulation and sleep. The suggestive link between DRD4 VNTR and daytime sleepiness, on the other hand, might be worth investigation in a sample enriched with younger adults. 
27148626	Light-dark alternation has always been the strongest external circadian "zeitgeber" for humans. Due to its growing technological preference, our society is quickly transforming toward a progressive "eveningness" (E), with consequences on personal circadian preference (chronotype), depending on gender as well. The aim of this study was to review the available evidence of possible relationships between chronotype and gender, with relevance on disturbances that could negatively impact general health, including daily life aspects.Electronic searches of the published literature were performed in the databases MEDLINE and Web of Science, by using the Medical Subject Heading (MeSH), when available, or other specific keywords.	Results were grouped into four general areas, i.e. (a) "General and Cardiovascular Issues", (b) "Psychological and Psychopathological Issues", (c) "Sleep and Sleep-Related Issues" and (d) "School and School-Related Issues". (a) E is associated with unhealthy and dietary habits, smoking and alcohol drinking (in younger subjects) and, in adults, with diabetes and metabolic syndrome; (b) E is associated with impulsivity and anger, depression, anxiety disorders and nightmares (especially in women), risk taking behavior, use of alcohol, coffee and stimulants, psychopathology and personality traits; (c) E has been associated, especially in young subjects, with later bedtime and wake-up time, irregular sleep-wake schedule, subjective poor sleep, school performance and motivation, health-related quality of life; (d) E was associated with lowest mood and lower overall grade point average (especially for women).	Eveningness may impact general health, either physical or mental, sleep, school results and achievements, especially in younger age and in women. The role of family support is crucial, and parents should be deeply informed that abuse of technological devices during night hours may lead to the immature adjustment function of children's endogenous circadian pacemakers.	
27148293	To successfully recruit pollinators, plants often release attractive floral scents at specific times of day to coincide with pollinator foraging. This timing of scent emission is thought to be evolutionarily beneficial to maximize resource efficiency while attracting only useful pollinators. Temporal regulation of scent emission is tied to the activity of the specific metabolic pathways responsible for scent production. Although floral volatile profiling in various plants indicated a contribution by the circadian clock, the mechanisms by which the circadian clock regulates timing of floral scent emission remained elusive. Recent studies using two species in the Solanaceae family provided initial insight into molecular clock regulation of scent emission timing. In Petunia hybrida, the floral volatile benzenoid/phenylpropanoid (FVBP) pathway is the major metabolic pathway that produces floral volatiles. Three MYB-type transcription factors, ODORANT 1 (ODO1), EMISSION OF BENZENOIDS I (EOBI), and EOBII, all of which show diurnal rhythms in mRNA expression, act as positive regulators for several enzyme genes in the FVBP pathway. Recently, in P. hybrida and Nicotiana attenuata, homologs of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL (LHY) have been shown to have a similar role in the circadian clock in these plants, and to also determine the timing of scent emission. In addition, in P. hybrida, PhLHY directly represses ODO1 and several enzyme genes in the FVBP pathway during the morning as an important negative regulator of scent emission. These findings facilitate our understanding of the relationship between a molecular timekeeper and the timing of scent emission, which may influence reproductive success. 
27148095	Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) is a genetic variation of the human CLOCK gene that is significantly associated with increased frequency of manic episodes in BD patients (2). The 3111T/C SNP is located in the 3'-untranslated region of the CLOCK gene. In this study, we sought to examine the functional implications of the human CLOCK 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock(-/-) knockout mice) with pcDNA plasmids containing the human CLOCK gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24-h time period. We found that the CLOCK3111C SNP resulted in higher mRNA levels than the CLOCK 3111T SNP. Furthermore, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with CLOCK 3111C expression, indicating that the 3'-UTR SNP affects the expression, function, and stability of CLOCK mRNA. 
27147994	Social insects control brood development by using different thermoregulatory strategies. Camponotus mus ants expose their brood to daily temperature fluctuations by translocating them inside the nest following a circadian rhythm of thermal preferences. At the middle of the photophase brood is moved to locations at 30.8°C; 8 h later, during the night, the brood is transferred back to locations at 27.5°C. We investigated whether daily thermal fluctuations experienced by developing pupae affect the neuroarchitecture in the adult brain, in particular in sensory input regions of the mushroom bodies (MB calyces). The complexity of synaptic microcircuits was estimated by quantifying MB-calyx volumes together with densities of presynaptic boutons of microglomeruli (MG) in the olfactory lip and visual collar regions. We compared young adult workers that were reared either under controlled daily thermal fluctuations of different amplitudes, or at different constant temperatures. Thermal regimes significantly affected the large (non-dense) olfactory lip region of the adult MB calyx, while changes in the dense lip and the visual collar were less evident. Thermal fluctuations mimicking the amplitudes of natural temperature fluctuations via circadian rhythmic translocation of pupae by nurses (amplitude 3.3°C) lead to higher numbers of MG in the MB calyces compared to those in pupae reared at smaller or larger thermal amplitudes (0.0, 1.5, 9.6°C), or at constant temperatures (25.4, 35.0°C). We conclude that rhythmic control of brood temperature by nursing ants optimizes brain development by increasing MG densities and numbers in specific brain areas. Resulting differences in synaptic microcircuits are expected to affect sensory processing and learning abilities in adult ants, and may also promote interindividual behavioral variability within colonies. 
27147467	Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are transcriptionally upregulated in response to low temperature. Featuring an RNA-recognition motif (RRM) and an arginine-glycine-rich (RGG) domain, these proteins display many similarities and specific disparities in the regulation of numerous molecular and cellular events. The resistance to serum withdrawal, endoplasmic reticulum stress, or other harsh conditions conferred by RBM3 has led to its reputation as a survival gene. Once CIRP protein is released from cells, it appears to bolster inflammation, contributing to poor prognosis in septic patients. A variety of human tumor specimens have been analyzed for CIRP and RBM3 expression. Surprisingly, RBM3 expression was primarily found to be positively associated with the survival of chemotherapy-treated patients, while CIRP expression was inversely linked to patient survival. In this comprehensive review, we summarize the evolutionary conservation of CIRP and RBM3 across species as well as their molecular interactions, cellular functions, and roles in diverse physiological and pathological processes, including circadian rhythm, inflammation, neural plasticity, stem cell properties, and cancer development. 

27146427	Fatigue is a major concern for patients with multiple sclerosis (MS). A clear definition of MS-related fatigue is a prerequisite for appropriate instruments for fatigue assessment. In turn, accurate assessment of fatigue in MS will enhance exploration of plausible mechanisms underlying this common and distressing symptom. Content/Objectives: To provide an integrative review of the current literature on theoretical models used to study fatigue in MS, instruments used to assess fatigue and other factors that impact fatigue during the various phases of MS.	PUBMED, OVID, Ovid Health Star, Ovid MEDINE, CINAHL, Health and Psychosocial Instruments (HaPI), and PsycINFO. Seventeen articles fit the inclusion criteria and were included in the review.	Definitions of MS-related fatigue are reviewed. Several studies found a link with neurotransmitter dysfunction, circadian rhythm, and the timing of fatigue. Central fatigue in MS is associated with neurotransmitters disruptions as well as circadian rhythm disorders, but the evidence is not strong. Perceptions of fatigue or fatigability may arise as either a primary or secondary manifestation of disease. Based on findings from the literature review, a theoretical model of fatigue in MS is proposed.	Future research on MS-related fatigue may consider a longitudinal design with a carefully selected self-report instrument to advance understanding of the underlying pathological mechanisms.	
27145834	Shift work disrupts the circadian rhythm and may cause menstruation disorders. This study assessed the impact of shift work on menstrual cycle in a population of Chinese nurses.Questionnaires on menstrual characteristics and shift schedules were sent to female nurses of the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU) and Guanghua Hospital of Stomatology (GHHS), affiliated to Sun Yat-sen University. Part I was a cross-sectional study and included 139 nurses in GHHS who had regular 8:00-17:30 working (non-shift group), and 334 nurses from FAHSYSU who worked shifts, a response rate of 67.5 % and 59.6 %, respectively (age ≤ 50 years). Menstrual patterns were compared and age-adjusted relative risks of shift work were analyzed. Part II was a nested case-control study. Cases were nurses in Part I who had regular cycle with mean cycle length (MCL) of 25-31 days and but at least 3 days variation in MCL after starting shift work (n = 45). Controls consisted of 67 nurses with matching shift patterns and age, but no MCL changes. A control non-shift age-matched group consisted of 30 GHHS nurses with no MCL changes. A follow-up second questionnaire was sent 2 years later.	In Part I, the shift group had a significantly higher proportion of nurses with menstrual cycle irregularity. The proportion of nurses with a cycle of 25-31 days decreased from 81.7 to 67.8 % after changing to shift work. Logistic regression analysis showed that night shift frequency was the only risk factor associated with cycle shortening. After adjusting for age, MCL was shorter when night work was performed > 7 times per month. In Part II, the mean change in MCL in the case group, including prolongation or shortening, was 4.115 ± 2.084 days after shift working. In the 2 years' follow-up, the MCL of the study group did not recover to the original length.	Rotating shift work can increase the prevalence of menstrual cycle irregularity. Night shift frequency was the only risk factor associated with cycle reduced. Changes in MCL did not show recovery over a follow-up period of 2 years.	
27145745	The present study aimed to clarify the effect of timing and type of supplementary grain in grazing dairy cows on herbage dry matter intake (HDMI), nitrogen utilization and milk production. Eight lactating cows were allowed to graze from evening to morning during three seasonal periods (spring, summer, autumn). They were randomly allocated to four treatments (timing: pre- (Pre) or post-grazing (Post), for large grain allotments consisting of 75% of daily grain offered; grain type: barley or corn) in 4 × 4 Latin square designs in each period. In the spring period, HDMI was greater for cows fed corn than those fed barley (P = 0.005), whereas cows in the Pre treatment had a similar HDMI, higher (P = 0.049) urinary purine derivative concentration and greater (P = 0.004) milk yield compared with cows in the Post treatment. In the summer and autumn periods, timing treatments did not affect HDMI, nitrogen utilization or milk production, but cows supplemented with barley had higher urinary purine derivatives concentration (P < 0.05) and milk yield (P < 0.05) compared with those supplemented with corn. The results indicate that large grain allotments immediately before evening grazing during early grazing seasons increased ruminal microbial protein synthesis and milk production without reducing HDMI regardless of grain type.
27145603	Most animals, including aquatic crustacean zooplankton, perform strong avoidance movements when exposed to a threat, such as ultraviolet radiation (UVR). We here show that the genera Daphnia and Bosmina instantly adjust their vertical position in the water in accordance with the present UVR threat, i.e., seek refuge in deeper waters, whereas other taxa show less response to the threat. Moreover, Daphnia repeatedly respond to UVR pulses, suggesting that they spend more energy on movement than more stationary taxa, for example, during days with fluctuating cloud cover, illustrating nonlethal effects in avoiding UVR threat. Accordingly, we also show that the taxa with the most contrasting behavioral responses differ considerably in photoprotection, suggesting different morphological and behavioral strategies in handling the UVR threat. In a broader context, our studies on individual and taxa specific responses to UVR provide insights into observed spatial and temporal distribution in natural ecosystems.
27144559	Sleep disorders are very common, often under-recognized and therefore undertreated, are associated with a myriad of medical conditions and could lead to significant impairment of quality of life. This review provides an up-to-date synopsis of common sleep disorders encompassing insufficient sleep syndrome, insomnia, circadian rhythm disorders and obstructive sleep apnea with a brief overview of epidemiology, screening, diagnostic testing and treatment. We also emphasize the emerging area of the intersection of sleep disorders and dermatologic conditions and present compelling data regarding underlying mechanisms including sleep dysfunction in relation to disorders of skin inflammation, aging and skin cancer. 
27145275	Non-thermal plasma (NTP) has been emerging as a potential cancer therapeutic. However, the practical use of NTP as a cancer therapy requires a better understanding of the precise mechanisms underlying NTP-induced DNA damage responses in order to achieve optimal efficacy. It has been shown that the addition of oxygen gas flow during NTP treatment (NTPO), when compared to NTP exposure alone, can induce a 2-3 fold greater generation of intracellular reactive oxygen species (ROS) in A549 cells. Here, we examined NTPO-induced DNA damage responses and found that NTPO generated a substantial number of genomic DNA lesions and breaks that activated ATR-mediated cell-cycle checkpoints. In addition, we discovered that NTPO-induced DNA lesions were primarily removed by base excision repair (BER) rather than by nucleotide excision repair (NER). Therefore, the inhibition of the BER pathway using a PARP1 inhibitor drastically induced the phosphorylation of γH2AX, and was followed by the programmed cell death of cancer cells. However, the knock-down of XPA, which inhibited the NER pathway, had no effect on NTPO-induced phosphorylation of γH2AX. Finally, in agreement with a recent report, we found a circadian rhythm of PARP1 activity in normal mouse embryonic fibroblasts that needed for cell viability upon NTPO treatment. Taken together, our findings provided an advanced NTP regimen for cancer treatment by combining NTPO treatment with chemical adjuvants for the inhibition of ATR- and PARP1-activated DNA damage responses, and circadian timing of treatment. 
27145011	Antiadiposity effects of caloric restriction (CR) are associated with reduced insulin/IGF-1 signaling, but it is unclear whether the effects of CR would be additive to genetically reducing circulating insulin. To address this question, we examined female Ins1(+/-):Ins2(-/-) mice and Ins1(+/+):Ins2(-/-) littermate controls on either an ad libitum or 60% CR diet. Although Igf1 levels declined as expected, CR was unable to reduce plasma insulin levels in either genotype below their ad libitum-fed littermate controls. In fact, 53-week-old Ins1(+/-):Ins2(-/-) mice exhibited a paradoxical increase in circulating insulin in the CR group compared with the ad libitum-fed Ins1(+/-):Ins2(-/-) mice. Regardless of insulin gene dosage, CR mice had lower fasting glucose and improved glucose tolerance. Although body mass and lean mass predictably fell after CR initiation, we observed a significant and unexpected increase in fat mass in the CR Ins1(+/-):Ins2(-/-) mice. Specifically, inguinal fat was significantly increased by CR at 66 weeks and 106 weeks. By 106 weeks, brown adipose tissue mass was also significantly increased by CR in both Ins1(+/-):Ins2(-/-) and Ins1(+/+):Ins2(-/-) mice. Interestingly, we observed a clear whitening of brown adipose tissue in the CR groups. Mice in the CR group had altered daily energy expenditure and respiratory exchange ratio circadian rhythms in both genotypes. Multiplexed analysis of circulating hormones revealed that CR was associated with increased fasting and fed levels of the obesogenic hormone, glucose-dependent insulinotropic polypeptide. Collectively these data demonstrate CR has paradoxical effects on adipose tissue growth in the context of genetically reduced insulin. 
27144030	Disruption of circadian rhythms results in metabolic dysfunction. Casein kinase 1 epsilon (CK1ε) is a canonical circadian clock gene. Null and tau mutations in CK1ε show distinct effects on circadian period. To investigate the role of CK1ε in body weight regulation under both regular chow (RC) and high fat (HF) diet conditions, we examined body weight on both RC and HF diets in CK1ε (-/-) and CK1ε (tau/tau) mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of CK1ε (tau/tau) mice on a 24 hr LD cycle, a separate set of CK1ε (tau/tau) mice were tested under both diet conditions on a 20 hr LD cycle, which more closely matches their endogenous period length. On the RC diet, both CK1ε (-/-) and CK1ε (tau/tau) mutants on a 24 hr LD cycle and CK1ε (tau/tau) mice on a 20 hr LD cycle exhibited significantly lower body weights, despite similar overall food intake and activity levels. On the HF diet, CK1ε (tau/tau) mice on a 20 hr LD cycle were protected against the development of HF diet-induced excess weight gain. These results provide additional evidence supporting a link between circadian rhythms and energy regulation at the genetic level, particularly highlighting CK1ε involved in the integration of circadian biology and metabolic physiology. 
27143721	Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERBα mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERBα may mediate the circadian effect on survival following VSV infection. Blocking REV-ERBα activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERBα-mediated inhibition of CCL2 expression during viral-induced encephalitis may have a protective effect.
27143002	An episode of postpartum psychosis can be devastating for a woman and her family, and it is vital we understand the factors involved in the aetiology of this condition. Sleep and circadian rhythm disruption is a plausible candidate but further research is needed that builds on the latest advances in chronobiology and neuroscience. 
27142972	Diurnal rhythms are recurring 24h patterns such as light/dark cycles that affect many natural environmental and biological processes. The cyanobacterium Synechococcus elongatus PCC 7942 (S. elongatus) produces its energy through photosynthesis and therefore its internal molecular machinery is strongly influenced by these diurnal rhythms. Moreover, it has one of the simplest, self-sustained, circadian rhythms, extensively studied functionally and structurally. These characteristics together with the relatively small genome of S. elongatus, make it an ideal model system for the study of diurnal and circadian rhythms. Although expression of many gene transcripts has been shown to fluctuate in phase with the circadian rhythm, fluctuations at the protein level were less pronounced. This led us to hypothesize that the diurnal adaptation occurs at the level of higher organization of protein complexes. Therefore, we probed the abundance and constituency of S. elongatus protein complexes during the day and night. Following several well-known complexes such as the RNA polymerase, the ribosome and photosynthetic protein complexes, we observe for the first time that these complexes change not only in abundance but also in constituency. Therefore, we conclude that the dynamic assembly of protein complexes is indeed also a key-player in the processes governing the diurnal rhythm.The succession of day and night periods imposes drastic changes in all living organisms. Cyanobacteria produce their energy through photosynthesis and are therefore strongly influenced by diurnal rhythms. The cyanobacteria, Synechococcus elongatus PCC 7942 (S. elongatus), also exhibit a self-sustained biological clock. The connection between the central circadian oscillator and its output to the rest of the cell is not completely known. It has been shown that the expression of many gene transcripts heavily fluctuates in phase with the circadian rhythm; however, our recent global proteomics investigation revealed that the diurnal fluctuations seemed to be less pronounced at the protein level. As many known regulatory functions depend on protein-protein interactions (PPIs) and/or protein assemblies and the fact that so few fluctuations in protein abundances were observed earlier, here we investigated the diurnal adaptation at the level of dynamic changes in protein assembly. The paper demonstrates that the combination of native protein complex fractionation and high-resolution proteomics provides insight in the regulation of megadalton protein assemblies in cyanobacteria, including the ribosomal and photosynthetic complexes. The differences observed between the light and dark conditions in these complexes indicate a cyclic regulation of essential cellular processes.	

27140951	Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.
27140828	Biological clock genes expressed in reproductive tissues play important roles in maintaining the normal functions of reproductive system. However, disruption of female circadian rhythm on oocyte fertilization, preimplantation embryo development and blastocyst implantation potential is still unclear. In this study, ovulation, in vivo and in vitro oocyte fertilization, embryo development, implantation and intracellular reactive oxygen species (ROS) levels in ovary and oviduct were studied in female Bmal1+/+ and Bmal1-/- mice. The number of naturally ovulated oocyte in Bmal1-/- mice decreased (5.2 ± 0.8 vs 7.8 ± 0.8, P < 0.001), with an increasing abnormal oocyte ratio (20.4 ± 3.5 vs 11.7 ± 2.0%, P = 0.001) after superovulation. Significantly lower fertilization rate and obtained blastocyst number were observed in Bmal1-/- female mice either mated with wild-type in vivo or fertilized by sperm from wild-type male mice in vitro (all P < 0.05). Interestingly, in vitro fertilization rate of oocytes derived from Bmal1-/- increased significantly compared with in vivo study (P < 0.01). After transferring blastocysts derived from Bmal1+/+ and Bmal1-/- female mice to pseudopregnant mice, the implantation sites of the latter decreased 5 days later (8.0 ± 0.8 vs 5.3 ± 1.0, P = 0.005). The intracellular ROS levels in the ovary on proestrus day and in the oviduct on metestrus day increased significantly in Bmal1-/- mice compared with that of Bmal1+/+ mice. Deletion of the core biological clock gene Bmal1 significantly decreases oocyte fertilization rate, early embryo development and implantation potential in female mice, and these may be possibly caused by excess ROS levels generated in ovary and oviduct. 
27140809	Epilepsy is one of the most common chronic neurologic disorders. Daily periodicity of epileptic seizures has been known for over a century. The diurnal patterns of epileptic seizures have also been observed in studies.To investigate the sleep/wake cycle, day/night, and 24-h periodicity of various seizure subtypes and seizure onset localizations in children.	We analyzed the clinical seizures of 170 consecutive epilepsy patients who underwent video-electroencephalography (EEG) monitoring over the last 5 years. Semiology of the seizures was classified according to the semiological seizure classification. Origin of the seizures was defined by the onset of ictal activity on EEG. Seizures were evaluated in terms of occurrence during the day (06:00-18:00 h) or night (18:00-06:00 h), in wakefulness or in sleep, and within a 3-h time interval throughout 24 h.	A total of 909 seizures were analyzed. Auras, dialeptic, myoclonic, hypomotor, atonic seizures, and epileptic spasms occurred more frequently in wakefulness; tonic, clonic, and hypermotor seizures occurred more frequently in sleep. Auras, dialeptic, and atonic seizures and epileptic spasms occurred more often during daytime; hypermotor seizures occurred more often at night. Generalized seizures were seen most frequently in wakefulness (between 12:00 and 18:00 h); frontal lobe seizures were seen at night and in sleep (between 24:00 and 03:00 h); temporal lobe seizures were seen in wakefulness (between 06:00 and 09:00 h and between 12:00 and 15:00 h); occipital seizures were seen during daytime and in wakefulness (between 09:00 and 12:00 h and between 15:00 and 18:00 h, respectively); parietal seizures were seen mostly during daytime.	Seizures in children occur in specific circadian patterns and in specific sleep/wake distributions depending on seizure onset location and semiology.	
27139082	The use of animal-borne instruments (ABIs), including biologgers and biotransmitters, has played an integral role in advancing our understanding of adjustments made by animals in their physiology and behavior across their annual and daily cycles and in response to weather and environmental change. Here, we review our research employing body temperature (Tb), light, and acceleration biologgers to measure patterns of physiology and behavior of a free-living, semi-fossorial hibernator, the arctic ground squirrel (Urocitellus parryii). We have used these devices to address a variety of physiological, ecological, and evolutionary questions within the fields of hibernation physiology, phenology, behavioral ecology, and chronobiology. We have also combined biologging with other approaches, such as endocrinology and tracking the thermal environment, to provide insights into the physiological mechanisms that underlie fundamental questions in biology including physiological performance trade-offs, timing and functional energetics. Finally, we explore the practical and methodological considerations that need to be addressed in biologging studies of free-living vertebrates and discuss future technological advancements that will increase the power and potential of biologging as a tool for assessing physiological function in dynamic and changing environments.
27138834	The regulation of the Hypothalamus-Pituitary-Adrenal axis (HPA-axis) with its end product cortisol seems to be affected in several psychiatric disorders. Although findings are not conclusive, internalizing symptoms have primarily been associated with higher diurnal cortisol levels and externalizing symptoms with lower cortisol levels. In this study on nine-year-olds in Nicaragua (n=111), we investigated associations between child psychiatric symptoms, using the Child Behavior Check List (CBCL), and saliva cortisol levels collected in the morning and afternoon, also adjusting for potential confounders. In line with previous findings, internalizing symptoms were significantly associated with higher morning, but not afternoon cortisol levels. Surprisingly, externalizing symptoms were also significantly associated with higher morning cortisol levels. Possibly, this association between externalizing symptoms and cortisol levels may be characteristic of early ages, representing a higher exposure to external stressors. The study highlights the need for prospective studies, following the development of the HPA-axis and its association with psychiatric symptoms.
27138767	Nocturnal polyuria in monosymptomatic nocturnal enuresis (MNE) has so far mainly been attributed to a disturbed circadian rhythm of renal water handling. Low vasopressin levels overnight correlate with absent maximal concentrating activity, resulting in an increased nocturnal diuresis with low urinary osmolality. Therefore, treatment with desmopressin is a rational choice. Unfortunately, 20 to 60 % of children with monosymptomatic enuresis are desmopressin-resistant. There is increasing evidence that other disturbed circadian rhythms might play a role in nocturnal polyuria. This review focuses on renal aspects in the pathophysiology of nocturnal polyuria in MNE, with special emphasis on circadian rhythms. Articles related to renal circadian rhythms and enuresis were searched through the PubMed library with the goal of providing a concise review.Nocturnal polyuria can only partially be explained by blunted circadian rhythm of vasopressin secretion. Other alterations in the intrinsic renal circadian clock system also seem to be involved, especially in desmopressin-resistant enuresis.	• Disturbance in the circadian rhythm of arginine vasopressin secretion is related to nocturnal polyuria in children with enuresis. • Desmopressin is recommended as a treatment for monosymptomatic nocturnal enuresis, working as a vasopressin analogue acting on V2 receptors in the collecting ducts of the kidney. What is New: • Other renal circadian rhythms might play a role in nocturnal polyuria, especially in desmopressin-resistant case.	
27136911	LY500307 is a highly selective estrogen receptor β (ERβ) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period. A population pharmacokinetics/pharmacodynamics (PK/PD) model that integrated Fourier series in an indirect response model was developed to describe the circadian rhythm of TT and the exposure-response relationship of LY500307 on TT.The maximum TT suppression (Emax ) was approximately 28.6%. The potency (EC50 ) of LY500307 on TT suppression was approximately 1.69 ng/mL with a 95%CI of 0.871 to 4.44 ng/mL. This model could provide inferences on LY500307 dose levels that would result in various magnitudes of TT suppression.	Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT.	
27136537	Flowering is a pivotal event in the life cycle of plants. miR172 has been widely confirmed to play critical roles in flowering time control by regulating its target gene expression in Arabidopsis. However, the role of its counterpart in soybean remains largely unclear. In the present study, we found that the gma-miR172a was regulated by a GIGANTEA ortholog, GmGIa, in soybean through miRNA metabolism. The expression analysis revealed that gma-miR172a has a pattern of diurnal rhythm expression and its abundance increased rapidly as plants grew until the initiation of flowering phase in soybean. One target gene of gma-miR172a, Glyma03g33470, was predicted and verified using a modified RLM 5'-RACE (RNA ligase-mediated rapid amplification of 5' cDNA ends) assay. Overexpression of gma-miR172a exhibited an early flowering phenotype and the expression of FT, AP1 and LFY were simultaneously increased in gma-miR172a-transgenic Arabidopsis plants, suggesting that the early flowering phenotype was associated with up-regulation of these genes. The overexpression of the gma-miR172a-resistant version of Glyma03g33470 weakened early flowering phenotype in the toe1 mutant of Arabidopsis. Taken together, our results suggested that gma-miR172a played an important role in GmGIa-mediated flowering by repressing Glyma03g33470, which in turn increased the expression of FT, AP1 and LFY to promote flowering in soybean. 
27135601	Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes in vivo. As genome-wide transcription is organized under the high-order chromosome structure, it is largely uncharted how circadian gene expression is influenced by chromosome architecture. We focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. Using circular chromosome conformation capture sequencing, we systematically examined the interacting loci of a Bmal1-bound super-enhancer upstream of a clock gene Nr1d1 in mouse liver. These interactions are largely stable in the circadian cycle and cohesin binding sites are enriched in the interactome. Global analysis showed that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites are associated with high circadian rhythmicity of transcription. A model integrating the effects of cohesin and CTCF markedly improved the mechanistic understanding of circadian gene expression. Further experiments in cohesin knockout cells demonstrated that cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. This study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure. 
27134599	Sleep deprivation and impaired sleep quality have been associated with poor health outcomes. Many patients experience sleep disturbances, which can increase the risk of medical conditions such as hypertension, obesity, stroke, and heart disease as well as increase overall mortality. Recent studies have suggested that there is a strong association between sleep disturbances and gastrointestinal diseases. Proinflammatory cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6, have been associated with sleep dysfunction. Alterations in these cytokines have been seen in certain gastrointestinal diseases, such as gastroesophageal reflux disease, inflammatory bowel disease, liver disorders, and colorectal cancer. It is important for gastroenterologists to be aware of the relationship between sleep disorders and gastrointestinal illnesses to ensure good care for patients. This article reviews the current research on the interplay between sleep disorders, immune function, and gastrointestinal diseases. 
27133904	Folic acid (FA) is an extremely important nutrient for brain formation and development. FA deficiency is highly linked to brain degeneration and age-related diseases, which are also associated with autophagic activities and circadian rhythm in hippocampal neurons. However, little is known how autophagy- and circadian-related genes in hippocampal neurons are regulated under FA deficiency. Here, hippocampal neuroncells (HT-22) were employed to determine the effect of FA deprivation (FD) on the expression of relevant genes and to reveal the potential role of glucocorticoid receptor (GR). FD increased autophagic activities in HT-22 cells, associated with significantly (P<0.05) enhanced GR activation indicated by higher ratio of GR phosphorylation. Out of 17 autophagy-related genes determined, 8 was significantly (P<0.05) up-regulated in FD group, which includes ATG2b, ATG3, ATG4c, ATG5, ATG10, ATG12, ATG13 and ATG14. Meanwhile, 4 out of 7 circadian-related genes detected, Clock, Cry1, Cry2 and Per2, were significantly (P<0.05) up-regulated. The protein content of autophagy markers, LC3A and LC3B, was also increased significantly (P<0.05). ChIP assay showed that FD promoted (P<0.05) GR binding to the promoter sequence of ATG3 and Per2. Moreover, MeDIP analysis demonstrated significant (P<0.05) hypomethylation in the promoter sequence of ATG12, ATG13 and Per2 genes. Together, we speculate that FD increases the transcription of autophagy- and circadian-related genes through, at least partly, GR-mediated pathway. Our results provide a basis for future investigations into the intracellular regulatory network in response to folate deficiency. 
27132952	Circadian rhythm sleep disorder-advanced sleep-phase type is a relatively uncommon disorder, mostly seen among the elderly population. Impaired circadian rhythms have been reported in neurodegenerative conditions; however, there are no reports of any circadian rhythm sleep disorder among patients with Parkinsonian syndromes. We report two patients who presented with this circadian rhythm disorder, and were then diagnosed with a Parkinsonian syndrome. The cases. A 65-year-old retired man presented with history of abrupt change in sleep schedules, sleeping around 6.30-7 p.m. and waking up around 3-4 a.m. for the last 2 months. On detailed examination, the patient was observed to have symmetrical bradykinesia and cogwheel rigidity of limbs. A diagnosis of multiple system atrophy was made, supported by MRI findings and evidence of autonomic dysfunction. Symptoms of change in sleep-wake cycles resolved over the next 1 year, while the patient was treated with dopaminergic therapy. A 47-year-old man, who was being evaluated for presurgical investigation for refractory temporal lobe epilepsy, presented with complaints suggestive of dysarthria, bradykinesia of limbs and frequent falls for 5 months. Simultaneously, he began to sleep around 7 p.m. and wake up at about 2-3 a.m. Examination revealed severe axial rigidity, restricted vertical gaze and bradykinesia of limbs. A diagnosis of progressive supranuclear palsy was made.This is the first report of Parkinson's plus syndromes presenting with a circadian rhythm sleep disorder-advanced sleep-phase type. More prospective assessment for circadian sleep disorders may introduce useful insights into similar associations.	
27132574	The diagnosis of male hypogonadism depends on an assessment of the clinical signs and symptoms of hypogonadism and serum testosterone level. Current clinical laboratory testosterone assay platforms include immunoassays and mass spectrometry. Despite significant advances to improve the accuracy and precision of the currently available assays, limited comparability exists between assays at the lower and upper extremes of the testosterone range. Because of this lack of comparability, there is no current gold standard assay for the assessment of total testosterone levels. 
27132483	Impaired circadian rhythmicity has been reported in several psychiatric disorders. Schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease. 
27132055	Neutrophils are the most abundant leukocytes in human blood. Beside being essential responders in bacterial and fungal infections, they also contribute to tissue reactions in many autoimmune and inflammatory diseases. Although several immune responses linked to neutrophil functions have been described to be rhythmic, the mechanism of the circadian regulation of these cells is still not understood. Characterization of the time-of-day-specific control of neutrophil responsiveness could help to better understand the pathomechanism of these inflammatory responses and design effective chronotherapy. Here we report that the time-dependent expression of core clock components in human neutrophils characteristically differs from that in mononuclear cells. Both the low expression and the reduced nuclear accumulation of the essential clock protein BMAL1 suggest that the molecular oscillator is down-regulated in neutrophils. By following the expression of the maturation marker Cxcr4 and morphological attributes (side-scattering properties and nuclear segmentation), we found that the distribution of young and aged cells within the peripheral neutrophil pool displays a daily rhythm. In addition, we detected synchronous fluctuations in the plasma level of the CXCR4 ligand CXCL12, an important regulator of cell trafficking within the bone marrow. We found that expression of another maturation marker, the core component of the superoxide generating NADPH oxidase, and parallelly, the superoxide producing capacity of neutrophils were also dependent on the time of the day. In line with this, number of opsonized bacteria engulfed by neutrophils also showed time-dependent differences, supporting that clearance of pathogens shows a daily rhythm. We suggest that maturation-dependent changes in neutrophil responsiveness rather than the cellular autonomous clock are involved in the daily regulation of human neutrophil functions. 
27130660	Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem largely from Pavlovian fear conditioning studies that focus on how a particular cue becomes capable of eliciting learned fear responses, thus oversimplifying the brain's fear system. Here we review fear from functional, mechanistic, and phylogenetic perspectives where environmental threats cause animals to alter their foraging strategies in terms of spatial and temporal navigation, and discuss whether the inferences we draw from fear conditioning studies operate in the natural world. 
27128901	Circadian rhythms are core regulators of a variety of mammalian physiologic processes and oscillate in a 24-h pattern. Many peripheral organs possess endogenous rhythmicity that is then modulated by a master clock; the skin is one of these peripheral organs. The dysregulation of rhythms is associated with decreased ability to ameliorate cellular stressors at a local and global level, which then increases the propensity for the development of neoplastic growths. In this article, we review the implications of altered circadian rhythms on DNA repair as well as modified gene expression of core clock proteins with particular focus on skin models. These findings are then correlated with epidemiologic data regarding skin cancer to showcase the effects of circadian disruption on this phenomenon. 
27128899	The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for 24 h after a day off. Significant differences were observed in peripheral skin temperature and cortisol levels between shift and daytime nurses. No differences in melatonin levels were obtained. Per2 maximum values were significantly different between the two groups. Shift nurses exhibited lower circadian variations compared to daytime nurses, and this may indicate an adjustment of the circadian biological clock to continuous shift schedules. Non-invasive procedures, such as peripheral skin temperature measurement, determination of cortisol and melatonin in saliva, and analysis of clock genes in hair follicle cells, may be effective approaches to extensively study the circadian clock in shift workers. 
27128529	To explore the circadian rhythm of neurally mediated syncope (NMS).411 patients with NMS (165 males and 246 females aged from 3 to 68years) were included in the study. All subjects underwent head-up tilt test (HUTT) and were carefully asked about the number of syncopal attacks and the periods (morning 06:00am-12:00am, afternoon 12:00am-18:00pm, evening 18:00pm-24:00pm, night 00:00am-06:00am) in which episodes occurred in.	(1) Syncopal attacks of all patients tended to occur in the morning (P=0.010); there was a statistical difference in the frequency of episodes in four periods through the day in HUTT positive patients (P=0.001), but there was no significant change of episodes within a day in HUTT negative group; and there was no statistical difference in circadian syncope distribution between HUTT negative and HUTT positive group or among patients with different HUTT responses (the orthostatic hypotension (OH) and orthostatic hypertension (OHT) patients were excluded). (2) The syncopal attacks of morning hours occurred more in males than females, but the episodes in the evening occurred more in females than males (P=0.034). (3) The younger the patients were, the chance of syncopal attacks in the morning increased; the older the patients were, they may have more episodes at night (P<0.001).	A distinct circadian variation in the frequency of syncopal episodes exists, with a peak in the morning, and there were statistical differences in circadian rhythm of syncopal episodes regarding gender and age.	
27128360	Comorbid ADHD symptoms may partly account for circadian rhythm disturbances in depression and anxiety disorders.Self-reported sleep characteristics of 2090 participants in the Netherlands Study of Depression and Anxiety were assessed using the Munich Chronotype Questionnaire. We defined 3 groups: healthy controls (HC), persons with lifetime depression and/or anxiety disorders (LDA), and those with both LDA and high ADHD symptoms (LDA+ADHD), using the Conner's Adult ADHD Rating Scale.	Sleep characteristics were least favorable in the LDA+ADHD group. Important group differences between LDA+ADHD, LDA and HC were found for extremely late chronotype (12% vs. 5% vs. 3%; p<.001), sleep duration <6h (15% vs. 5% vs. 4%; p<.001), and for an indication of the Delayed Sleep Phase Syndrome (DSPS; 16% vs. 8% vs. 5%; p<.001). After adjustment for covariates, including depression and anxiety, presence of ADHD symptoms increased the odds ratio for late chronotype (OR=2.6; p=.003), indication of DSPS (OR=2.4; p=.002), and sleep duration <6h (OR=2.7; p=.007).	ADHD conceptually overlaps with symptom presentation of depression and anxiety. We used a cross-sectional study design, and used self reported sleep characteristics.	High ADHD symptoms were associated with an increased rate of circadian rhythm sleep disturbances in an already at-risk population of people with depression and/or anxiety disorders. Circadian rhythm sleep disorders, as often seen in ADHD are not entirely due to any comorbid depression and/or anxiety disorder. Adequate treatment of such sleep problems is needed and may prevent serious health conditions in the long term.	
27127054	Diamond is a promising material for a number of bio-applications, including the fabrication of platforms for attachment and investigation of neurons and of neuroprostheses, such as retinal implants. In the current work ultrananocrystalline diamond (UNCD) films were deposited by microwave plasma chemical vapor deposition, modified by UV/O3 treatment or NH3 plasma, and comprehensively characterized with respect to their bulk and surface properties, such as crystallinity, topography, composition and chemical bonding nature. The interactions of insect circadian pacemaker neurons with UNCD surfaces with H-, O- and NH2-terminations were investigated with respect to cell density and viability. The fast and strong attachment achieved without application of adhesion proteins allowed for advantageous modification of dispersion protocols for the preparation of primary cell cultures. Centrifugation steps, which are employed for pelletizing dispersed cells to separate them from dispersing enzymes, easily damage neurons. Now centrifugation can be avoided since dispersed neurons quickly and strongly attach to the UNCD surfaces. Enzyme solutions can be easily washed off without losing many of the dispersed cells. No adverse effects on the cell viability and physiological responses were observed as revealed by calcium imaging. Furthermore, the enhanced attachment of the neurons, especially on the modified UNCD surfaces, was especially advantageous for the immunocytochemical procedures with the cell cultures. The cell losses during washing steps were significantly reduced by one order of magnitude in comparison to controls. In addition, the integration of a titanium grid structure under the UNCD films allowed for individual assignment of physiologically characterized neurons to immunocytochemically stained cells. Thus, employing UNCD surfaces free of foreign proteins improves cell culture protocols and immunocytochemistry with cultured cells. The fast and strong attachment of neurons was attributed to a favorable combination of topography, surface chemistry and wettability. 
27126917	The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P ≤ 5× 10-8 (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 × 10-8 ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 × 10-8 ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.
27125665	Metabolic functions are synchronized by the circadian clock setting daily patterns of food intake, nutrient delivery, and behavioral activity. Here, we study the impact of chronic jet-lag (CJL) on metabolism, and test manipulations aimed to overcome potential alterations. We recorded weight gain in C57Bl/6 mice under chronic 6 h advances or delays of the light-dark cycle every 2 days (ChrA and ChrD, respectively). We have previously reported ChrA, but not ChrD, to induce forced desynchronization of locomotor activity rhythms in mice (Casiraghi et al. 2012). Body weight was rapidly increased under ChrA, with animals tripling the mean weight gain observed in controls by day 10, and doubling it by day 30 (6% vs. 2%, and 15% vs. 7%, respectively). Significant increases in retroperitoneal and epidydimal adipose tissue masses (172% and 61%, respectively), adipocytes size (28%), and circulating triglycerides (39%) were also detected. Daily patterns of food and water intake were abolished under ChrA In contrast, ChrD had no effect on body weight. Wheel-running, housing of animals in groups, and restriction of food availability to hours of darkness prevented abnormal increase in body weight under ChrA Our findings suggest that the observed alterations under ChrA may arise either from a direct effect of circadian disruption on metabolism, from desynchronization between feeding and metabolic rhythms, or both. Direction of shifts, timing of feeding episodes, and other reinforcing signals deeply affect the outcome of metabolic function under CJL Such features should be taken into account in further studies of shift working schedules in humans. 
27124968	Arterial hypertension is a chronic disease which represents a major risk factor for damage of cardiovascular system. Insufficient control of elevated blood pressure is associated with the development of target organ damage, increased cardiovascular morbidity and mortality with a adverse prognostic value. Using ambulatory blood pressure monitoring (ABPM) we can improve the overall management of elderly patients at which the prevalence of arterial hypertension is particularly high.
27124542	Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12 h light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise.
27124253	A holistic exploration of the experience of how nurses integrate pregnancy and employment is lacking among the global nursing literature.The purpose of this research was to explore how primiparous U.S. nurses integrated pregnancy and full-time employment.	Using a grounded theory approach, 20 nurses from the United States, who were pregnant and delivered their first baby-while employed full time on 12-hour work shifts-provided a firsthand account of how they incorporated pregnancy with professional nursing employment.	The basic social process, "becoming someone different," emerged to explain how U.S. nurses integrated pregnancy and full-time employment in early and late stages. Four core categories were: (a) "looking different, feeling different,"(b) "expectations while expecting," (c) "connecting differently," and (d) "transitioning labor."	Within early and late stages, pregnant nurses becoming someone different navigate through various social interactions with peers and patients alike, with meaning assigned to those experiences. Research with pregnant nurses from other countries, nurses working in settings other than acute care, and multiparous nurses is needed to further expand on these findings.	
27123980	Mammalian Cryptochromes, CRY1 and CRY2, function as principal regulators of a transcription-translation-based negative feedback loop underlying the mammalian circadian clockwork. An F-box protein, FBXL3, promotes ubiquitination and degradation of CRYs, while FBXL21, the closest paralog of FBXL3, ubiquitinates CRYs but leads to stabilization of CRYs. Fbxl3 knockout extremely lengthened the circadian period, and deletion of Fbxl21 gene in Fbxl3-deficient mice partially rescued the period-lengthening phenotype, suggesting a key role of CRY protein stability for maintenance of the circadian periodicity. Here, we employed a proteomics strategy to explore regulators for the protein stability of CRYs. We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP) associates with CRY1 and CRY2 and stabilizes CRYs through deubiquitination. Treatment with USP7-specific inhibitor or Usp7 knockdown shortened the circadian period of the cellular rhythm. We identified another CRYs-interacting protein, TAR DNA binding protein 43 (TDP-43), an RNA-binding protein. TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. The present study identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process of CRY proteins for period determination in the mammalian circadian clockwork.
27123963	Measuring morningness-eveningness is an important aspect of individual differences because it is associated with many aspects of personality and health. The present study outlines recent advancements in the field of measurement and proposes an improved assessment of morningness-eveningness, such as the measurement of circadian amplitude, updating and reflecting new item developments, addressing the clock time based measures, the morning-biased items and the aspect of uni versus multidimensionality. Four studies have been carried out in Germany to present a novel development (with a total sample of N = 1181). In study I, the exploratory factor analysis (EFA) revealed three dimensions, one of morningness, one of eveningness and one of amplitude/stability. Then, items were reduced to present a clearer factor structure by removing ambiguous items. In the second study, a shortened questionnaire was applied, with 15 items (5 per construct), but Confirmatory Factor Analysis (CFA) did not provide acceptable fit indices. Refining items were made in study III, which again showed a clearer factor structure in EFA, and subsequently, in study IV, the refined set of 15 items provided a good fit of a CFA. The final questionnaire was tested for validity by applying clock times, personality questions and alertness ratings. Thus, this newly developed questionnaire contains three distinct dimensions. To reflect the new content, the scale is labelled morningness-eveningness-stability-scale improved (MESSi). 
27123825	Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) clock, which is the main oscillator and peripheral clock. SCN clock can be entrained by both photic and non-photic stimuli, and an interaction exists between photic and non-photic entrainment. Moreover, peripheral circadian clocks can be entrained not only by scheduled restricted feeding, but also by scheduled exercise. Thus, the entrainment of peripheral circadian clocks may be the result of an interaction between the entrainment caused by feeding and exercise. In this study, we examined the effect of wheel-running exercise on the phase of the peripheral clocks (kidney, liver and submandibular gland) in PER2::LUC mice under various feeding schedules. Phase and waveforms of the peripheral clocks were not affected by voluntary wheel-running exercise. Exercise for a period of 4 h during the early dark period (morning) delayed the peripheral clocks, while exercise for the same duration during the late dark period (evening) advanced the peripheral clocks. The feeding phase was advanced and delayed by evening and morning exercise, respectively, suggesting that the feeding pattern elicited by the scheduled exercise may entrain the peripheral clocks. Exercise did not affect the phase of the peripheral clock under the 1 meal per day schedule. When the phase of the peripheral clocks was advanced by the feeding schedule of 2 or 4 meals per day during light and/or dark periods, wheel-running exercise during the morning period significantly and equally shifted the phase of all organs back to the original positions observed in mice maintained under free-feeding conditions and with no exercise. When the schedule of 2 meals per day during the dark period failed to affect the phase of peripheral clock, morning exercise did not affect the phase. Wheel-running exercise increased the levels of serum corticosterone, and the injection of dexamethasone/corticosterone instead of exercise shifted a phase that had advanced under the feeding schedule of 2 meals per day, back to the normal position. The liver and submandibular glands exhibit higher sensitivity to dexamethasone than the kidneys. In adrenalectomized mice, treadmill-induced normalization of the advanced phase under a feeding schedule of 2 meals per day was not observed. In summary, scheduled exercise-induced phase shifts were weaker compared to scheduled feeding-induced phase shifts. The phase advance caused by the feeding schedule of 2 or 4 meals per day was suppressed by wheel-running, treadmill exercise or dexamethasone/corticosterone injection in the early dark period (morning). Corticosterone release may be involved in exercise-induced phase shift of peripheral clocks. These results suggest that there is an interaction between the phase shifts caused by feeding and exercise schedules in peripheral clocks. 
27123378	Melatonin is a key hormone in the regulation of circadian rhythms of vertebrates, including songbirds. Understanding diurnal melatonin fluctuations and being able to reverse or simulate natural melatonin levels are critical to investigating the influence of melatonin on various behaviors such as singing in birds. Here we give a detailed overview of natural fluctuations in plasma melatonin concentration throughout the night in the zebra finch. As shown in previous studies, we confirm that "lights off" initiates melatonin production at night in a natural situation. Notably, we find that melatonin levels return to daytime levels as early as two hours prior to the end of the dark-phase in some individuals and 30 min before "lights on" in all animals, suggesting that the presence of light in the morning is not essential for cessation of melatonin production in zebra finches. Thus, the duration of melatonin production seems not to be specified by the length of night and might therefore be less likely to directly couple circadian and annual rhythms. Additionally, we show that natural melatonin levels can be successfully simulated through a combination of light-treatment (daytime levels during subjective night) and the application of melatonin containing skin-cream (nighttime levels during subjective day). Moreover, natural levels and their fluctuation in the transition from day to night can be imitated, enabling the decoupling of the effects of melatonin, for example on neuronal activity, from sleep and circadian rhythmicity. Taken together, our high-resolution profile of natural melatonin levels and manipulation techniques open up new possibilities to answer various melatonin related questions in songbirds. 
27121502	Circadian rhythms of triatomines, vectors of the etiological agent Trypanosoma cruzi responsible for Chagas disease, have been extensively studied in adults of the two most epidemiologically relevant vector species, Rhodnius prolixus and Triatoma infestans. However, little attention has been dedicated to the activity patterns in earlier developmental stages, even though triatomine nymphs are equally capable of transmitting T. cruzi to humans. Because circadian rhythms may differ even between closely related species, studies that focus on this behavioral trait can also be used to shed light on the taxonomy of controversial taxa, which becomes especially relevant regarding vector species.We compared the daily locomotor activity patterns of second- and third-instar nymphs of Rhodnius prolixus and Rhodnius robustus in order to unveil possible behavioral differences between these cryptic species. Mitochondrial and nuclear markers were sequenced to confirm species identification.	Nymphs of both species had a bimodal pattern of locomotion and similar daily activity patterns, but R. prolixus is more active under light/dark cycles and depicts a more pronounced activity rhythm under constant darkness conditions.	We describe the implementation of an often-used automated method for the recording of individual locomotor activity to differentiate sibling species of Rhodnius with distinct epidemiological relevance. The higher levels of activity observed in the nymphs of R. prolixus could potentially contribute to increased vector capacity.	
27121237	While changes in the composition of breast milk throughout the lactation period are well known, little is known about the antioxidative capacity of breast milk and its regulation as a function of time of day.The aim of this study was to evaluate the antioxidative capacity in breast milk and its regulation by time of day.	Melatonin, superoxide dismutase (SOD), glutathione peroxidase 3 (Gpx3) concentrations, and the total antioxidative capacity (TAOC) were analyzed in 105 breast milk samples and 12 maternal serum samples from 21 healthy nursing mothers.	Comparison between daytime breast milk (collected from 1000-2200 h) and nighttime breast milk (collected from 2200-1000 h) revealed significantly higher concentrations of melatonin and Gpx3 in nighttime milk (melatonin: 1.5 pg/mL [1.0-2.1] day vs 7.3 pg/mL [3.8-13.6] night, median [quartiles], with an estimated mean night-to-day ratio of 5.2 [3.9, 7.1], P < .001; Gpx3: 1436 ng/mL [765-2060] day vs 1800 ng/mL [1242-2297] night, night-to-day difference 192.1 [0.6, 383.7], P = .049). Subgroup analysis showed that melatonin had a circadian rhythm in both preterm and term milk, with a significantly higher nighttime concentration ( P < .001), while antioxidant enzymes had a circadian rhythm only in preterm milk, with a significantly higher nighttime concentration for Gpx3 and a significant higher daytime concentration for SOD and TAOC ( P = .041 and P = .049, respectively). We found no significant correlation between the concentration of melatonin and the concentration of SOD, Gpx3, or TAOC. Moreover, there were no significant correlations observed between gestational age and the concentration of melatonin and antioxidant enzymes.	Because of its higher melatonin and Gpx3 content, future research is needed to determine if preterm nighttime milk ought to be the first choice in the feeding of high-risk preterm infants.	
27121187	Mitochondria play a critical role in regulating cellular functions, such as redox signaling, calcium homeostasis, and apoptosis. Also, mitochondria are crucial for neurogenesis and neuronal functions. Melatonin is an indole analog hormone, which is generally produced by the pineal gland. It plays a vital role in circadian rhythm and act as a powerful antioxidant by scavenging free radicals, immunomodulators, and anticancer agents. Schizophrenia and mood disorders are the two major psychiatric disorders. Disturbances of sleep and circadian rhythms are well-known symptoms of schizophrenia and mood disorders (bipolar disorder, major depression). Since melatonin has a regulator effect on circadian rhythm and sleep quality, it has a close interaction with schizophrenia and mood disorders. Herein, we aimed to summarize the effects of melatonin on mitochondrial activity in schizophrenia and mood disorders. 
27120624	Daylength used as a management tool has powerful implications on the welfare of both broilers and turkeys. Near-constant light results in many detrimental impacts, including lack of behavioural rhythms and circadian melatonin rhythms. Both are suggestive that sleep fragmentation could result in birds reared on long photoperiods, which can lead to the same negative health and physiological responses as total sleep deprivation. An indirect comparison of the welfare implications of graded levels of daylength on broilers and turkeys clearly indicate that long daylengths depress welfare by increasing mortality, reducing mobility, increasing ocular pathologies and changing behaviour in both species. Furthermore, long daylengths change melatonin secretion patterns and eliminate behavioural and melatonin circadian rhythms, which were measured in broilers in these works. However, feather pecking in turkeys was reduced when birds were exposed to long daylengths. Exactly how much darkness should be included in a management program to maximize welfare will depend on the species, the age of marketing, and in turkeys, bird gender. 
27120102	Planned burning is a preventative strategy aimed at decreasing fuel loads to reduce the severity of future wildfire events. During planned burn operations, firefighters can work long shifts. Furthermore, remote burning locations may require firefighters to sleep away from home between shifts. The existing evidence surrounding firefighters' sleep during such operations is exclusively anecdotal. The aims of the study were to describe firefighters' sleep during planned burn operations and evaluate the impact of the key operational factors (shift start time, shift length and sleeping location) that may contribute to inadequate sleep. Thirty-three salaried firefighters were recruited from Australia's fire agencies and sleep was measured objectively using wrist actigraphy for four weeks. All variables were examined in two conditions: (1) burn days, and (2) non-burn days. Time in bed, total sleep time, sleep latency and sleep efficiency were evaluated objectively. Subjective reports of pre- and post-sleep fatigue, sleep location, sleep quality, sleep quantity, number of times woken and sleep timing were also recorded. Analyses revealed no differences in measures of sleep quantity and quality when comparing non-burn and burn days. Total sleep time was less when planned burn shifts were >12 h. However, on burn days, work shift start time as well as sleeping location did not impact firefighters' sleep quantity. Self-reported levels of pre- and post-sleep fatigue were greater on burn days compared to non-burn days. These findings indicate that sleep quantity and quality are not compromised during planned burn operations <12 h in duration. 
27117840	Circadian alignment is crucial for body-weight management, and for metabolic health. In this context, circadian alignment consists of alignment of sleep, meal patterns and physical activity. During puberty a significant reduction in sleep duration occurs, and pubertal status is inversely associated with sleep duration. A consistent inverse association between habitual sleep duration and body-weight development occurs, independent of possible confounders. Research on misalignment reveals that circadian misalignment affects sleep-architecture and subsequently disturbs glucose-insulin metabolism, substrate oxidation, leptin- and ghrelin concentrations, appetite, food reward, hypothalamic-pituitary-adrenal-axis activity and gut-peptide concentrations enhancing positive energy balance and metabolic disturbance. Not only aligning meals and sleep in a circadian way is crucial, also regular physical activity during the day strongly promotes the stability and amplitude of circadian rhythm, and thus may serve as an instrument to restore poor circadian rhythms. Endogenicity may play a role in interaction of these environmental variables with a genetic predisposition. In conclusion, notwithstanding the separate favourable effects of sufficient daily physical activity, regular meal patterns, sufficient sleep duration and quality sleep on energy balance, the overall effect of the amplitude and stability of the circadian rhythm, perhaps including genetic predisposition, may integrate the separate effects in an additive way.
27117258	Behavioral studies are important tools for understanding the development and pathology of neurological diseases. Zebrafish are an emerging alternative model in behavioral and neurological studies as the behavioral repertoire of zebrafish (Danio rerio) is similar to humans, and nervous system structures and functions are highly conserved. In this study, we investigated alterations in day/night locomotor activity of free swimming, feeding wild-type zebrafish larvae (8-15dpf) due to changes in the rhythm of light/dark cycles or caloric content of food. We furthermore exposed zebrafish larvae to continuous stress by applying alternated minor vibrations. Under altered rhythms of light/dark cycle's zebrafish larvae still expressed a distinct light/dark activity pattern but the total activity was reduced compared to control animals. When the larvae were exposed to continuous light, they still had coordinated resting cycles but maximal activity and excitation rates after feeding were increased, indicating that food became the new zeitgeber. Feeding food of high caloric content induced continuously high activity levels during light cycles and significantly elevated activity levels during the dark. Exposure to continuous vibrations lowered total activity levels. We showed previously that changes in environmental factors like light/dark cycles or changes in caloric content of food can affect adipogenesis, lipid composition, and circadian rhythm of free swimming, feeding larvae but this is the first time showing how theses factor alter behavior.
27115868	The purpose of the study was to investigate the effects of shift work on the psychomotor and postural performance of night workers. The study included 20 polysomnography technicians working schedule of 12-h night shift by 36-h off. On the first day of protocol, the body mass and height were measured, and an actigraph was placed on the wrist of each participant. On the second day of protocol, sleepiness by Karolinska Sleepiness Scale, postural control by force platform (30 seconds) and psychomotor performance by Psychomotor Vigilance Task (10 minutes) were measured before and after 12-h night work. Results showed that after 12-h night work, sleepiness increased by 59% (p<0.001), postural control variables increased by 9% (p = 0.048), and 14% (p = 0.006). Mean reaction time, and the number of lapses of attention increased by 13% (p = 0.006) and 425% (p = 0.015), respectively, but the mean reciprocal reaction time decreased by 7%. In addition, there were correlations between sleepiness and postural control variables with opened eyes (r = 0.616, 95% confidence interval [CI] = 0.361-0.815; r = 0.538; 95% CI = 0.280-0.748) and closed eyes (r = 0.557; 95% CI = 0.304-0.764, r = 0497; 95% CI = 0.325-0.715) and a pronounced effect of sleepiness on postural sway (R2 = 0.393; 95% CI = 0.001-0.03). Therefore, 12-h night work system and sleepiness showed a negative impact in postural and psychomotor vigilance performance of night workers. As unexpected, the force platform was feasibility to detect sleepiness in this population, underscoring the possibility of using this method in the workplace to prevent occupational injuries and accidents.
27114907	Mammalian physiology and behavior follow daily rhythms that are orchestrated by endogenous timekeepers known as circadian clocks. Rhythms in transcription are considered the main mechanism to engender rhythmic gene expression, but important roles for posttranscriptional mechanisms have recently emerged as well (reviewed in Lim and Allada (2013) [1]). We have recently reported on the use of ribosome profiling (RPF-seq), a method based on the high-throughput sequencing of ribosome protected mRNA fragments, to explore the temporal regulation of translation efficiency (Janich et al., 2015 [2]). Through the comparison of around-the-clock RPF-seq and matching RNA-seq data we were able to identify 150 genes, involved in ribosome biogenesis, iron metabolism and other pathways, whose rhythmicity is generated entirely at the level of protein synthesis. The temporal transcriptome and translatome data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE67305. Here we provide additional information on the experimental setup and on important optimization steps pertaining to the ribosome profiling technique in mouse liver and to data analysis. 
27114886	Time-of-day effects in human psychological functioning have been known of since the 1800s. However, outside of research specifically focused on the quantification of circadian rhythms, their study has largely been neglected. Moves toward online data collection now mean that psychological investigations take place around the clock, which affords researchers the ability to easily study time-of-day effects. Recent analyses have shown, for instance, that implicit attitudes have time-of-day effects. The plausibility that these effects indicate circadian rhythms rather than selection effects is considered in the current study. There was little evidence that the time-of-day effects in implicit attitudes shifted appropriately with factors known to influence the time of circadian rhythms. Moreover, even variables that cannot logically show circadian rhythms demonstrated stronger time-of-day effects than did implicit attitudes. Taken together, these results suggest that time-of-day effects in implicit attitudes are more likely to represent processes of selection rather than circadian rhythms, but do not rule out the latter possibility. 
27114521	Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (β3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

27113500	Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established.We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN).	In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress.	Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression.	
27113386	The core circadian oscillator of cyanobacteria consists of three proteins, KaiA, KaiB, and KaiC. This circadian oscillator could be functionally reconstituted in vitro with these three proteins, and therefore has been a very important model in circadian rhythm research. KaiA can bind to KaiC and then stimulate its phosphorylation, but their interaction mechanism remains elusive. In this study, we followed the "second-site suppressor" strategy to investigate the interaction mechanism of KaiA and KaiC. Using protein sequence analyses, we showed that there exist co-varying residues in the binding interface of KaiA and KaiC. The followed mutagenesis study verified that these residues are important to the functions of KaiA and KaiC, but their roles could not be fully explained by the reported complex structures of KaiA and KaiC derived peptides. Combining our data with previous reports, we suggested a dynamic interaction mechanism in KaiA-KaiC interaction, in which both KaiA and the intrinsically disordered tail of KaiC undergo significant structural changes through conformational selection and induced fit during the binding process. At last, we presented a mathematic model to support this hypothesis and explained the importance of this interaction mechanism for the KaiABC circadian oscillator.
27112187	Awakening responses in salivary cortisol (CAR) and alpha-amylase (AAR) constitute proxies of morning activation patterns of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, respectively. Previous studies suggest that the CAR is decreased at weekends and at late awakening. However, it is insufficiently studied (a) whether this also applies to the AAR and (b) whether week(end)-day and awakening time interact with each other. Using an ecological momentary assessment design, 48 healthy young adults (60% women) were investigated over a 7-d period (Study 1), and 27 chronic pain patients diagnosed with fibromyalgia syndrome were examined over a 14-d period (Study 2). For the assessment of the CAR and AAR, participants provided saliva samples each morning (upon awakening, 30 min after awakening). Preprogrammed electronic diary devices were used to track week(end)-day and exact time of saliva sampling (awakening time). In Study 1, CAR was unrelated to weekend, awakening time, or their interaction, whereas only early awakening time was positively associated with AAR. In Study 2, week-days as well as early awakening times on week-days predicted increased CAR. AARs were not predicted by week(end)-day, awakening times, or their interaction. These findings suggest that time-related factors may influence awakening responses, particularly the impact of week(end)-day on the CAR and the impact of awakening times on the AAR. Since week(end)-day and awakening times may negatively affect awakening responses, these potential confounding factors should be assessed and controlled for, particularly in studies assessing both CAR and AAR.
27110555	Advantageous times for different people are different to some extent, considering the effective physiological changes during the circadian rhythm, in terms of the peak time of physiological activities. The goal of this study is to compare the educational achievement of students, with different morning-evening habits, in completing difficult and easy courses.This research is a retrospective descriptive-analytical study, which has been conducted on students of the fifth semester of General Medicine in the Faculty of Medicine, Isfahan University of Medical Sciences. The morning-evening habits of the students were determined by the Horne-Strauss 19-item questionnaire. The students were asked to determine the courses that were 'difficult' and 'easy,' using a researcher-made questionnaire. The students' scores in the considered courses during the five semesters were obtained from the Education Department of the Faculty and analyzed using the descriptive t-test, analysis of variance (ANOVA), and the multivariate regression test in the SPSS software.	Sixty-three students (67% girls and 33% boys) participated in this study, of whom 11, 60, and 29% were morning, morning-evening, and evening students, respectively. The mean scores of the difficult courses in all five semesters were reduced in the evening pattern compared to the morning and morning-evening patterns. Reduction of the mean score in the difficult courses, in the evening group, compared with the morning-evening and morning groups was observed in all five semesters among girls, but in three semesters among boys.	This study showed that evening students experienced academic failure in difficult courses, which required a more cognitive performance. It is recommended that difficult specialized courses be presented at hours when all student groups have a better cognitive performance.	
27110271	In study designs with repeated measures for multiple subjects, population models capturing within- and between-subjects variances enable efficient individualized prediction of outcome measures (response variables) by incorporating individuals response data through Bayesian forecasting. When measurement constraints preclude reasonable levels of prediction accuracy, additional (secondary) response variables measured alongside the primary response may help to increase prediction accuracy. We investigate this for the case of substantial between-subjects correlation between primary and secondary response variables, assuming negligible within-subjects correlation. We show how to determine the accuracy of primary response predictions as a function of secondary response observations. Given measurement costs for primary and secondary variables, we determine the number of observations that produces, with minimal cost, a fixed average prediction accuracy for a model of subject means. We illustrate this with estimation of subject-specific sleep parameters using polysomnography and wrist actigraphy. We also consider prediction accuracy in an example time-dependent, linear model and derive equations for the optimal timing of measurements to achieve, on average, the best prediction accuracy. Finally, we examine an example involving a circadian rhythm model and show numerically that secondary variables can improve individualized predictions in this time-dependent nonlinear model as well. 
27108942	Salivary steroid testing represents a valuable source of biological information; however, the proper measurement of low salivary levels is challenging for direct immunoassays, lacking adequate sensitivity and specificity and causing poor inter-laboratory reproducibility. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has overcome previous analytical limits, often providing results deviating from previous knowledge. Nowadays, LC-MS/MS is being introduced in clinical laboratories for salivary cortisol testing; however, so far only a few studies have reported thorough biological validation based on LC-MS/MS data. In this study, we provide a thorough analytical, pre-analytical and biological validation of an LC-MS/MS method for the measurement of salivary cortisol (F) and of its inactive metabolite cortisone (E). Analytes were extracted from 50μl of saliva, were then separated in 7.5min LC-gradient and detected by negative electrospray ionization-multiple reaction monitoring. The reliability of a widely diffused collection device, Salivette(®), was assessed and the overall procedure was validated. The diurnal cortisol and cortisone fluctuation in saliva and serum was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects. The assay allowed the quantitation of F and E down to 39.1 and 78.1pg/ml, with an imprecision range of 5.5-9.5%, 3.9-14.1% and 2.6-14.4%, and an accuracy range of 105.5-113.1%, 88.5-98.7% and 90.7-96.7% for both analytes at low, medium and high levels, respectively. Salivette(®) provided comparable results and better precision (CV<1.0%) as referred to direct spitting (CV<13.0%). A parallel diurnal rhythm in saliva and serum was observed for cortisol and cortisone, with values lowering from the morning to the evening time points (P<0.0001). While salivary E linearly correlated to total serum F (R(2)=0.854, P<0.001), salivary F showed an exponential relationship (R(2)=0.903, P<0.001) with serum F reflecting the free circulating fraction. A non linear association between E and F was observed in saliva (R(2)=0.941, p<0.001) consistent with the type II 11β-HSD activity. We concluded that our LC-MS/MS method allowed a sensitive evaluation of salivary levels of cortisol and cortisone. The simultaneous determination of both hormones in saliva allowed the differential estimation of the active and of the total glucocorticoid exposure over the daytime. The assay could provide further insight into the comprehension of normal and dysfunctional glucocorticoid circadian rhythm. 

27108448	Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease. 
27106579	In the fruitfly Drosophila melanogaster, circadian rhythms of locomotor activity under constant darkness are controlled by pacemaker neurons. To understand how behavioral rhythmicity is generated by the nervous system, it is essential to identify the output circuits from the pacemaker neurons. A recent study of Drosophila has suggested that pacemaker neurons project to mushroom body (MB) neurons, which are considered the memory center in Drosophila. MBs also regulate spontaneous locomotor activity without learning, suggesting that MB neuronal activity regulates behavioral rhythms. However, the importance of MBs in generating behavioral rhythmicity remains controversial because contradicting results have been reported as follows: (1) locomotor activity in MB-ablated flies is substantially rhythmic, but (2) activation of restricted neuronal populations including MB neurons induces arrhythmic locomotor activity. Here, we report that neurotransmission in MBs is required for behavioral rhythmicity. For adult-specific disruption of neurotransmission in MBs, we used the GAL80/GAL4/UAS ternary gene expression system in combination with the temperature-sensitive dynamin mutation shibire(ts1). Blocking of neurotransmission in GAL4-positive neurons including MB neurons induced arrhythmic locomotor activity, whereas this arrhythmicity was rescued by the MB-specific expression of GAL80. Our results indicate that MB signaling plays a key role in locomotor activity rhythms in Drosophila. 
27106353	To determine whether the promoter polymorphism -203A>C of cholesterol-7α-hydroxylase encoding gene (CYP7A1) affects diurnal variation in CYP7A1 enzyme activity.The study included 16 healthy male volunteers - 8 homozygous for -203A and 8 homozygous for the -203C allele of CYP7A1. Three 15-hour examinations (from 7am to 10pm) were carried out for each of the participants: after one-day treatment with cholestyramine; after one-day treatment with chenodeoxycholic acid (CDCA); and a control examination without any treatment. The plasma concentration of 7α-hydroxy-4-cholesten-3-one (C4), a marker of CYP7A1 activity, was determined in all the experiments at 90-min intervals.	CYP7A1 activity was up-regulated after treatment with cholestyramine and suppressed after treatment with CDCA. There were no differences between -203A and -203C allele carriers in the response of enzyme activity to both drugs. In the control experiment, -203A allele carriers displayed diurnal variation in enzyme activity, whereas CYP7A1 activity did not change in -203C allele carriers. These results were confirmed by modeling the dynamics of C4 using polynomial regression.	The promoter polymorphism of the CYP7A1 gene has a pronounced impact on diurnal variation in CYP7A1 activity.	
27106109	Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis. 
27105958	It is unclear whether the poor autonomic flexibility or dysregulation observed in patients with posttraumatic stress disorder (PTSD) represents a pre-trauma vulnerability factor or results from exposure to trauma. We used an animal model of PTSD to assess the association between the behavioral response to predator scent stress (PSS) and the cardiac autonomic modulation in male and female rats. The rats were surgically implanted with radiotelemetry devices to measure their electrocardiograms and locomotor activity (LMA). Following baseline telemetric monitoring, the animals were exposed to PSS or sham-PSS. Continuous telemetric monitoring (24h/day sampling) was performed over the course of 7days. The electrocardiographic recordings were analyzed using the time- and frequency-domain indexes of heart rate variability (HRV). The behavioral response patterns were assessed using the elevated plus maze and acoustic startle response paradigms for the retrospective classification of individuals according to the PTSD-related cut-off behavioral criteria. During resting conditions, the male rats had significantly higher heart rates (HR) and lower HRV parameters than the female rats during both the active and inactive phases of the daily cycle. Immediately after PSS exposure, both the female and male rats demonstrated a robust increase in HR and a marked drop in HRV parameters, with a shift of sympathovagal balance towards sympathetic predominance. In both sexes, autonomic system habituation and recovery were selectively inhibited in the rats whose behavior was extremely disrupted after exposure to PSS. However, in the female rats, exposure to the PSS produced fewer EBR rats, with a more rapid recovery curve than that of the male rats. PSS did not induce changes to the circadian rhythm of the LMA. According to our results, PTSD can be conceptualized as a disorder that is related to failure-of-recovery mechanisms that impede the restitution of physiological homeostasis. 
27105762	We investigated the relationships among nocturnal polyuria, sleep apnea and body fluid volume to elucidate the pathophysiology of nocturia in sleep apnea syndrome.We enrolled 104 consecutive patients who underwent polysomnography for suspected sleep apnea syndrome. Self-assessed symptom questionnaires were administered to evaluate sleep disorder and lower urinary tract symptoms, including nocturia. Voiding frequency and voided volume were recorded using a 24-hour frequency-volume chart. Body fluid composition was estimated in the morning and at night using bioelectric impedance analysis. Frequency-volume chart data were analyzed in 22 patients after continuous positive airway pressure therapy.	Patients with nocturnal polyuria showed a higher apnea-hypopnea index (33.9 vs 24.2, p = 0.03) and a larger circadian change in extracellular fluid adjusted to lean body mass (0.22 vs -0.19, p = 0.019) than those without nocturnal polyuria. These relations were more evident in patients 65 years old or older than in those 64 years or younger. A multivariate linear regression model showed an independent relationship of nocturnal polyuria with the apnea-hypopnea index and the circadian change in extracellular fluid adjusted to lean body mass (p = 0.0012 and 0.022, respectively). Continuous positive airway pressure therapy significantly improved nocturnal polyuria and nocturia only in patients with nocturnal polyuria.	This study identified sleep apnea and the circadian change in extracellular fluid as independent factors for nocturnal polyuria.	
27104378	Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption. 
27103936	Expression of the clock family of genes in the suprachiasmatic nuclei (SCN) regulates the molecular control of circadian timing. Increasing evidence also implicates clock gene activity in the development of mood disorders. In particular, variation in the PER3 clock gene has been shown to influence diurnal preference and sleep homeostasis. However, there is not currently a clear association between PER3 polymorphisms and mood. This is possibly because the PER3 gene has been shown to influence homeostatic sleep drive, rather than circadian timing, and the PER3 gene may be behaviorally relevant only under chronic sleep loss conditions.To test the association between PER3 allele status and impaired mood, a total of 205 healthy women were genotyped for PER3 allele status and responded to previously-validated psychological questionnaires surveying self-reported sleep habits (MEQ, PSQI) and mood. Our mood measures included two measures of short-term, transient mood (state anxiety and mood disturbance) and two measures of longer term, ongoing mood (trait anxiety and depressive symptomology).	The PER3 genotype distribution was 88 (42.9%) for PER3(4/4), 98 (47.8%) for PER3(4/5), and 19 (9.3%) for PER3(5/5). Our sleep duration x genotype interaction analyses showed that, relative to longer allele carriers, PER3(4/4) genotypes were at greater risk for transient psychological effects (mood and state anxiety) when they reported reduced sleep durations.	Sleep duration plays a critical role in understanding the extent to which PER3 allele status relates to mood states.	
27103935	Limited research has compared the circadian phase-shifting effects of bright light and exercise and additive effects of these stimuli. The aim of this study was to compare the phase-delaying effects of late night bright light, late night exercise, and late evening bright light followed by early morning exercise. In a within-subjects, counterbalanced design, 6 young adults completed each of three 2.5-day protocols. Participants followed a 3-h ultra-short sleep-wake cycle, involving wakefulness in dim light for 2h, followed by attempted sleep in darkness for 1 h, repeated throughout each protocol. On night 2 of each protocol, participants received either (1) bright light alone (5,000 lux) from 2210-2340 h, (2) treadmill exercise alone from 2210-2340 h, or (3) bright light (2210-2340 h) followed by exercise from 0410-0540 h. Urine was collected every 90 min. Shifts in the 6-sulphatoxymelatonin (aMT6s) cosine acrophase from baseline to post-treatment were compared between treatments. Analyses revealed a significant additive phase-delaying effect of bright light + exercise (80.8 ± 11.6 [SD] min) compared with exercise alone (47.3 ± 21.6 min), and a similar phase delay following bright light alone (56.6 ± 15.2 min) and exercise alone administered for the same duration and at the same time of night. Thus, the data suggest that late night bright light followed by early morning exercise can have an additive circadian phase-shifting effect. 
27103934	Shift work is associated with both sleepiness and reduced performance. The aim of this study was to examine cognitive performance, sleepiness, and sleep quality among petrochemical control room shift workers. Sixty shift workers participated in this study. Cognitive performance was evaluated using a number of objective tests, including continuous performance test, n-back test, and simple reaction time test; sleepiness was measured using the subjective Karolinska Sleepiness Scale (KSS); and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. ANCOVA, t-test, and repeated-measures ANOVA were applied for statistical analyses, and the significance level was set at p < 0.05. All variables related to cognitive performance, except for omission error, significantly decreased at the end of both day and night shifts (p < 0.0001). There were also significant differences between the day and night shifts in terms of the variables of omission error (p < 0.027) and commission error (p < 0.036). A significant difference was also observed between daily and nightly trends of sleepiness (p < 0.0001) so that sleepiness was higher for the night shift. Participants had low sleep quality on both day and night shifts, and there were significant differences between the day and night shifts in terms of subjective sleep quality and quantity (p < 0.01). Long working hours per shift result in fatigue, irregularities in the circadian rhythm and the cycle of sleep, induced cognitive performance decline at the end of both day and night shifts, and increased sleepiness in night shift. It, thus, seems necessary to take ergonomic measures such as planning for more appropriate shift work and reducing working hours. 
27103886	Neuropeptides produced from prohormones by selective action of endopeptidases are vital signaling molecules, playing a critical role in a variety of physiological processes, such as addiction, depression, pain, and circadian rhythms. Neuropeptides bind to post-synaptic receptors and elicit cellular effects like classical neurotransmitters. While each neuropeptide could have its own biological function, mass spectrometry (MS) allows for the identification of the precise molecular forms of each peptide without a priori knowledge of the peptide identity and for the quantitation of neuropeptides in different conditions of the samples. MS-based neuropeptidomics approaches have been applied to various animal models and conditions to characterize and quantify novel neuropeptides, as well as known neuropeptides, advancing our understanding of nervous system function over the past decade. Here, we will present an overview of neuropeptides and MS-based neuropeptidomic strategies for the identification and quantitation of neuropeptides. 
27103673	This Review presents a broad overview of adaptations of truly Arctic and Antarctic mammals and birds to the challenges of polar life. The polar environment may be characterized by grisly cold, scarcity of food and darkness in winter, and lush conditions and continuous light in summer. Resident animals cope with these changes by behavioural, physical and physiological means. These include responses aimed at reducing exposure, such as 'balling up', huddling and shelter building; seasonal changes in insulation by fur, plumage and blubber; and circulatory adjustments aimed at preservation of core temperature, to which end the periphery and extremities are cooled to increase insulation. Newborn altricial animals have profound tolerance to hypothermia, but depend on parental care for warmth, whereas precocial mammals are well insulated and respond to cold with non-shivering thermogenesis in brown adipose tissue, and precocial birds shiver to produce heat. Most polar animals prepare themselves for shortness of food during winter by the deposition of large amounts of fat in times of plenty during autumn. These deposits are governed by a sliding set-point for body fatness throughout winter so that they last until the sun reappears in spring. Polar animals are, like most others, primarily active during the light part of the day, but when the sun never sets in summer and darkness prevails during winter, high-latitude animals become intermittently active around the clock, allowing opportunistic feeding at all times. The importance of understanding the needs of the individuals of a species to understand the responses of populations in times of climate change is emphasized. 
27103419	Aquatic organisms face multiple stressors in natural ecosystems. More and more often painkillers are detected in surface waters since their prescription has increased worldwide within the last years. Here we examined the effects of the non-steroidal anti-inflammatory drug (NSAID) diclofenac and hypoxia on three-spined sticklebacks (Gasterosteus aculeatus). We exposed sticklebacks to an environmentally relevant concentration of diclofenac (1μg/L) for 14days, to 24h of hypoxia (2.0mg O2/L), and a combination of both. Hypoxia and diclofenac both can be associated with oxidative stress in fish, but it is unclear whether they would act synergistically. Expression analysis of genes related to antioxidant response, hypoxia response, and chemical metabolism in gills showed that diclofenac alone had little effect, while the combination of hypoxia and diclofenac affected transcript levels most, indicating synergistic effects of these stressors. Of the antioxidant enzymes, only superoxide dismutase activity remained unchanged by treatments, while glutathione peroxidase (GPx) was the most affected antioxidant response on both the transcript and activity levels. Our results suggest that diclofenac may lead to suppressed catalase (CAT) activity but increased GPx activity, probably as compensatory mechanism to remove increasing H2O2 in the gills, and that this response is not affected by hypoxia. The activities of lactate dehydrogenase, CAT, and GPx also showed temporal variability during treatments, which can be attributable to tissue-specific circadian rhythms. Our study shows how responses to NSAIDs and hypoxia can interact in fish, suggesting that getting more insight into temporal variation and about the different levels of regulation of environmental responses is necessary in future studies. 
27102916	Genetic background and clinical picture of mood disorders (MD) are complex and may depend on many genes and their potential interactions as well as environmental factors. Therefore, clinical variations, or endophenotypes, were suggested for association studies. The aim of the study was to investigate association between the chronotype (CH) and quality of sleep characteristics with polymorphisms CLOCK, ARNTL, TIMELESS and PER3 genes in MD. We included a total sample of 111 inpatients and 126 healthy controls. To assess CH we applied Morningness-Eveningness Questionnaire (MEQ). Additionally, we defined the quality and patterns of sleep using The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). We applied Kruskal-Wallis test to determine associations. The main positive findings refer to associations between selected polymorphisms and: 1) chronotype with the ARNTL gene (rs11824092 and rs1481892) and the CLOCK (rs1268271) 2) sleep duration with the CLOCK gene (rs3805148) and the TIM gene (rs2291739) 3) daytime dysfunction with the PER3 gene (rs228727, rs228642, rs10864315) 4) subjective sleep quality with the ARNTL gene (rs11824092, rs1982350) 5) sleep disturbances with the ARNTL gene (rs11600996) We also found the significant epistatic interactions between polymorphism of the PER3 gene (rs2640909) & the CLOCK gene (rs11932595) and following sleep quality variables: sleep duration, habitual sleep efficiency and subjective sleep quality. The present study suggests a putative role of the analyzed clock genes polymorphisms in chronotype in the control group and in sleep quality disturbances in the course of MD. The results indicate that PSQI variables can be used to refine phenotype in association studies of clock genes in MD. 
27102330	Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.	Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.	The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.	
27102075	The circadian rhythm transcription factors CLOCK and BMAL1 are essential for AML cell growth. 

27101434	We assessed salivary melatonin levels in renal transplant (RTx) recipients who participated in a randomised, multicentre wait-list controlled trial on the effect of bright light therapy on their sleep and circadian rhythms. A large proportion of RTx recipients in our cohort had unexpectedly low melatonin values, which precluded calculation of the dim-light melatonin onset (DLMO) as a circadian marker. Thus, the aim of this post hoc analysis was to describe the melatonin profile of home-dwelling RTx recipients diagnosed with sleep-wake disturbances (SWDs). The participants were characterised by means of sleep questionnaires, validated psychometric instruments [Pittsburgh sleep quality Index (PSQI), Epworth sleepiness scale (ESS), Morningness-Eveningness Questionnaire (MEQ) and Depression, Anxiety and Stress Scale (DASS)] in addition to melatonin assay in saliva. Data were analysed with descriptive statistics and group comparisons made with appropriate post hoc tests. RTx recipients [n = 29 (aged 54.83 ± 13.73, transplanted 10.62 ± 6.84 years ago)] were retrospectively grouped into two groups: RTx recipients whose dim light melatonin onset (DLMO) could be calculated (n = 11) and those whose DLMO could not be calculated (n = 18). RTx recipients having a measurable DLMO had a number of differences from those without DLMO: they were younger [46.4 ± 14.9 compared to 60.0 ± 10.3 (p = .007)], had higher haemoglobin values [135.36 ± 12.01 versus 122.82 ± 11.56 (p = .01)], less anxiety [4 (0;8) versus 12 (6.5;14) (p = .021)] and a better overall sense of coherence [SOC Score: 71.09 ± 12.78 versus 56.28 ± 15.48 (p = 0.013)]. These results suggest that RTx recipients whose DLMO could be calculated have less health impairments, underlying the relevance of a stable circadian system. 
27101232	2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a selective mGlu5 receptor (mGluR5) antagonist intensively studied as potential novel anxiolytic drug. In the adult, MPEP activates stress-related areas, including the paraventricular nucleus of the hypothalamus (PVNh). However, it is unknown if MPEP targets similar structures in the juvenile brain as well.Here we examined by immunohistochemical methods the induction pattern of the neuronal activity marker c-Fos by MPEP at peri-pubertal stages (postnatal day P16, P24, P32 and P40) in C57BL6/N mice.	Despite the previously reported sharply diminished hypothalamic mGluR5 expression during postnatal development, we found a highly conserved PVNh activation by MPEP together with c-Fos expression in the extended amygdala. Interestingly, MPEP also robustly activated the paraventricular nucleus of the thalamus (PVT) and suprachiasmatic nucleus (SCN), regions associated with the modulation of circadian rhythms.	These results indicate a conserved activation pattern induced by MPEP in the young vs. adult brain especially in brain areas regulating stress and circadian rhythms and may be of importance regarding the effect of mGluR5 antagonists in the treatment of mood disorders during juvenile development.	
27101215	The discrepancy between biological and social rhythms known as social jetlag (SJL) is common in modern society and has a range of negative consequences for cognitive functioning, well-being and health. Social jetlag is typical for people with late chronotypes. As shown earlier, the prevalence of individuals with a late chronotype is higher among the residents of high latitudes. Therefore, a higher rate of detection of people with SJL should be expected in the North. In this study we assessed the detection rate of SJL among 62 young inhabitants of the European North of Russia (the Komi Republic), and the relationship between SJL, the circadian rhythm of the wrist temperature, and the cortisol awakening response (CAR). The detection rate of SJL was 65% among the people examined. A significant decrease in the amplitude (A) of circadian rhythm of wrist temperature: (β = -0.34 (CI 95%: -0.66 to -0.33); F1,60 = 10.4; p < 0.0001; η(2) = 0.31), an increased incidence of depression: No-SJL = 4.5%; SJL = 17.5% (H = 4.84; p < 0.05), and a tendency for an increase in CAR was also observed in the SJL group. There were sex differences in sensitivity to SJL. Females with SJL but not males had higher global seasonality scores (β = 0.51 (CI 95%: 0.21 to 0.81); F1,33 = 10.9; p < 0.002; η(2) =0.24), shorter sleep duration (β = -0.52 (CI 95%: -0.82 to -0.22); F1,33 = 12.9; p < 0.001; η(2) = 0.28), worse sleep quality (β = 0.39 (CI 95%: 0.07 to 0.72); F1,33 = 6.31; p < 0.017; η(2) = 0.16) and lower A of circadian rhythm of wrist temperature (β = -0.18 (CI 95%: -0.55 to 0.18); F1,33 = 4.48; p < 0.043; η(2) = 0.13) compared with females without SJL. Thus, our data indicate that 40 of 62 participants of investigation had social jetlag. A decrease of the amplitude of the circadian rhythm of the wrist temperature appears to be an objective marker of SJL. Social jetlag had a strong negative impact on females but not on males. 
27099465	With aging, the crystalline lens turns yellowish, which increases the absorption of wavelengths in the blue electromagnetic spectrum, reducing their photoreception in the retina. Since these wavelengths are the main stimulus in the regulation of the circadian rhythm, progressive reduction in their transmission is associated with chronic sleep disturbances and depression in elderly patients. Cataract extraction improves circadian photoreception at any age. However, lenses that block blue waves have 27% to 38% less melatonin suppression than lenses that block only ultraviolet (UV) rays.To assess the depression symptoms in subjects who have had bilateral phacoemul-sification and intraocular lens (IOL) implants, one group with yellow chromophore IOLs and the other group with transparent IOLs were compared.	Association to Prevent Blindness in Mexico (APEC), Hospital "Dr Luis Sánchez Bulnes".	This was an observational, cross-sectional, and single-center study.	Twenty-six subjects between 60 and 80 years of age, with a history of bilateral phacoemulsification and placement of the same type of IOL in both eyes from 4 to 12 months prior to the study, who attended the follow-up visits and agreed to participate in this study, and provided signed informed consent were included in the study. They were asked to answer the short version of the 15-item Geriatric Depression Scale.	The average age of the study participants was 72.5±5.94 years. The group without chromophore included 46.1% (n=12) of the patients and the group with chromophore included 53.9% (n=14) of the patients (P=0.088).	In the group of patients with IOLs that block the passage of blue light, the depression rate was 21.4%, a rate similar to that observed in the elderly population, whereas no patients in the group with transparent IOLs had depression.	
27097888	Systems biology provides opportunities to fully understand the genes and pathways in disease pathogenesis. We used literature knowledge and unbiased multiple data meta-analysis paradigms to analyze microarray datasets across different mouse strains and acute allergic asthma models. Our combined gene-driven and pathway-driven strategies generated a stringent signature list totaling 933 genes with 41% (440) asthma-annotated genes and 59% (493) ignorome genes, not previously associated with asthma. Within the list, we identified inflammation, circadian rhythm, lung-specific insult response, stem cell proliferation domains, hubs, peripheral genes, and super-connectors that link the biological domains (Il6, Il1ß, Cd4, Cd44, Stat1, Traf6, Rela, Cadm1, Nr3c1, Prkcd, Vwf, Erbb2). In conclusion, this novel bioinformatics approach will be a powerful strategy for clinical and across species data analysis that allows for the validation of experimental models and might lead to the discovery of novel mechanistic insights in asthma. 
27097688	Through evolution, most of the living species have acquired a time keeping system to anticipate daily changes caused by the rotation of the Earth. In all of the systems this pacemaker is based on a molecular transcriptional/translational negative feedback loop able to generate rhythmic gene expression with a period close to 24 hours. Recent evidences suggest that post-transcriptional regulations activated mostly by systemic cues play a fundamental role in the process, fine tuning the time keeping system and linking it to animal physiology. Among these signals, we consider the role of lipid transport and metabolism regulated by SCP2. Mice harboring a deletion of the Scp2 locus present a modulated diurnal accumulation of lipids in the liver and a perturbed activation of several signaling pathways including PPARα, SREBP, LRH-1, TORC1 and its upstream regulators. This defect in signaling pathways activation feedbacks upon the clock by lengthening the circadian period of animals through post-translational regulation of core clock regulators, showing that rhythmic lipid transport is a major player in the establishment of rhythmic mRNA and protein expression landscape. 
27097327	Women with a diagnosis of bipolar and major depressive disorders are at higher risk to develop postpartum depression. The primary objective of this longitudinal study was to determine whether daily activity rhythms and sleep parameters differ between women with and without a history of a mood disorder across the perinatal period. A secondary objective was to determine whether changes in these parameters were associated with postpartum mood. In total, 33 women were included in this study, 15 of which had a history of a mood disorder (high-risk group) and 18 who did not (low-risk group). Sleep and daily rhythms were assessed subjectively and objectively during the third trimester (≥26 weeks gestation) and again at 6-12 weeks postpartum. Mood was also assessed at both time points. Women in the high-risk group showed greater subjective daily rhythms and sleep disturbances across the perinatal period. Objective sleep efficiency was worse in the high-risk group in the postpartum period. Changes in both subjective daily rhythms and objective sleep efficiency were predictive of changes in depressive symptoms across the perinatal period. These findings encourage the development of preventative therapeutics to ensure circadian rhythm and sleep stability throughout the perinatal period. 
27097227	This study examined the impact of competition on the sleep/wake behaviour of elite athletes. The sleep/wake behaviour of Australian Rules Football players was assessed with wrist activity monitors on the night immediately before, and the night immediately after, a day game and an evening game. The time of day that a game occurred had a marked influence on sleep/wake behaviour later that night. After the evening game, sleep onset was later, time in bed was shorter and total sleep obtained was less than after the day game. It is yet to be determined whether a reduction in sleep after evening games impairs recovery. 
27096291	The accuracy of sleep/wake estimates derived with actigraphy is often dependent on researchers being able to discern non-wear times from sleep or quiescent wakefulness when confronted by discrepancies in a sleep log. Without knowing when an accelerometer is being worn, non-wear could be inferred from periods of inactivity unlikely to occur while in bed. Data collected in our laboratory suggest that more than 50% of inactive periods during time in bed are <8 min in duration. This duration may be an appropriate minimum threshold for routine non-wear classification during self-reported wake. Higher thresholds could be chosen to derive non-wear definitions for self-reported bedtimes depending on the desired level of certainty. To determine non-wear at thresholds of 75%, 95% and 99%, for example, would require periods of inactivity lasting ≥18 min, ≥53 min and ≥85 min, respectively. 
27096153	An individual's chronotype is a trait which reflects his/her diurnal preferences for the times of rest and activities, and displays a continuum from morningness to eveningness. Studies have shown that eveningness tends to be associated with a less healthy lifestyle, including increased likelihood of developing obesity. In this study, we examined the relationship between chronotype and food intake, physical sleep and activity in 72 resident physicians (52 women and 20 men). Assessments included chronotype evaluation by the Horne and Ostberg Morningness-Eveningness questionnaire (MEQ); food intake pattern through a self-administered food diary that was kept over the course of 3 non-successive days; physical activity level, using the Baecke questionnaire (BQ); sleep quality and quantity using the Pittsburgh Sleep Quality Index (PSQI); and sleepiness, Epworth Sleepiness Scale (ESS). Linear regression analyses, after adjustments for age, sex, body mass index (BMI), hours of additional work per week ESS and total physical activity score, showed that the chronotype score was negatively associated with cholesterol (coefficient = -0.24; p = 0.04), sweets (coefficient = -0.27, p = 0.03) and vegetables (coefficient = -0.26; p = 0.04) intakes. Following the same statistical adjustments, the chronotype score was positivity associated with leisure-time index (coefficient = 0.26, p = 0.03) and BQ total score (coefficient = 0.27, p = 0.03). We concluded that most issues related to nutrition problems and unhealthy lifestyle were associated with scores indicative of eveningness. These findings emphasize the importance of assessing an individual's chronotype when examining feeding behavior.
27095816	Ocular clocks, first identified in the retina, are also found in the retinal pigment epithelium (RPE), cornea, and ciliary body. The retina is a complex tissue of many cell types and considerable effort has gone into determining which cell types exhibit clock properties. Current data suggest that photoreceptors as well as inner retinal neurons exhibit clock properties with photoreceptors dominating in nonmammalian vertebrates and inner retinal neurons dominating in mice. However, these differences may in part reflect the choice of circadian output, and it is likely that clock properties are widely dispersed among many retinal cell types. The phase of the retinal clock can be set directly by light. In nonmammalian vertebrates, direct light sensitivity is commonplace among body clocks, but in mice only the retina and cornea retain direct light-dependent phase regulation. This distinguishes the retina and possibly other ocular clocks from peripheral oscillators whose phase depends on the pace-making properties of the hypothalamic central brain clock, the suprachiasmatic nuclei (SCN). However, in mice, retinal circadian oscillations dampen quickly in isolation due to weak coupling of its individual cell-autonomous oscillators, and there is no evidence that retinal clocks are directly controlled through input from other oscillators. Retinal circadian regulation in both mammals and nonmammalian vertebrates uses melatonin and dopamine as dark- and light-adaptive neuromodulators, respectively, and light can regulate circadian phase indirectly through dopamine signaling. The melatonin/dopamine system appears to have evolved among nonmammalian vertebrates and retained with modification in mammals. Circadian clocks in the eye are critical for optimum visual function where they play a role fine tuning visual sensitivity, and their disruption can affect diseases such as glaucoma or retinal degeneration syndromes. 
27095405	UVR8 (UV Resistance Locus 8) is an ultraviolet-B (UV-B; 280-315nm) light receptor that is involved in regulating many aspects of plant growth and development. UV-B irradiation can increase the development of flower and fruit coloration in many fruit trees, such as grape, pear and apple. Previous investigations of the structure and functions of UVR8 in plants have largely focused on Arabidopsis. Here, we isolated the UVR8 gene from apple (Malus domestica) and analyzed its function in transgenic Arabidopsis. Genomic and protein sequence analysis showed that MdUVR8 shares high similarity with the AtUVR8 protein from Arabidopsis, including the conserved seven-bladed β-propeller, the C27 region, the 3 "GWRHT" motifs and crucial amino-acid residues (14 Trps, 2 Args). A point mutation prediction and three-dimensional structural analysis of MdUVR8 indicated that it has a similar structure to AtUVR8 and that the crucial residues are also important in MdUVR8. In terms of transcript levels, MdUVR8 expression was up-regulated by UV-B light, which suggests that its expression follows a 24-h circadian rhythm. Using heterologous expression of MdUVR8 in both uvr8-1 mutant and wild-type (WT) Arabidopsis, we found that MdUVR8 regulates hypocotyl elongation and gene expression under UV-B light. These data provide functional evidence for a role of MdUVR8 in controlling photomorphogenesis under UV-B light and indicate that the function of UVR8 is conserved between Arabidopsis and apple. Furthermore, we examined the interaction between MdUVR8 and MdCOP1 (constitutive photomorphogenic1) using a yeast two-hybrid assay and a co-immunoprecipitation assay. This interaction provides a direction for investigating the regulatory mechanisms of the UV-B-light pathway in apple. 
27095397	B-box (BBX) proteins are zinc finger proteins containing B-box domains, which have roles in Arabidopsis growth and development. However, little is known concerning rice BBXs. Herein, we identified a rice BBX protein, Oryza sativa BBX14 (OsBBX14). OsBBX14 is highly expressed in flag leaf blades. OsBBX14 expression shows a diurnal rhythm under photoperiodic conditions and subsequent continuous white light. OsBBX14 is located in the nucleus and has transcriptional activation potential. OsBBX14-overexpression (OsBBX14-OX) lines exhibited delayed heading date under long-day (LD) and short-day (SD) conditions, whereas RNAi lines of OsBBX14 lines had similar heading dates to the WT. The florigen genes, Hd3a and RFT1, were downregulated in the OsBBX14-OX lines under LD and SD conditions. Under LD conditions, Hd1 was expressed higher in the OsBBX14-OX lines than in the wild type (WT), and the rhythmic expression of circadian clock genes, OsLHY and OsPRR1, was changed in OsBBX14-OX lines. Thus, OsBBX14 acts as a floral repressor by promoting Hd1 expression under LD conditions, probably because of crosstalk with the circadian clock. Under SD conditions, Ehd1 expression was reduced in OsBBX14-OX lines, but Hd1 and circadian clock gene expressions were unaffected, indicating that OsBBX14 acts as a repressor of Ehd1. Our findings suggested that OsBBX14 regulates heading date differently under LD and SD conditions. 
27094388	Both, DNA and RNA nucleoside modifications contribute to the complex multi-level regulation of gene expression. Modified bases in tRNAs modulate protein translation rates in a highly dynamic manner. Synonymous codons, which differ by the third nucleoside in the triplet but code for the same amino acid, may be utilized at different rates according to codon-anticodon affinity. Nucleoside modifications in the tRNA anticodon loop can favor the interaction with selected codons by stabilizing specific base pairs. Similarly, weakening of base pairing can discriminate against binding to near-cognate codons. mRNAs enriched in favored codons are translated in higher rates constituting a fine-tuning mechanism for protein synthesis. This so-called codon bias establishes a basic protein level, but sometimes it is necessary to further adjust the production rate of a particular protein to actual requirements, brought by, e.g., stages in circadian rhythms, cell cycle progression or exposure to stress. Such an adjustment is realized by the dynamic change of tRNA modifications resulting in the preferential translation of mRNAs coding for example for stress proteins to facilitate cell survival. Furthermore, tRNAs contribute in an entirely different way to another, less specific stress response consisting in modification-dependent tRNA cleavage that contributes to the general down-regulation of protein synthesis. In this review, we summarize control functions of nucleoside modifications in gene regulation with a focus on recent findings on protein synthesis control by tRNA base modifications. 
27094070	This review presented an introduction of the visual pathway related circadian rhythm regulation system: the intrinsically photosensitive retinal ganglion cells-suprachiasmatic nucleus-pineal gland-melatonin axis, and discussed the impact of light with different wave length and irradiation received by retina on circadian rhythm and sleep habit. A hypothesis was proposed consequently that the high morbidity of sleep disorder in elderly might be partially attributable to the long-term blue light blocking status induced by age-related cataract. A number of relative literatures were reviewed and a novel research direction was advanced on improving circadian rhythm and sleep condition in elderly based on the current knowledge. (Chin J Ophthalmol, 2016, 52: 309-314). 
27093926	Senescence-accelerated mouse (SAM) is inbred lines of mice originally developed from AKR/J mice. Among the six SAM prone (SAMP) substrains, 8- to 12-month-old SAMP8 have long been used as a model of age-related cognitive impairments. However, little is still known for younger SAMP8 mice. Here, we examined the phenotypical characteristics of 4-month-old SAMP8 using a battery of behavioral tests. Four-month-old SAMP8 mice failed to recognize spatially displaced object in an object recognition task and performed poorly in the probe test of the Morris water maze task compared to SAMR1, suggesting that SAMP8 have impaired spatial memory. In addition, young SAMP8 exhibited enhanced anxiety-like behavior in an open field test and showed depression-like behavior in the forced-swim test. Their circadian rhythm was also disrupted. These abnormal behaviors of young SAMP8 are similar to behavioral alterations also observed in aged mice. In summary, age-related behavioral alterations occur in SAMP8 as young as 4 months old. 
27093617	The aim of the study was to investigate whether postmenopausal women show differences in circadian-related variables and sleep characteristics compared with premenopausal women, and to analyze potential associations between these circadian-related variables and abdominal fat distribution or metabolic syndrome (MetS) components.A total of 177 women were studied (127 premenopausal, 50 postmenopausal). Sixty percent of the total population was overweight/obese, with no significant differences between premenopausal (60%) and postmenopausal women (62%) (P = 0.865). Wrist temperature (WT) and rest-activity cycles were measured during 8 consecutive days, and sleep and food diaries collected. MetS characteristics and daily patterns of saliva cortisol were analyzed. Sleep characteristics were assessed with domiciliary polysomnography.	Postmenopausal women showed a less robust rhythm in WT with lower amplitude (°C) (0.8 ± 0.4 vs 0.9 ± 0.5) (P < 0.05) and lower mean temperature values at the midpoint of sleep than premenopausal women. Postmenopausal women were also more morning-type than premenopausal women, showing a phase advance of approximately 1 hour in WT and rest-activity rhythms, and more morning-type habits (earlier sleep onset/offset and breakfast intake) (P < 0.05). Postmenopausal women showed higher levels of activity in the morning and lower in the evening compared with premenopausal women (P < 0.05). Daily variability in cortisol was significantly reduced in postmenopausal women compared with premenopausal women (P < 0.05). Postmenopausal women had increased frequency of sleep-related breathing abnormalities (P < 0.0001). In the women studied, abdominal fat and MetS were associated with an increase in circadian alterations (high fragmentation and low amplitude of the rhythm) (P < 0.05).	Postmenopausal women exhibit loss of circadian robustness and an increase in sleep abnormalities compared with premenopausal women.	
27093576	The aim of the present study was to investigate how broad personality dimensions and dispositional resistance to change are associated with mastery of work among shift workers. A total of 285 shift workers employed in rotating shifts with morning, evening and night work and night shift schedules in a municipality in Norway completed electronic questionnaires. The findings suggest that the broad personality dimensions neuroticism and conscientiousness were significant predictors of perceived work mastery among shift workers in this sample, whereas the narrow trait dispositional resistance to change was not. 
27092731	Data on the association between shift work and hypertension are controversial. Sleep restriction is hypothesized to be involved in this relationship. Since on-shift nap can partly compensate for sleep deprivation among night workers, this investigation is aimed at (i) comparing the prevalence of hypertension among workers considering both current and former night work, (ii) testing the association between on-shift naps and hypertension among night workers, and (iii) analyzing the influence of sleep complaints in the association between on-shift nap and hypertension. Nap was defined as a sleep episode with duration shorter than the average nighttime sleep. A cross-sectional study was performed at the 18 largest public hospitals in Rio de Janeiro, Brazil, in 2010-2011 (N = 2588 female registered nurses). Nurses were informally allowed to nap for up to three consecutive hours during working nights. Workers completed a multidimensional questionnaire including self-reported information on physician diagnosis of hypertension, napping, and sleep complaints (insomnia, diurnal sleepiness, and non-satisfactory sleep). Epidemiological and statistical treatment of data included binomial logistic regression and interaction tests. Higher chances of hypertension were observed for both current and former night workers compared with workers with no previous experience in night work, i.e. exclusive day workers (OR = 1.68; CI95% 1.22-2.33 and OR = 1.40; CI95% 1.01-1.96, respectively) after adjustment for age, race/ethnicity, physical activity, smoking, alcohol consumption, insomnia, weekly work hours, and BMI. Compared with exclusive day workers, both non-nappers and nappers were at a higher likelihood of reporting hypertension (OR = 1.93 CI95% 1.35-2.79 and OR = 1.41 CI95% 1.08-2.20, respectively). An interaction was observed between napping behavior and insomnia (p = 0.037). In the whole sample of night workers, the lower OR for nappers was confirmed when they were directly compared with non-nappers (OR = 0.76 CI95% 0.59-0.98). Analysis of night workers stratified by insomnia showed a significant reduction in OR for nappers (compared to non-nappers) only among insomniacs (OR = 0.58). Napping during night work may be a protective factor for hypertension, particularly among insomniacs. Factors related to melatonin secretion, blood pressure control, and blood pressure dipping patterns are likely to be involved in the relationship between on-shift napping and blood pressure.
27092579	The present study investigates the impact of chronotype, social jetlag and sleep duration on self-perceived health, measured by Work Ability Index (WAI), within an industrial setting. Between 2011 and 2013, 2474 day and shift workers participated in a health check offered by an occupational health promotion program and filled out the Munich ChronoType Questionnaire (adapted to the rotational 12-h schedule for shift workers) and the WAI. We computed sleep duration on work and free days, chronotype, and social jetlag. We used linear regression models to examine chronotype, sleep duration and social jetlag for association with the WAI sum score, and proportional odds models to estimate the combined effect of social jetlag and sleep duration. Participants reported an average daily sleep duration of 7.35 h (SD: 1.2 h), had an average chronotype of 3:08 a.m. (SD: 1 h), and the average social jetlag corresponded to 1.96 h (SD: 2.05 h). Increasing social jetlag and shorter sleep duration were independently associated with a decreasing WAI, while chronotype per se was not associated with WAI. Short sleep duration combined with high social jetlag significantly increased the risk of poor WAI (OR = 1.36; 95% CI: 1.09-1.72), while long sleep duration and high social jetlag were not associated with poor WAI (OR = 1.09; 95% CI: 0.88-1.35). Our results add to a growing body of literature, suggesting that circadian misalignment, but not chronotype per se, may be critical for health. Our results indicate that longer sleep may override the adverse effects of social jetlag on WAI. 
27092523	Chronotherapy involves the administration of medication in coordination with the body's circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects. The aim of this study is to investigate the "time of administration" recommendations on chronotherapy for commonly-prescribed medicines in Australia. This study also aimed to explore the quality of information on the timing of administration presented in drug information sources, such as consumer medicine information (CMI) and approved product information (PI). Databases were searched for original research studies reporting on the impact of "time of administration" of the 30 most commonly-prescribed medicines in Australia for 2014. Further, time of administration recommendations from drug information sources were compared to the evidence from chronotherapy trials. Our search revealed 27 research studies, matching the inclusion and exclusion criteria. In 56% (n = 15) of the research studies, the therapeutic effect of the medicine varied with the time of administration, i.e., supported chronotherapy. For some medicines (e.g., simvastatin), circadian-based optimal administration time was evident in the information sources. Overall, dedicated studies on the timing of administration of medicines are sparse, and more studies are required. As it stands, information provision to consumers and health professionals about the optimal "time" to take medications lags behind emerging evidence. 
27092404	Approximately 10% of the employed population in the United States works in multiple jobs. They are more likely to work long hours and in nonstandard work schedules, factors known to impact sleep duration and quality, and increase the risk of injury. In this study we used multivariate regression models to compare the duration of sleep in a 24-hour period between workers working in multiple jobs (MJHs) with single job holders (SJHs) controlling for other work schedule and demographic factors. We used data from the Bureau of Labor Statistics US American Time Use Survey (ATUS) pooled over a 9-year period (2003-2011). We found that MJHs had significantly reduced sleep duration compared with SJHs due to a number of independent factors, such as working longer hours and more often late at night. Male MJHs, working in their primary job or more than one job on the diary day, also had significantly shorter sleep durations (up to 40 minutes less on a weekend day) than male SJHs, even after controlling for all other factors. Therefore, duration of work hours, time of day working and duration of travel for work may not be the only factors to consider when understanding if male MJHs are able to fit in enough recuperative rest from their busy schedule. Work at night had the greatest impact on sleep duration for females, reducing sleep time by almost an hour compared with females who did not work at night. We also hypothesize that the high frequency or fragmentation of non-leisure activities (e.g. work and travel for work) throughout the day and between jobs may have an additional impact on the duration and quality of sleep for MJHs. 
27091961	The sleep-wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep-wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.
27091539	Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls.Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm.	Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption.	Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1.	
27091523	Our study aims to explore the associations between outdoor nighttime lights (ONL) and sleep patterns in the human population.Cross-sectional telephone study of a representative sample of the general US population age 18 y or older. 19,136 noninstitutionalized individuals (participation rate: 83.2%) were interviewed by telephone. The Sleep-EVAL expert system administered questions on life and sleeping habits; health; sleep, mental and organic disorders (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; International Classification of Sleep Disorders, Second Edition; International Classification of Diseases, 10(th) Edition). Individuals were geolocated by longitude and latitude. Outdoor nighttime light measurements were obtained from the Defense Meteorological Satellite Program's Operational Linescan System (DMSP/OLS), with nighttime passes taking place between 19:30 and 22:30 local time. Light data were correlated precisely to the geolocation of each participant of the general population sample.	Living in areas with greater ONL was associated with delayed bedtime (P < 0.0001) and wake up time (P < 0.0001), shorter sleep duration (P < 0.01), and increased daytime sleepiness (P < 0.0001). Living in areas with greater ONL also increased the dissatisfaction with sleep quantity and quality (P < 0.0001) and the likelihood of having a diagnostic profile congruent with a circadian rhythm disorder (P < 0.0001).	Although they improve the overall safety of people and traffic, nighttime lights in our streets and cities are clearly linked with modifications in human sleep behaviors and also impinge on the daytime functioning of individuals living in areas with greater ONL.	
27091519	Individual differences in sleep timing have been widely recognized and are of particular relevance in adolescents and young adults who often show mild to severely delayed sleep. The biological mechanisms underlying the between-subject variance remain to be determined. Recent human genetics studies showed an association between sleep timing and melanopsin gene variation, but support for functional effects on downstream pathways and behavior was not demonstrated before. We therefore investigated the association between the autonomic (i.e., pupil diameter) and behavioral (i.e., sleep timing) readouts of two different downstream brain areas, both affected by the same melanopsin-dependent retinal phototransduction: the olivary pretectal nucleus (OPN) and the suprachiasmatic nucleus (SCN).Our study population included 71 healthy individuals within an age range with known vulnerability to a delayed sleep phase (16.8-35.7 y, 37 males, 34 females). Pupillometry was performed to estimate functionality of the intrinsic melanopsin-signaling circuitry based on the OPN-mediated post-illumination pupil response (PIPR) to blue light. Sleep timing was quantified by estimating the SCN-mediated mid-sleep timing in three different ways in parallel: using a chronotype questionnaire, a sleep diary, and actigraphy.	All three measures consistently showed that those individuals with a later mid-sleep timing had a more pronounced PIPR (0.03 < P < 0.05), indicating a stronger blue-light responsiveness of the intrinsic melanopsin-based phototransduction circuitry.	Trait-like individual differences in the melanopsin phototransduction circuitry contribute to individual differences in sleep timing. Blue light-sensitive young individuals are more prone to delayed sleep.	
27090880	Circadian clocks are endogenous biochemical oscillators that control daily behavioral rhythms in all living organisms. In fruit fly, the circadian rhythms are typically studied using power spectra of multiday behavioral recordings. Despite decades of study, a quantitative understanding of the temporal shape of Drosophila locomotor rhythms is missing. Locomotor recordings have been used mostly to extract the period of the circadian clock, leaving these data-rich time series largely underutilized. The power spectra of Drosophila and mouse locomotion often show multiple peaks in addition to the expected at T ~ 24 h. Several theoretical and experimental studies have previously used these data to examine interactions between the circadian and other endogenous rhythms, in some cases, attributing peaks in the T < 24 h regime to ultradian oscillators. However, the analysis of fly locomotion was typically performed without considering the shape of time series, while the shape of the signal plays important role in its power spectrum. To account for locomotion patterns in circadian studies we construct a mathematical model of fly activity. Our model allows careful analysis of the temporal shape of behavioral recordings and can provide important information about biochemical mechanisms that control fly activity.Here we propose a mathematical model with four exponential terms and a single period of oscillation that closely reproduces the shape of the locomotor data in both time and frequency domains. Using our model, we reexamine interactions between the circadian and other endogenous rhythms and show that the proposed single-period waveform is sufficient to explain the position and height of >88 % of spectral peaks in the locomotion of wild-type and circadian mutants of Drosophila. In the time domain, we find the timescales of the exponentials in our model to be ~1.5 h(-1) on average.	Our results indicate that multiple spectral peaks from fly locomotion are simply harmonics of the circadian period rather than independent ultradian oscillators as previously reported. From timescales of the exponentials we hypothesize that model rates reflect activity of the neuropeptides that likely transduce signals of the circadian clock and the sleep-wake homeostat to shape behavioral outputs.	
27090429	A master brain clock, localized to the hypothalamic suprachiasmatic nucleus (SCN), coordinates daily rhythms of physiology and behavior. Within the SCN, interconnected individual neurons are oscillators that, as an ensemble, function to send a coherent timing signal to the brain and body. However, individually, these neurons display different amplitudes, periods, and phases of oscillation. The dynamic properties of the SCN have been characterized over several spatial levels of analysis, from proteins to cells to tissues, and over several temporal ranges, from milliseconds to weeks. Modeling tools guide empirical research in this complex and multiscale spatiotemporal environment. Given that the SCN is a prototypical example of oscillating neural systems, principles of its organization hold promise as general prototypes of rhythms in other frequencies. 
27090227	Human chronotypes (differences in preference for early or late rising each day) have been extensively studied in recent years, but no attempt has been made to compare human chronotypes with the chronotypes of other animal species. We evaluated behavioral chronotypes in 16 mammalian species along a body size gradient of five orders of magnitude (from mice to cattle). Individuals of all species were studied under a 12L:12D photoperiod in a thermoneutral environment with food and water available at all times. Rhythms of locomotor activity were analyzed for onset time, acrophase, and robustness. Neither of these rhythmic parameters was significantly related to body size, but onset time and acrophase varied considerably from species to species, thus characterizing diurnal and nocturnal species. Chronotype spreads ranged from less than an hour in sheep to almost 24h in cats, thus extending both below and above the human chronotype spread of 6h. The variability of chronotype (as quantified by the standard deviation of group means) was much larger between species than within species and also larger between individuals of a species than within individuals on consecutive days. These results help situate the matter of human chronotypes within the broader context of variability in the phase angle of entrainment of circadian rhythms in animals.
27089370	The 24-h day involves cycles in environmental factors that impact organismal fitness. This is thought to select for organisms to regulate their temporal biology accordingly, through circadian and diel rhythms. In addition to rhythms in abiotic factors (such as light and temperature), biotic factors, including ecological interactions, also follow daily cycles. How daily rhythms shape, and are shaped by, interactions between organisms is poorly understood. Here, we review an emerging area, namely the causes and consequences of daily rhythms in the interactions between vectors, their hosts and the parasites they transmit. We focus on mosquitoes, malaria parasites and vertebrate hosts, because this system offers the opportunity to integrate from genetic and molecular mechanisms to population dynamics and because disrupting rhythms offers a novel avenue for disease control. 
27089043	The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25-1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75-4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep. 
27088881	Several studies have shown a bidirectional relationship between insomnia and pain. The aim of this study was to evaluate whether working hours and type of occupation are associated with insomnia, pain and insomnia plus pain. Insomnia and musculoskeletal pain symptoms were measured in airline pilots, rural workers and factory workers using validated indexes. Rural and night work were predictors for the outcomes (insomnia and pain). However, musculoskeletal pain was found to be a predictor of insomnia but not vice versa. The current findings suggest that working hours and type of occupation play a role in the sleep-pain relationship.
27088753	The aim of this longitudinal study on novice police officers was to investigate inter-individual differences in sleep response to shift work, and to identify potential baseline predictors thereof. A total of 42 subjects were assessed at baseline, prior to commencing shift work. They were re-assessed during three follow-up sessions within the first 2 years of shift work exposure after approximately 4, 12, and 20 months of rotating shift work. Wrist actigraphy and sleep logs were used to investigate nocturnal sleep at baseline and daytime sleep after night shifts during the follow-up sessions. Actigraphically estimated total sleep time and subjective sleep quality were analyzed as outcome variables, using mixed-effects analysis of variance. Systematic inter-individual differences were observed in the overall response of these outcome variables to shift work. In this sample, flexibility of sleeping habits and gender were found to be predictors of daytime total sleep time in the first 2 years of shift work exposure. Flexibility of sleeping habits and subjective quality of nighttime sleep prior to shift work were found to be predictors of subjective quality of daytime sleep. These results suggest that it may be possible to detect and even predict sleep deficiencies in response to shift work early on, which could be a basis for the development of individualized interventions to improve shift work tolerance.
27088730	Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies.The present work was designed in an attempt to determine guidelines in the field of salt-induced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry).	In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges.	Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites.	
27088628	Electric light is one of the signature inventions of human beings. A problem, however, is that electric light can confuse our endogenous circadian rhythmicity. It has now become apparent that circadian biology is fundamental to the functioning and adaptation of almost all life forms. In the modern world, everyone is exposed to electric light during the day and night, and thereby can experience some level of circadian disruption. Perhaps as a canary in the coal mine, study of people whose work hours include nighttime (shift workers) is beginning to yield insights on the adverse health effects of circadian disruption from electric light. 
27088160	The Cape mole rat Georychus capensis is a solitary subterranean rodent found in the western and southern Cape of South Africa. This approximately 200-gram bathyergid rodent shows a nocturnal circadian rhythm, but sleep in this species is yet to be investigated. Using telemetric recordings of the electroencephalogram (EEG) and electromyogram (EMG) in conjunction with video recordings, we were able to show that the Cape mole rat, like all other rodents, has sleep periods composed of both rapid eye movement (REM) and slow-wave (non-REM) sleep. These mole rats spent on average 15.4 h awake, 7.1 h in non-REM sleep and 1.5 h in REM sleep each day. Cape mole rats sleep substantially less than other similarly sized terrestrial rodents but have a similar percentage of total sleep time occupied by REM sleep. In addition, the duration of both non-REM and REM sleep episodes was markedly shorter in the Cape mole rat than has been observed in terrestrial rodents. Interestingly, these features (total sleep time and episode duration) are similar to those observed in another subterranean bathyergid mole rat, i.e. Fukomys mechowii. Thus, there appears to be a bathyergid type of sleep amongst the rodents that may be related to their environment and the effect of this on their circadian rhythm. Investigating further species of bathyergid mole rats may fully define the emerging picture of sleep in these subterranean African rodents. 
27088110	G protein-coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that terminate G protein-coupled receptor (GPCR) signaling by phosphorylating the receptor and inducing its internalization. In addition to their canonical function, some GRKs can phosphorylate non-GPCR substrates and regulate GPCR signaling in a kinase-independent manner. GPCRs are abundantly expressed in the suprachiasmatic nucleus (SCN), a structure in the mammalian brain that serves as the central circadian pacemaker. Various facets of circadian timekeeping are under the influence of GPCR signaling, and thus are potential targets for GRK regulation. Despite this, little attention has been given to the role of GRKs in circadian rhythms. In this research highlight, we discuss our latest findings on the functional involvement of GRK2 in mammalian circadian timekeeping in the SCN. Using grk2 knockout mice, we demonstrate that GRK2 is critical for maintaining proper clock speed and ensuring that the clock is appropriately synchronized to environmental light cycles. Although grk2 deficiency expectedly alters the expression of a key GPCR in the SCN, our study also reveals that GRK2 has a more direct function that touches the heart of the circadian clock.
27088090	The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study. 
27087445	Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome. 
27086336	The aim of this paper is to present the subjective insomnia prevalence. Assessment of sleep problems was a part of NATPOL study conducted to explore the risk factors for cardiovascular diseases.The study group consisted of 2,413 people (1,245 females and 1,168 males) aged 18-79 and it was representative for the Polish population. Questions concerning sleep were included in the questionnaire designed specifically for the NATPOL study, which assessed cardiovascular risk factors. The questionnaire was applied personally by trained nurses at place of residence of study subjects. Only results concerning sleep complaints are presented in this paper.	The prevalence of sleep complaints was 50.5% (58.9 % in women, 41.4% in men). Subjective insomnia was most prevalent in women aged 60-79 and it was reported by 74.8%. Difficulties in falling asleep were reported by 60.2%, difficulties in falling asleep by 45.5 % and early morning awakenings by 26.4% of respondents.	Study results suggest that self-reported insomnia is a common problem in general population of Poland. The most common sleep problem is impaired sleep initiation. Insomnia complaints are most prevalent in women and in the older age groups.	
27086112	Histone methylation is an epigenetic modification mechanism that regulates gene expression in eukaryotic cells. Jumonji C domain-containing demethylases are involved in removal of methyl groups at lysine or arginine residues. The JmjC domain-only member, JMJ30/JMJD5 of Arabidopsis, is a component of the plant circadian clock. Although some plant circadian clock genes undergo alternative splicing in response to external cues, there is no evidence that JMJ30/JMJD5 is regulated by alternative splicing. In this study, the expression of an Arabidopsis JMJ30/JMJD5 ortholog in Medicago truncatula, MtJMJC5, in response to circadian clock and abiotic stresses were characterized. The results showed that MtJMJC5 oscillates with a circadian rhythm, and undergoes cold specifically induced alternative splicing. The cold-induced alternative splicing could be reversed after ambient temperature returning to the normal. Sequencing results revealed four alternative splicing RNA isoforms including a full-length authentic protein encoding variant, and three premature termination condon-containing variants due to alternative 3' splice sites at the first and second intron. Under cold treatment, the variants that share a common 3' alternative splicing site at the second intron were intensively up-regulated while the authentic protein encoding variant and the premature termination condon-containing variant only undergoing a 3' alternative splicing at the first intron were down regulated. Although all the premature termination condon-harboring alternative splicing variants were sensitive to nonsense-mediated decay, the premature termination codon-harboring alternative splicing variants sharing the 3' alternative splicing site at the second intron showed less sensitivity than the one only containing the 3' alternative slicing site at the first intron under cold treatment. These results suggest that the cold-dependent alternative splicing of MtJMJC5 is likely a species or genus-specific mechanism of gene expression regulation on RNA levels, and might play a role in epigenetic regulation of the link between the circadian clock and ambient temperature fluctuation in Medicago. 

27085910	We tested the hypothesis whether daily food availability period would restore rhythmicity in individuals with disrupted circadian behavior with no effect on appetite regulation. Particularly, we investigated the effects of timed food availability on activity behavior, and Fos and neuropeptide Y expressions in Indian weaverbirds (Ploceus philippinus) under atypical light conditions. Initially, weaverbirds in 3 groups of 7-8 each were entrained to 7L:17D (25: <0.3lx) with food ad libitum. Thereafter, food availability was restricted for 7h such that it overlapped with the light period. After a week, 7L:17D was replaced with 3.5L: 3.5D (T7, group 1), 3.5L: 20.5D (T24, group 2) or constant dim light, LLdim (<0.3lx, group 3) for 5weeks. Food cycles synchronized the circadian activity behavior, albeit with group differences, but did not affect body mass, blood glucose levels or testis size. Further, Fos, not NPY mRNA or peptide, expression measured at ZT2 and ZT14 (ZT0=time of food given) showed significant group differences in the hippocampus, dorsomedial hypothalamus and infundibular nuclear complex. Another identical experiment examined after-effects of the 3 light conditions on persistence of the circadian rhythms. Weaverbirds exposed for 4weeks to identical food but different light conditions, as above, were released into the free-running condition of food ad libitum and LLdim. Circadian rhythms were decayed in birds previously exposed to T7 LD cycle. Overall, these results show that timed meal restores rhythmicity in individuals with circadian rhythm disruptions without involving neuropeptide Y, the key appetite regulatory molecule.
27085862	Within a chronobiological perspective, the present study aimed to describe 24 h of sleep-wake cycle, motor activity, and food intake patterns in different body mass index (BMI) categories of children through 7 days of actigraphic recording.Height and weight were objectively measured for BMI calculation in a sample of 115 Italian primary schoolchildren (10.21 ± 0.48 years, 62.61 % females). According to BMI values, 2.60 % were underweight, 61.70 % were of normal weight, 29.60 % were overweight and 6.10 % were obese. Participants wore a wrist actigraph continuously for 7 days to record motor activity and describe sleep-wake patterns. In addition, participants were requested to push the event-marker button of the actigraph each time they consumed food to describe their circadian eating patterns.	BMI group differences were found for sleep quantity (i.e. midpoint of sleep and amplitude), while sleep quality, 24-h motor activity and food intake patterns were similar between groups. Regression analyses showed that BMI was negatively predicted by sleep duration on schooldays. BMI was also predicted by motor activity and by food intake frequencies recorded at particular times of day during schooldays and at the weekend.	The circadian perspective seems to provide promising insight into childhood obesity, but this aspect needs to be further explored.	
27085855	The present research aimed to investigate the existence of clock gene expression rhythms in tilapia, their endogenous origin, and how light and feeding cycles synchronize these rhythms. In the first experiment, two groups of fish were kept under an LD cycle and fed at two different time points: in the middle of the light (ML) or in the middle of the dark (MD) phase. In the second experiment, fish fed at ML was fasted and kept under constant lighting (LL) conditions for 1 day. In both experiments, the samples from central (optic tectum and hypothalamus) and peripheral (liver) tissues were collected every 3 h throughout a 24 h cycle. The expression levels of clock genes bmal1a, clock1, per1b, cry2a, and cry5 were analyzed by quantitative PCR. All the clock genes analyzed in brain regions showed daily rhythms: clock1, bmal1a, and cry2a showed the acrophase approximately at the end of the light phase (ZT 8:43-11:22 h), whereas per1b and cry5 did so between the end of the dark phase and the beginning of the light phase, respectively (ZT 21:16-4:00 h). These rhythms persisted under constant conditions. No effect of the feeding time was observed in the brain. In the liver, however, the rhythms of clock1 and cry5 were influenced by feeding, and a shift was observed in the MD fish group (ZT 3:58 h for clock1 and 11:20 h for cry5). This study provides the first insights into the molecular clock of tilapia, a very important fish species for aquaculture. It also reveals the endogenous origin of clock gene rhythms and the ability of feeding time to shift the phase in some clock genes in the peripheral, but not the central, oscillator. 
27085778	The circadian clock regulates various physiological and behavioral rhythms such as feeding and locomotor activity. Feeding at unusual times of the day (inactive phase) is thought to be associated with obesity and metabolic disorders in experimental animals and in humans.The present study aimed to determine the underlying mechanisms through which time-of-day-dependent feeding influences metabolic homeostasis.	We compared food consumption, wheel-running activity, core body temperature, hormonal and metabolic variables in blood, lipid accumulation in the liver, circadian expression of clock and metabolic genes in peripheral tissues, and body weight gain between mice fed only during the sleep phase (DF, daytime feeding) and those fed only during the active phase (NF, nighttime feeding). All mice were fed with the same high-fat high-sucrose diet throughout the experiment. To the best of our knowledge, this is the first study to examine the metabolic effects of time-imposed restricted feeding (RF) in mice with free access to a running wheel.	After one week of RF, DF mice gained more weight and developed hyperphagia, higher feed efficiency and more adiposity than NF mice. The daily amount of running on the wheel was rapidly and obviously reduced by DF, which might have been the result of time-of-day-dependent hypothermia. The amount of daily food consumption and hypothalamic mRNA expression of orexigenic neuropeptide Y and agouti-related protein were significantly higher in DF, than in NF mice, although levels of plasma leptin that fluctuate in an RF-dependent circadian manner, were significantly higher in DF mice. These findings suggested that the DF induced leptin resistance. The circadian phases of plasma insulin and ghrelin were synchronized to RF, although the corticosterone phase was unaffected. Peak levels of plasma insulin were remarkably higher in DF mice, although HOMA-IR was identical between the two groups. Significantly more free fatty acids, triglycerides and cholesterol accumulated in the livers of DF, than NF mice, which resulted from the increased expression of lipogenic genes such as Scd1, Acaca, and Fasn. Temporal expression of circadian clock genes became synchronized to RF in the liver but not in skeletal muscle, suggesting that uncoupling metabolic rhythms between the liver and skeletal muscle also contribute to DF-induced adiposity.	Feeding at an unusual time of day (inactive phase) desynchronizes peripheral clocks and causes obesity and metabolic disorders by inducing leptin resistance, hyperphagia, physical inactivity, hepatic fat accumulation and adiposity.	
27084533	The mammalian circadian clock regulates day-night fluctuations in various physiological processes. The circadian clock consists of the central clock in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks in peripheral tissues. External environmental cues, including light/dark cycles, food intake, stress, and exercise, provide important information for adjusting clock phases. This review focuses on stress and exercise as potent entrainment signals for both central and peripheral clocks, especially in regard to the timing of stimuli, types of stressors/exercises, and differences in the responses of rodents and humans. We suggest that the common signaling pathways of clock entrainment by stress and exercise involve sympathetic nervous activation and glucocorticoid release. Furthermore, we demonstrate that physiological responses to stress and exercise depend on time of day. Therefore, using exercise to maintain the circadian clock at an appropriate phase and amplitude might be effective for preventing obesity, diabetes, and cardiovascular disease.
27084528	Sustained glucagon infusion increases hepatic glucose production, but this effect is transient due to hypothalamic glucagon signaling. In hypoglycemia, glucagon acts as a major defense to sustain the blood glucose level and this raises the question regarding glucagon signaling associated glucose production in prolonged fasting hypoglycemia. In this study, we investigated the proteins associated with hypothalamic glucagon signaling and liver gluconeogenesis during fasting hypoglycemia.8-9week old, male C57BL6/J mice were fasted for 4, 8, 12, 18, 24, 30, 36 or 42h. In the hypothalamus, we investigated glucagon signaling by analyzing the glucagon receptor and its downstream protein, peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1) expression. In the liver, we investigated gluconeogenesis by analyzing p-protein kinase A (PKA)(Ser/Thr) substrate and phosphoenolpyruvate carboxykinase - cytosolic (PEPCK-C) expression using the western blotting technique.	The elevated or trended higher hypothalamic glucagon receptor and PGC-1 expressions at 18 and 42h were correlated with the attenuated liver p-PKA(Ser/Thr) substrate expression. The attenuated hypothalamic glucagon receptor and PGC-1 expressions at 12, 24, 30 and 36h were correlated with the elevated or trended higher liver p-PKA(Ser/Thr) substrate expression.	The hypothalamic glucagon signaling during fasting hypoglycemia might have been modulated by circadian rhythm and this possibly attenuates the liver p-PKA(Ser/Thr) substrate to modify the gluconeogenesis pathway. This mechanism will help to understand the hyperglucagonemia associated complications in diabetes.	
27084204	Early morning off (EMO) is a symptom experienced by patients with Parkinson's disease (PD) in any stage of the illness; however, few studies have explored its prevalence. Thus, the impact of EMO on patient Quality of Life (QOL) and caregiver burden is unclear.A QOL questionnaire was administered to members of the Japan Parkinson's Disease Association and their caregivers via mail using the PD questionnaire - 8 (PDQ-8), which measures the appearance of EMO. The analysis assessed the responses from 2205 completed surveys.	Patients who felt they had EMO amounted to 79.8%, with 37.8% of respondents stating that EMO was a daily occurrence. The prevalence of EMO increased as the Hoehn and Yahr stage increased, but was observed at a rate of 52.4% even in patients at Stage 1. The QOL of those with EMO was significantly reduced (p<0.0001), and the odds of caregivers feeling a sense of burden was higher for the group that experienced EMO even after adjusting for age of patient, age of caregivers, disease duration, relationship to patient, and Hoehn and Yahr stage.	The prevalence of EMO in the survey results was high, significantly lowering the patients' QOL. Interestingly, EMO was also observed in the early stage of the disease. Since the presence of EMO impacts patients' QOL and caregiver burden, medical intervention and appropriate gathering of information for such intervention should be considered.	
27083091	Areas of biology such as cell and molecular biology have been dominated by research directed at constructing mechanistic explanations that identify parts and operations that when organized appropriately are responsible for the various phenomena they investigate. Increasingly the mechanisms hypothesized involve non-sequential organization of non-linear operations and so exceed the ability of researchers to mentally rehearse their behavior. Accordingly, scientists rely on tools of computational modeling and dynamical systems theory in advancing dynamic mechanistic explanations. Using circadian rhythm research as an exemplar, this paper explores the variety of roles computational modeling is playing. They serve not just to determine whether the mechanism will produce the desired behavior, but in the discovery process of hypothesizing mechanisms and in understanding why proposed mechanisms behave as they do. 
27082989	Amino acids are essential to grape berry and seed development and they are transferred to the reproductive structures through the phloem and xylem from various locations within the plant. The diurnal and seasonal dynamics of xylem and phloem amino acid composition in the leaf petiole and bunch rachis of field-grown Cabernet Sauvignon are described to better understand the critical periods for amino acid import into the berry. Xylem sap was extracted by the centrifugation of excised leaf petioles and rachises, while phloem exudate was collected by immersing these structures in an ethylenediaminetetraacetic acid (EDTA) buffer. Glutamine and glutamic acid were the predominant amino acids in the xylem sap of both grapevine rachises and petioles, while arginine and glycine were the principal amino acids of the phloem exudate. The amino acid concentrations within the xylem sap and phloem exudate derived from these structures were greatest during anthesis and fruit set, and a second peak occurred within the rachis phloem at the onset of ripening. The concentrations of the amino acids within the phloem and xylem sap of the rachis were highest just prior to or after midnight while the flow of sugar through the rachis phloem was greatest during the early afternoon. Sugar exudation rates from the rachis was greater than that of the petiole phloem between anthesis and berry maturity. In summary, amino acid and sugar delivery through the vasculature to grape berries fluctuates over the course of the day as well as through the season and is not necessarily related to levels near the source. 
27082492	Disorders of rhythmicity can cause a variety of pathologies and are known to impair processes involved in metabolism, as well as in cardiovascular disease and cancer. Developing strategies to treat or prevent such diseases is a new challenge for medicine. Rhythms depend on a complex multi-oscillatory circadian network which, in mammals, is hierarchically organized with the suprachiasmatic nuclei (SCN) as master clock. The SCN, thus form an ideal structure for target discovery in circadian pathologies.The development of strategies to treat or prevent disorders of rhythmicity is a new challenge for medicine. Several pharmacological approaches have been suggested, but until now, it has been mostly melatonin (MTL) or MTL-agonists which have demonstrated usefulness in modulating clock activities in vivo. A great number of structurally different MTL receptor ligands have been developed, some of which are already approved and marketed as drugs. The MTL receptor involved in phase-shifting circadian rhythms (chronobiotic effect) is the MT1 subtype.	As the two receptor subtypes for MTL may have divergent functions, the development of highly selective MT1 and MT2 agonists (and antagonists) is key for the discovery of novel therapeutic agents in specifically defined circadian pathologies. The identification of cells expressing the different MTL receptor subtypes should also permit a better understanding of MLT physiology/pharmacology.	
27082460	The aim of this study was to examine the sleep strategies used in breaks between consecutive shifts. For two weeks, 253 shiftworkers collected data regarding the timing of all shifts and sleeps. The final dataset included 395 between-shift breaks that had a standard duration (i.e. ~16 h). If a break included an entire night, participants had a single sleep on 80-93% of occasions, but if a break occurred predominantly during the daytime, participants had more than one sleep on 41-50% of occasions. These data indicate that the sleep strategy employed is influenced by the time-of-day that a break occurs. 
27082283	We examined whether the beneficial impact of work time control (WTC) on sleep leads to lower accident risk, using data from a nationally representative survey conducted in Sweden. Logistic regressions examined WTC in 2010 and 2012 as predictors of accidents occurring in the subsequent 2 years (N = 4840 and 4337, respectively). Sleep disturbance and frequency of short sleeps in 2012 were examined as potential mediators of the associations between WTC in 2010 and subsequent accidents as reported in 2014 (N = 3636). All analyses adjusted for age, sex, education, occupational category, weekly work hours, shift work status, job control and perceived accident risk at work. In both waves, overall WTC was inversely associated with accidents (p = 0.048 and p = 0.038, respectively). Analyses of the sub-dimensions of WTC indicated that Control over Daily Hours (influence over start and finish times, and over length of shift) did not predict accidents in either wave, while Control over Time-off (CoT; influence over taking breaks, running private errands during work and taking paid leave) predicted fewer accidents in both waves (p = 0.013 and p = 0.010). Sleep disturbance in 2012 mediated associations between WTC/CoT in 2010 and accidents in 2014, although effects' sizes were small (effectWTC = -0.006, 95% confidence interval [CI] = -0.018 to -0.001; effectCoT = -0.009, 95%CI = -0.022 to -0.001; unstandardized coefficients), with the indirect effects of sleep disturbance accounting for less than 5% of the total direct and indirect effects. Frequency of short sleeps was not a significant mediator. WTC reduces the risk of subsequently being involved in an accident, although sleep may not be a strong component of the mechanism underlying this association. 
27082274	The stable and persisting preference for activities in the late evening (i.e. eveningness) is associated with a higher risk for depression, suicidality, and non-remission in major depression. The present study investigated symptom patterns in hospitalized patients with depressive syndromes in relation to morningness-eveningness (chronotypes). Depressive symptoms (Beck Depression Inventory [BDI-II]) and chronotype (German version of the Morningness-Eveningness Questionnaire [D-MEQ]) were assessed after admission and before discharge in inpatients with mainly major depression. Group differences of BDI-II single items and three BDI-II factors (cognitive, affective, somatic) between patients divided at the D-MEQ sample median into "morning preference" (MP) and "evening preference" (EP) were calculated. Data from 64 consecutively admitted patients (31MP/33EP) were analyzed. Both groups (MP/EP) were comparable regarding age, sex, diagnosis, length of stay, and subjective sleep quality, BDI-II scores were significantly higher in EP than in MP at admission. At admission and discharge, cognitive symptoms were significantly more pronounced in EP vs. MP; non-significant differences between EP and MP were found for affective and somatic symptoms. The results underline the importance of the trait-like chronotype for severity and symptomatology in patients with depressive disorders. The patients' chronotype should be taken into account in diagnostics and treatment of depressive disorders.
27082143	Quick returns (intervals of <11 h between the end of one shift and the start of the next) are associated with short sleeps and fatigue on the subsequent shift. Recent evidence suggests that shift workers regard quick returns as being more problematic than night work. The current study explored quick returns and night work in terms of their impact on sleep, unwinding, recovery, exhaustion, satisfaction with work hours and work-family interference. Data from the 2006 cohort of Swedish nursing students within the national Longitudinal Analysis of Nursing Education (LANE) study were analysed (N = 1459). Respondents completed a questionnaire prior to graduation (response rate 69.2%) and 3 years after graduation (65.9%). The analyses examined associations between frequency of quick returns and night work and measures taken in year three, while adjusting for confounding factors (in year three and prior graduation). Frequency of quick returns was a significant predictor of poor sleep quality, short sleeps, unwinding, exhaustion, satisfaction with work hours and work-to-family interference, with higher frequency predicting more negative outcomes. Quick returns did not predict recovery after rest days. Frequency of night work did not predict any of the outcomes. In conclusion, quick returns were an important determinant of sleep, recovery and wellbeing, whereas night work did not show such an association.
27081298	To test whether Müller glia of the mammalian retina have circadian rhythms.We used Müller glia cultures isolated from mouse lines or from humans and bioluminescent reporters of circadian clock genes to monitor molecular circadian rhythms. The clock gene dependence of the Müller cell rhythms was tested using clock gene knockout mouse lines or with siRNA for specific clock genes.	We demonstrated that retinal Müller glia express canonical circadian clock genes, are capable of sustained circadian oscillations in isolation from other cell types, and exhibit unique features of their molecular circadian clock compared to the retina as a whole. Mouse and human Müller cells demonstrated circadian clock function; however, they exhibited species-specific differences in the gene dependence of their clocks.	Müller cells are the first mammalian retinal cell type in which sustained circadian rhythms have been demonstrated in isolation from other retinal cells.	
27080202	There are notable differences between Asians and Westerners regarding hypertension (HTN) and the relationship between HTN and cardiovascular disease (CVD). Asians show greater morning surges in blood pressure (BP) and a steeper slope illustrating the link between higher BP and the risk of CVD events. It is thus particularly important for Asian hypertensives to achieve 24-h BP control, including morning and night-time control. There are three components of 'perfect 24-h BP control:' the 24-h BP level, nocturnal BP dipping, and BP variability (BPV), such as the morning BP surge that can be assessed by ambulatory BP monitoring. The morning BP-guided approach using home BP monitoring (HBPM) is the first step toward perfect 24-h BP control, followed by the control of nocturnal HTN. We have been developing new HBPM devices that can measure nocturnal BP. BPV includes different time-phase variability from the shortest beat-by-beat, positional, diurnal, day-by-day, visit-to-visit, seasonal, and yearly changes. The synergistic resonance of each type of BPV would produce a great dynamic BP surge (resonance hypothesis), which triggers a CVD event, especially in the high-risk patients with systemic hemodynamic atherothrombotic syndrome (SHATS). In the future, the innovative management of HTN based on the simultaneous assessment of the resonance of all of the BPV phenotypes using a beat by beat wearable 'surge' BP monitoring device (WSP) and an information and communication technology (ICT)-based data analysis system will produce a paradigm shift from 'dots' BP management to 'seamless' ultimate individualized 'anticipation medication' for reaching a zero CVD event rate.

27079518	The circadian system serves one of the most fundamental properties present in nearly all organisms: it generates 24-h rhythms in behavioral and physiological processes and enables anticipating and adapting to daily environmental changes. Recent studies indicate that the circadian system is important in regulating the daily rhythm in glucose metabolism. Disturbance of this circadian control or of its coordination relative to the environmental/behavioral cycle, such as in shift work, eating late, or due to genetic changes, results in disturbed glucose control and increased type 2 diabetes risk. Therefore, an in-depth understanding of the mechanisms underlying glucose regulation by the circadian system and its disturbance may help in the development of therapeutic interventions against the deleterious health consequences of circadian disruption. 
27078711	Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women. 
27078501	Autophagy is essential for normal cellular survival and activity. Circadian rhythms of autophagy have been studied in several peripheral organs but not yet reported in the brain. Here, we measured the circadian rhythm of autophagy-related proteins in mouse hippocampus and tested the effect of sleep fragmentation (SF). Expressions of the autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and beclin were determined by western blotting and immunohistochemistry. Both the hippocampal LC3 signal and the ratio of its lipid-conjugated form LC3-II to its cytosolic form LC3-I showed a 24 h rhythm. The peak was seen at ZT6 (1 pm) and the nadir at ZT16 (1 am). The LC3 immunoreactivity in hippocampal CA1 pyramidal neurons also distributed differently, with more diffuse cytoplasmic appearance at ZT16. Chronic SF had a mild effect to disrupt the 24 h rhythm of LC3 and beclin expression. Interestingly, a greater effect of SF was seen after 24 h of recovery sleep when LC3-II expression was attenuated at both the peak and trough of circadian activities. Overall, the results show for the first time that the hippocampus has a distinct rhythm of autophagy that can be altered by SF.
27078397	The dominant endogenous clock, named the suprachiasmatic nucleus (SCN), regulates circadian rhythms of behavioral and physiological activity in mammals. One of the main characteristics of the SCN is that the animal maintains a circadian rhythm with a period close to 24 h in the absence of a daily light-dark cycle (called the free running period). The free running period varies among species due to heterogeneity of the SCN network. Previous studies have shown that the heterogeneity in cellular coupling as well as in intrinsic neuronal periods shortens the free running period. Furthermore, as derived from experiments, one neuron's coupling strength is negatively associated with its period. It is unknown what the effects of this association between coupling strength and period are on the free running period and how the heterogeneity in coupling strength influences this free running period. In the present study we found that in the presence of a negative relationship between one neuron's coupling strength and its period, surprisingly, the dispersion of coupling strengths increases the free running period. Our present finding may shed new light on the understanding of the heterogeneous SCN network and provides an alternative explanation for the diversity of free running periods between species. 
27078176	Sleep inertia is a safety concern for shift workers returning to work soon after waking up. Split duty schedules offer an alternative to longer shift periods, but introduce additional wake-ups and may therefore increase risk of sleep inertia. This study investigated sleep inertia across a split duty schedule. Sixteen participants (age range 21-36 years; 10 females) participated in a 9-day laboratory study with two baseline nights (10 h time in bed, [TIB]), four 24-h periods of a 6-h on/6-h off split duty schedule (5-h TIB in off period; 10-h TIB per 24 h) and two recovery nights. Two complementary rosters were evaluated, with the timing of sleep and wake alternating between the two rosters (2 am/2 pm wake-up roster versus 8 am/8 pm wake-up roster). At 2, 17, 32 and 47 min after scheduled awakening, participants completed an 8-min inertia test bout, which included a 3-min psychomotor vigilance test (PVT-B), a 3-min Digit-Symbol Substitution Task (DSST), the Karolinska Sleepiness Scale (KSS), and the Samn-Perelli Fatigue Scale (SP-Fatigue). Further testing occurred every 2 h during scheduled wakefulness. Performance was consistently degraded and subjective sleepiness/fatigue was consistently increased during the inertia testing period as compared to other testing times. Morning wake-ups (2 am and 8 am) were associated with higher levels of sleep inertia than later wake-ups (2 pm and 8 pm). These results suggest that split duty workers should recognise the potential for sleep inertia after waking, especially during the morning hours. 
27077948	Metabolic homeostasis requires coordination between circadian clocks in different tissues. Also, systemic signals appear to be required for some transcriptional rhythms in the mammalian liver and the Drosophila fat body. Here we show that free-running oscillations of the fat body clock require clock function in the PDF-positive cells of the fly brain. Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF). NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver. These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms. 
27077691	Neurobehavioural impairment on the first night shift is often greater than on subsequent night shifts due to extended wakefulness. The aim of the study was to determine whether a 1-h afternoon nap prior to the first night shift is sufficient to produce neurobehavioural performance at levels comparable to the second night shift. Twelve male volunteers (mean age 22.9 years) participated in a laboratory protocol that simulated two 12-h night shifts. A nap preceded the first shift and a 7-h daytime sleep was scheduled between shifts. Neurobehavioural performance and subjective sleepiness measured across each night did not significantly differ between first and second shifts. 
27077524	Short naps on night shift are recommended in some industries. There is a paucity of evidence to verify the sustained recovery benefits of short naps in the last few hours of the night shift. Therefore, the current study aimed to investigate the sustained recovery benefits of 30 and 10-min nap opportunities during a simulated night shift. Thirty-one healthy participants (18F, 21-35 y) completed a 3-day, between-groups laboratory study with one baseline night (22:00-07:00 h time in bed), followed by one night awake (time awake from 07:00 h on day two through 10:00 h day three) with random allocation to: a 10-min nap opportunity ending at 04:00 h, a 30-min nap opportunity ending at 04:00 h or no nap (control). A neurobehavioral test bout was administered approximately every 2 h during wake periods. There were no significant differences between nap conditions for post-nap psychomotor vigilance performance after controlling for pre-nap scores (p > 0.05). The 30-min nap significantly improved subjective sleepiness compared to the 10-min nap and no-nap control (p < 0.05). The 10-min nap significantly worsened negative mood compared to the 30-min nap and no-nap control (p < 0.01). Contrary to some evidence suggesting "power naps" can help to alleviate performance decrements, a 30-min nap opportunity at approximately 04:00 h was found to improve subjective, but not objective sleepiness. A 10-min nap may lead to increased negative mood in the hours following the nap due to a "short nap aversion" effect.
27077442	Twelve-hour shift systems have become more popular in industry. Survey data of shift length, shift rotation speed, self-rated sleep, satisfaction and perceived health were investigated for the associations among 599 predominantly male Finnish industrial employees. The studied forward-rotating shift systems were 12-h fast (12fast, DDNN------, n = 268), 8-h fast (8fast, MMEENN----, n = 161) and 8-h slow (8slow, MMMM-EEEE-NNNN, n = 170). Satisfaction with shift system differed between the groups (p < 0.01) after controlling for age, gender, shift work experience and self-rated stress. In the 12fast, 98% of employees were satisfied with their shift system (75% 8fast, 54% 8slow). Negative effects on sleep and alertness were rare (8%) in the 12fast group (53% 8fast, 66% 8 slow, p < 0.01) and self-reported sleep difficulties were less frequent than in the 8fast and 8slow groups (8%, 27%, 41%, respectively, p < 0.01). The self-reported average sleep duration (12fast 7:50, 8fast 7:24, 8slow 7:15, p < 0.01), and shift-specific sleep before and between morning shifts and after first night shift were longer in the 12fast group. Perceived negative effects of the current shift system on general health (12fast 4%, 8fast 30%, 8slow 41%, p < 0.001) and work-life balance (12fast 8%, 8fast 52%, 8slow 63%, p < 0.001) differed strongly between the groups. In conclusion, the perceived effects of shift work were dependent on both shift length and shift rotation speed: employees in the 12-h rapidly forward-rotating shift system were most satisfied, perceived better work-life balance and slept better than the employees in the 8fast or especially the employees in the 8-h slowly rotating systems.
27077244	The aim is to show how different definitions affect the proportion of shifts classified as night shifts. The Danish Working Hour Database was used to calculate number of night shifts according to eight definitions. More than 98% of the total night shifts were night shifts by use of both the reference definition (at least 3 h of work between 24:00 and 05:00) and definitions using a period during the night. The overlap with definitions based on starting and ending time was less pronounced (64-71 %). The proportion of classified night shifts differs little when night shifts are based on definitions including a period during the night. Studies based on other definitions may be less comparable. 
27076261	In most persons, blood pressure (BP) rises slowly during late sleep, increases rapidly upon morning awakening and commencement of diurnal activity, exhibits two - morning and afternoon/early evening - daytime peaks, shows a minor midday nadir, and undergoes a decline during nighttime sleep by 10-20% in systolic BP and somewhat lesser amount in diastolic BP relative to wake-time means. Nyctohemeral cycles of ambient temperature, light, noise and behaviorally driven temporal patterns in food, liquid, salt, and stimulant consumption, mental/emotional stress, posture, and physical activity intensity plus circadian rhythms of wake/sleep, pineal gland melatonin synthesis, autonomic and central nervous, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, renin-angiotensin-aldosterone, renal hemodynamic, endothelial, vasoactive peptide, and opioid systems constitute the key regulators and determinants of the BP 24 h profile. Environmental and behavioral cycles are believed to be far more influential than circadian ones. However, the facts that the: i) BP 24 h pattern of secondary hypertension, e.g., diabetes and renal disease, is characterized by absence of BP fall during sleep, and ii) scheduling of conventional long-acting medications at bedtime, rather than morning, results in much better hypertension control and vascular risk reduction, presumably because highest drug concentration coincides closely with the peak of most key circadian determinants of the BP 24 h profile, indicate endogenous rhythmic influences are of greater importance than previously appreciated.
27076076	Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network. 
27076073	One of the most predictable aspects of conscious life is the daily sleep-wake cycle, which is programmed by an internal clock that exerts broad effects on behavior and physiology. Studies of He et al. (2016) identify a small molecule clock modulator that improves metabolism, revealing that enhancing circadian function benefits health. 
27075857	In mammals, the circadian system is composed of a principal circadian oscillator located in the suprachiasmatic nucleus (SCN) and a number of subordinate oscillators in extra-SCN brain regions and peripheral tissues/organs. However, how the time-keeping functions of this multiple oscillator circuit are affected by aberrant lighting environments remains largely unknown. In the present study, we investigated the effects of chronic light exposure in the middle of the night on the circadian system by comparing the mice housed in a 12:4:4:4-h L:DLD condition with the controls in 12:12-h L:D condition. Daily rhythms in locomotor activity were analyzed and the expression patterns of protein products of clock genes Period1 and Period2 (PER1 and PER2) were examined in the SCN and extra-SCN brain regions, including the dorsal striatum, hippocampus, paraventricular nucleus (PVN), and basolateral amygdala (BLA). Following 2 weeks of housing in the L:DLD condition, animals showed disturbed daily rhythms in locomotor activity and lacked daily rhythms of PER1 and PER2 in the SCN. In the extra-SCN brain regions, the PER1 and PER2 rhythms were affected in a region-specific pattern, such that they were relatively undisturbed in the striatum and hippocampus, phase-shifted in the BLA, and abolished in the PVN. In addition, mice in the L:DLD condition showed increased anxiety-like behaviors and reduced brain-derived neurotropic factor messenger RNA expression in the hippocampus, amygdala, and medial prefrontal cortex, which are brain regions that are involved in emotional regulation. These results indicate that nighttime light exposure leads to circadian disturbances not only by abolishing the circadian rhythms in the SCN but also by inducing misalignment among brain oscillators and negatively affects emotional processing. These observations serve to identify risks associated with decisions regarding lifestyle in our modern society. 
27074515	Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behaviour and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes. A fundamental knowledge gap exists, however, between circadian gene expression cycles and the biochemical mechanisms that ultimately facilitate circadian regulation of cell biology. Here we report circadian rhythms in the intracellular concentration of magnesium ions, [Mg(2+)]i, which act as a cell-autonomous timekeeping component to determine key clock properties both in a human cell line and in a unicellular alga that diverged from each other more than 1 billion years ago. Given the essential role of Mg(2+) as a cofactor for ATP, a functional consequence of [Mg(2+)]i oscillations is dynamic regulation of cellular energy expenditure over the daily cycle. Mechanistically, we find that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression. The global regulation of nucleotide triphosphate turnover by intracellular Mg(2+) availability has potential to impact upon many of the cell's more than 600 MgATP-dependent enzymes and every cellular system where MgNTP hydrolysis becomes rate limiting. Indeed, we find that circadian control of translation by mTOR is regulated through [Mg(2+)]i oscillations. It will now be important to identify which additional biological processes are subject to this form of regulation in tissues of multicellular organisms such as plants and humans, in the context of health and disease. 
27073550	The aim of this study was to construct the eukaryotic expression vector pEGFP-N1-hPer2 and assess its expression in the human osteosarcoma cell line MG63. Total mRNA was extracted from human osteosarcoma MG63 cells, the human period 2 (hPer2) gene was obtained by reverse transcription-polymerase chain reaction (RT-PCR) and cloned into the pEGFP-N1 vector, then the recombinant pEGFP-N1-hPer2 plasmid was constructed and transfected into MG63 cells using Lipofectamine 2000. The expression of hPer2 in MG63 cells was measured by quantitative RT-PCR and western blot analysis. The accurate construction of pEGFP-N1-hPer2 was verified by double enzyme digestion and DNA sequencing. hPer2 gene expression in the transfected cells was assessed by RT-qPCR and western blot analysis. In conclusion, the recombinant pEGFP-N1-hPer2 plasmid was constructed successfully, and expressed effectively in MG63 cells.
27072828	Chronic kidney disease (CKD) is increasingly encountered in pregnancy, and hypertension is frequently concomitant. In pregnancy, the prevalence of CKD is estimated to be about 3%, while the prevalence of chronic hypertension is about 5-8%. The prevalence of hypertension and CKD in pregnancy is unknown. Both are independently related to adverse pregnancy outcomes, and the clinical picture merges with pregnancy-induced hypertension and preeclampsia. Precise risk quantification is not available, but risks linked to CKD stage, hypertension, and proteinuria are probably multiplicative, each at least doubling the rates of preterm and early preterm delivery, small for gestational age babies, and related outcomes. Differential diagnosis (based upon utero-placental flows, fetal growth, and supported by serum biomarkers) is important for clinical management. In the absence of guidelines for hypertension in CKD pregnancies, the ideal blood pressure goal has not been established; we support a tailored approach, depending on compliance, baseline control, and CKD stages, with strict blood pressure monitoring. The choice of antihypertensive drugs and the use of diuretics and of erythropoiesis-stimulating agents (ESAs) are still open questions which only future studies may clarify.

27071129	A mechanism for integrating light perception and the endogenous circadian clock is central to a plant's capacity to coordinate its growth and development with the prevailing daily light/dark cycles. Under short-day (SD) photocycles, hypocotyl elongation is maximal at dawn, being promoted by the collective activity of a quartet of transcription factors, called PIF1, PIF3, PIF4, and PIF5 (phytochrome-interacting factors). PIF protein abundance in SDs oscillates as a balance between synthesis and photoactivated-phytochrome-imposed degradation, with maximum levels accumulating at the end of the long night. Previous evidence shows that elongation under diurnal conditions (as well as in shade) is also subjected to circadian gating. However, the mechanism underlying these phenomena is incompletely understood. Here we show that the PIFs and the core clock component Timing of CAB expression 1 (TOC1) display coincident cobinding to the promoters of predawn-phased, growth-related genes under SD conditions. TOC1 interacts with the PIFs and represses their transcriptional activation activity, antagonizing PIF-induced growth. Given the dynamics of TOC1 abundance (displaying high postdusk levels that progressively decline during the long night), our data suggest that TOC1 functions to provide a direct output from the core clock that transiently constrains the growth-promoting activity of the accumulating PIFs early postdusk, thereby gating growth to predawn, when conditions for cell elongation are optimal. These findings unveil a previously unrecognized mechanism whereby a core circadian clock output signal converges immediately with the phytochrome photosensory pathway to coregulate directly the activity of the PIF transcription factors positioned at the apex of a transcriptional network that regulates a diversity of downstream morphogenic responses. 
27070740	The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine. 
27070477	Morning shift sleep restriction has been associated with higher plasma IL-6 levels. The aim of this study was to investigate the effect of sleep duration on salivary IL-6. Sleep duration of morning shift workers was estimated by actigraphy. Workers with "longer sleep duration" (LSD; N = 6) and "shorter sleep duration" (SSD; N = 15) were then compared regarding salivary IL-6 levels determined at 14:00 h, bed and wake times. SSD workers did not show daily variation of IL-6 and presented higher levels at bedtime and 14:00 h compared to LSD workers. In this study, SSD is associated with an increase in salivary IL-6 content.
27070367	On-call working time arrangements are increasingly common, involve work only in the event of an unpredictable incident and exist primarily outside of standard hours. Like other non-standard working time arrangements, on-call work disrupts sleep and can therefore have negative effects on health, safety and performance. Unlike other non-standard working time arrangements, on-call work often allows sleep opportunities between calls. Any sleep obtained during on-call periods will be beneficial for waking performance. However, there is evidence that sleep while on call may be of substantially reduced restorative value because of the expectation of receiving the call and apprehension about missing the call. In turn, waking from sleep to respond to a call may be associated with temporary increases in performance impairment. This is dependent on characteristics of both the preceding sleep, the tasks required upon waking and the availability and utility of any countermeasures to support the transition from sleep to wake. In this paper, we critically evaluate the evidence both for and against sleeping during on-call periods and conclude that some sleep, even if it is of reduced quality and broken by repeated calls, is a good strategy. We also note, however, that organisations utilising on-call working time arrangements need to systematically manage the likelihood that on-call sleep can be associated with temporary performance impairments upon waking. Given that the majority of work in this area has been laboratory-based, there is a significant need for field-based investigations of the magnitude of sleep inertia, in addition to the utility of sleep inertia countermeasures. Field studies should include working with subject matter experts to identify the real-world impacts of changes in performance associated with sleeping, or not sleeping, whilst on call. 
27070265	This study sought to assess associations between work stressors and work ability in a cohort (2009-2012) of 498 hospital workers. Time-dependent variables associated with the Work Ability Index (WAI) were evaluated using general linear mixed models. Analyses included effects of individual and work characteristics. Except for work demands, the work stressors (job control, social support, effort-reward imbalance, overcommitment and work-related activities that cause pain/injury) were associated with WAI (p < 0.050) at intercept and in the time interaction. Daytime work and morning shift work were associated with decreased WAI (p < 0.010). Work stressors negatively affected work ability over time independently of other variables. 
27070173	Undergraduate students experience a form of circadian misalignment - known as "social jetlag" - that represents the discrepancy in timing between their circadian and social clocks. Whilst social jetlag is not dependent upon chronotype, the two phenomena tend to be related; evening types show a tendency to have a greater social jetlag, for example. Moreover, evening types have been found to be more likely to have inadequate eating habits than do morning types. The objective of this study was to examine the relationship between chronotype, social jetlag, perceived sleep debt and dietary intake in Brazilian undergraduate students. The chronotype was derived from mid-sleep time on free days (MSF) at the weekend. Social jetlag was calculated as the absolute difference between mid-sleep time on weekdays and weekends. Perceived sleep debt was calculated using the difference between students' preferred weekday sleep duration and their self-reported actual weekday sleep duration. Correlations were found between chronotype and breakfast time (r = 0.24, p = 0.003) and lunch time (r = 0.19, p = 0.01). Multiple regression analyses showed that chronotype was positively associated with consumption of meat (β = 0.21; p = 0.003); social jetlag was negatively associated with consumption of beans (β = -0.16; p = 0.02) and perceived sleep debt was positively associated with consumption of beverages (β = 0.15; p = 0.02) and dairy products (β = 0.17; p = 0.01) and negatively associated with consumption of cereals and pasta (β = -0.16; p = 0.02). It is concluded that, in undergraduate students, chronotype (MSF), social jetlag and perceived sleep debt can influence the type and amount of some food groups consumed at mealtimes. 
27069330	The circadian rhythm of human circulating lipid components was studied under nearnormal tropical conditions in 162 healthy volunteers (103 males and 59 females; 7 to 75 years of age). They followed a diurnal activity from about 06:00 to about 22:00 and nocturnal rest. These volunteers were divided into four groups: Group A (7-20 years), Group B (21-40 years), Group C (41-60 years) and Group D (61-75 years), comprising 42, 60, 35 and 25 participants, respectively. A marked circadian rhythm was demonstrated for each studied variable in each group by population-mean cosinor analysis (almost invariably p < 0.001). Furthermore, circadian rhythm characteristics were compared among the 4 groups by parameter tests and regressed as a function of age, separately for males and females. A second-order polynomial characterized the MESOR of HDL cholesterol, phospholipids and total lipids, as well as the 24-h amplitude of total cholesterol and phospholipids. The 24-h amplitude of total lipids decreased linearly with age. The 24-h acrophase of the oldest age group (Group D) was advanced in the case of total cholesterol, HDL cholesterol, and total lipids, whereas that of phospholipids was delayed. Mapping the circadian rhythm (an important component of the broader time structure or chronome, which includes a. o., trends with age and extra-circadian components) of lipid components is needed to explore their role in the aging process in health. 
27068699	Kisspeptin, the neuropeptide product of the Kiss1 gene, is critical in driving the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (Arc) of the hypothalamus mediate differential effects, with the Arc regulating negative feedback of sex steroids and the AVPV regulating positive feedback, vital for the preovulatory surge and gated under circadian control. We aimed to characterize hypothalamic Kiss1 and Kiss1r mRNA expression in nonpregnant and pregnant mice, and investigate potential circadian regulation. Anterior and posterior hypothalami were collected from C57BL/6J mice at diestrus, proestrus, and days 6, 10, 14, and 18 of pregnancy, at six time points across 24h, for real-time PCR analysis of gene expression. Analysis confirmed that Kiss1 mRNA expression in the AVPV increased at ZT13 during proestrus, with a luteinizing hormone surge observed thereafter. No diurnal regulation was seen at diestrus or at any stage of pregnancy. Anterior hypothalamic Avp mRNA expression exhibited no diurnal variation, but Avpr1a peaked at 12:00h during proestrus, possibly reflecting the circadian input from the suprachiasmatic nucleus to AVPV Kiss1 neurons. Rfrp (Npvf) expression in the posterior hypothalamus did not demonstrate diurnal variation at any stage. Clock genes Bmal1 and Rev-erbα were strongly diurnal, but there was little change between diestrus/proestrus and pregnancy. Our data indicate the absence of the circadian input to Kiss1 in pregnancy, despite high gestational estradiol levels and normal clock gene expression, and may suggest a disruption of a kisspeptin-specific diurnal rhythm that operates in the nonpregnant state. 
27066876	Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic understanding of the cell-autonomous molecular circadian oscillator and the circadian timing system as a whole has opened new conceptual and methodological lines of investigation to understand first, the clock's impact on a specific drug's daily variations or the effects/side effects of environmental substances, and second, how clock-controlled pathways are coordinated within a given tissue or organism. Today, there is an increased understanding of the circadian modulation of drug effects. Moreover, several molecular strategies are being developed to treat disease-dependent and drug-induced clock disruptions in humans. 
27066796	In mammals, sleep is categorized by two main sleep stages, rapid eye movement (REM) and non-REM (NREM) sleep that are known to fulfill different functional roles, the most notable being the consolidation of memory. While REM sleep is characterized by brain activity similar to wakefulness, the EEG activity changes drastically with the emergence of K-complexes, sleep spindles and slow oscillations during NREM sleep. These changes are regulated by circadian and ultradian rhythms, which emerge from an intricate interplay between multiple neuronal populations in the brainstem, forebrain and hypothalamus and the resulting varying levels of neuromodulators. Recently, there has been progress in the understanding of those rhythms both from a physiological as well as theoretical perspective. However, how these neuromodulators affect the generation of the different EEG patterns and their temporal dynamics is poorly understood. Here, we build upon previous work on a neural mass model of the sleeping cortex and investigate the effect of those neuromodulators on the dynamics of the cortex and the corresponding transition between wakefulness and the different sleep stages. We show that our simplified model is sufficient to generate the essential features of human EEG over a full day. This approach builds a bridge between sleep regulatory networks and EEG generating neural mass models and provides a valuable tool for model validation.
27066526	Light therapy has shown promise as a nonpharmacological treatment to help regulate abnormal sleep-wake patterns and associated behavioral issues prevalent among individuals diagnosed with Alzheimer's disease and related dementia (ADRD). The present study investigated the effectiveness of a lighting intervention designed to increase circadian stimulation during the day using light sources that have high short-wavelength content and high light output.Thirty-five persons with ADRD and 34 caregivers completed the 11-week study. During week 1, subjective questionnaires were administered to the study participants. During week 2, baseline data were collected using Daysimeters and actigraphs. Researchers installed the lighting during week 3, followed by 4 weeks of the tailored lighting intervention. During the last week of the lighting intervention, Daysimeter, actigraph and questionnaire data were again collected. Three weeks after the lighting intervention was removed, a third data collection (post-intervention assessment) was performed.	The lighting intervention significantly increased circadian entrainment, as measured by phasor magnitude and sleep efficiency, as measured by actigraphy data, and significantly reduced symptoms of depression in the participants with ADRD. The caregivers also exhibited an increase in circadian entrainment during the lighting intervention; a seasonal effect of greater sleep efficiency and longer sleep duration was also found for caregivers.	An ambient lighting intervention designed to increase daytime circadian stimulation can be used to increase sleep efficiency in persons with ADRD and their caregivers, and may also be effective for other populations such as healthy older adults with sleep problems, adolescents, and veterans with traumatic brain injury.	
27066180	Light is the most important environmental cue to entrain the circadian clock in most animals. In the fruit fly Drosophila melanogaster, the light entrainment mechanisms of the clock have been well-studied. The Drosophila brain contains approximately 150 neurons that rhythmically express circadian clock genes. These neurons are called "clock neurons" and control behavioral activity rhythms. Many clock neurons express the Cryptochrome (CRY) protein, which is sensitive to UV and blue light, and thus enables clock neurons deep in the brain to directly perceive light. In addition to the CRY protein, external photoreceptors in the Drosophila eyes play an important role in circadian light-input pathways. Recent studies have provided new insights into the mechanisms that integrate these light inputs into the circadian network of the brain. In this review, we will summarize the current knowledge on the light entrainment pathways in the Drosophila circadian clock. 
27065164	The neuroendocrine hypothalamus is composed of the tuberal and anterodorsal hypothalamus, together with the median eminence/neurohypophysis. It centrally governs wide-ranging physiological processes, including homeostasis of energy balance, circadian rhythms and stress responses, as well as growth and reproductive behaviours. Homeostasis is maintained by integrating sensory inputs and effecting responses via autonomic, endocrine and behavioural outputs, over diverse time-scales and throughout the lifecourse of an individual. Here, we summarize studies that begin to reveal how different territories and cell types within the neuroendocrine hypothalamus are assembled in an integrated manner to enable function, thus supporting the organism's ability to survive and thrive. We discuss how signaling pathways and transcription factors dictate the appearance and regionalization of the hypothalamic primordium, the maintenance of progenitor cells, and their specification and differentiation into neurons. We comment on recent studies that harness such programmes for the directed differentiation of human ES/iPS cells. We summarize how developmental plasticity is maintained even into adulthood and how integration between the hypothalamus and peripheral body is established in the median eminence and neurohypophysis. Analysis of model organisms, including mouse, chick and zebrafish, provides a picture of how complex, yet elegantly coordinated, developmental programmes build glial and neuronal cells around the third ventricle of the brain. Such conserved processes enable the hypothalamus to mediate its function as a central integrating and response-control mediator for the homeostatic processes that are critical to life. Early indications suggest that deregulation of these events may underlie multifaceted pathological conditions and dysfunctional physiology in humans, such as obesity.
27063959	We investigated potential pathophysiological relationships between interleukin 18 (IL-18) and dyslipidemia, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Compared with Il18(+/+) mice, IL-18 knockout (Il18(-/-)) mice developed hypercholesterolemia and hyper-high-density-lipoprotein-cholesterolemia as well as hypertriglyceridemia as they aged, and these disorders occurred before the manifestation of obesity and might cause secondary NASH. The analyses of molecular mechanisms involved in the onset of dyslipidemia, NAFLD, and NASH in Il18(-/-) mice identified a number of genes associated with these metabolic diseases. In addition, molecules related to circadian rhythm might affect these extracted genes. The intravenous administration of recombinant IL-18 significantly improved dyslipidemia, inhibited the body weight gain of Il18(+/+) mice, and prevented the onset of NASH. The expression of genes related to these dysfunctions was also affected by recombinant IL-18 administration. In conclusion, this study demonstrated the critical function of IL-18 in lipid metabolism and these findings might contribute to the progress of novel treatments for NAFLD or NASH. 
27061919	Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune, and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder (PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Recent experimental findings also support a specific role of the fundamental synchronizing pineal hormone melatonin in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress and epigenetics, all processes affected in PTSD. In the current paper, we review available literature underpinning a potentially beneficiary role of an add-on melatonergic treatment in PTSD pathophysiology and PTSD-related symptoms. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. We conclude that adjuvant melatonergic treatment could provide a potentially promising treatment strategy in the management of PTSD and especially PTSD-related syndromes and comorbidities. Rigorous preclinical and clinical studies are needed to validate this hypothesis. 
27061301	The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circadian clock and hormone signaling pathways. 
27061101	Light-responsive neurones in the rat suprachiasmatic nucleus discharge with a harmonic distribution of interspike intervals, whereas unresponsive neurones seldom do. This harmonic patterning has a fundamental frequency of close to 30 Hz, and is the same in light-on cells as in light-off cells, and is unaffected by exposure to light. Light-on cells are more active than light-off cells in both subjective day and subjective night, and both light-on cells and light-off cells respond more strongly to changes in light intensity during the subjective night than during the subjective day. Paired recordings indicate that the discharge of adjacent light-responsive cells is very tightly synchronized. The gap junction inhibitor carbenoxolone increases the spontaneous activity of suprachiasmatic nucleus neurones but does not block the harmonic discharge patterning.The suprachiasmatic nucleus (SCN) of the hypothalamus has an essential role in orchestrating circadian rhythms of behaviour and physiology. In the present study, we recorded from single SCN neurons in urethane-anaesthetized rats, categorized them by the statistical features of their electrical activity and by their responses to light, and examined how activity in the light phase differs from activity in the dark phase. We classified cells as light-on cells or light-off cells according to how their firing rate changed in acute response to light, or as non-responsive cells. In both sets of light-responsive neurons, responses to light were stronger at subjective night than in subjective day. Neuronal firing patterns were analysed by constructing hazard functions from interspike interval data. For most light-responsive cells, the hazard functions showed a multimodal distribution, with a harmonic sequence of modes, indicating that spike activity was driven by an oscillatory input with a fundamental frequency of close to 30 Hz; this harmonic pattern was rarely seen in non-responsive SCN cells. The frequency of the rhythm was the same in light-on cells as in light-off cells, was the same in subjective day as at subjective night, and was unaffected by exposure to light. Paired recordings indicated that the discharge of adjacent light-responsive neurons was very tightly synchronized, consistent with electrical coupling.	
27060253	In the past few years mounting evidences have highlighted the tight correlation between circadian rhythms and metabolism. Although at the organismal level the central timekeeper is constituted by the hypothalamic suprachiasmatic nuclei practically all the peripheral tissues are equipped with autonomous oscillators made up by common molecular clockworks represented by circuits of gene expression that are organized in interconnected positive and negative feed-back loops. In this study we exploited a well-established in vitro synchronization model to investigate specifically the linkage between clock gene expression and the mitochondrial oxidative phosphorylation (OxPhos). Here we show that synchronized cells exhibit an autonomous ultradian mitochondrial respiratory activity which is abrogated by silencing the master clock gene ARNTL/BMAL1. Surprisingly, pharmacological inhibition of the mitochondrial OxPhos system resulted in dramatic deregulation of the rhythmic clock-gene expression and a similar result was attained with mtDNA depleted cells (Rho0). Our findings provide a novel level of complexity in the interlocked feedback loop controlling the interplay between cellular bioenergetics and the molecular clockwork. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
27060181	In the well-known "dress" photograph, people either see the dress as blue with black stripes or as white with golden stripes. We suggest that the perception of colors is guided by the scene interpretation and the inferred positions of light sources. We tested this hypothesis in two online studies using color matching to estimate the colors observers see, while controlling for individual differences in gray point bias and color discrimination. Study 1 demonstrates that the interpretation of the dress corresponds to differences in perceived colors. Moreover, people who perceive the dress as blue-and-black are two times more likely to consider the light source as frontal, than those who see the white-and-gold dress. The inferred light sources, in turn, depend on the circadian changes in ambient light. The interpretation of the scene background as a wall or a mirror is consistent with the perceived colors as well. Study 2 shows that matching provides reliable results on differing devices and replicates the findings on scene interpretation and light sources. Additionally, we show that participants' environmental lighting conditions are an important cue for perceiving the dress colors. The exact mechanisms of how environmental lighting and circadian changes influence the perceived colors of the dress deserve further investigation.
27058663	Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.
27058656	Alterations of the circadian clock have been linked to cancer development. Puram et al. (in this issue) now uncover differential requirements between healthy hematopoietic and diseased leukemic stem cells for core circadian transcription factors, wherein leukemic cells depend on the clock machinery for survival and growth.
27058653	We examined the relationship between sleep duration and arterial stiffness among a multi-ethnic cohort, and whether the associations differed among ethnic minority groups in the Netherlands. Data were derived from 10 994 participants (aged 18-71 years) of the Healthy Life in an Urban Setting (HELIUS) study. Self-reported sleep duration was categorized into: short (<7 h/night), healthy (7-8 h/night) and long (≥9 h/night). Arterial stiffness was assessed by duplicate pulse-wave velocity (PWV in m/s) measurements using the Arteriograph system. The association of sleep duration with PWV was analysed using linear regression (β) with 95% confidence interval (CI). Results showed that neither short nor long sleep was related to PWV in all ethnic groups, except for long sleep in Dutch men which was associated with higher PWV (indicating stiffer arteries) after adjustment for potential confounders (β = 0.67, 95%CI, 0.23-1.11). Our study showed no convincing evidence that sleep duration was related to arterial stiffness among various ethnic groups. The link between sleep duration and cardiovascular outcomes does not seem to operate through arterial stiffness. Further research is needed to consolidate these findings.
27058450	Daily variation in the absorption, metabolism and excretion of toxic substances will ultimately determine the actual concentration to which the cells and tissues are exposed. In aquaculture, Atlantic salmon (Salmo salar) can be frequently exposed to hydrogen peroxide (H2O2) to treat topical skin and gill infections, particularly in relation to parasitic infections (e.g. sea lice Lepeophtheirus salmonis and amoebic gill disease caused by Neoparamoeba perurans). It is well accepted that the time of administration influences pharmacodynamics and pharmacokinetics of drugs which in turn affects their efficacy and toxicity. Consequently, a better understanding of drug side effects as a function of time of day exposure would help to improve treatment efficacy and fish welfare. To this end, salmon were exposed to H2O2 (1500 mg/L) for 20 min at six different times of the day during a 24-h cycle and we investigated the time-dependent effects of exposure on physiological stress (glucose, lactate and cortisol) and antioxidant enzyme expression (gpx1, cat, Mn-sod and hsp70) in liver and gills. In addition, at each sampling point, 8 control fish were also sampled. Our results revealed that the time of administration of H2O2 caused significant differences in the induction of both physiological and oxidative stress responses. Glucose and lactate were higher in the treated fish during daytime whereas cortisol levels appeared to be systematically increased (>1000 ng/mL) after H2O2 treatment irrespective of exposure time, although differences with control levels were higher during the day. In liver, gene expression of antioxidant enzymes displayed daily rhythmicity in both treated and control groups and showed higher mRNA expression levels in salmon treated with H2O2 at ZT6 (6 h after lights onset). In gills, rhythmic expression was only found for gpx1 in the control fish and for hsp70 and Mn-sod in the treated groups. However, in the treated salmon, higher gene expression levels of all the investigated enzymes were also observed at ZT6-10. Clock gene expression showed rhythmicity only in the liver in accordance with the daily rhythm of enzyme expression observed in this tissue. Altogether, this study provides first evidence of chronotoxicity in Atlantic salmon treated with H2O2 and suggests increased sublethal toxic effect during the first half of the day. These results have direct relevance to the salmon and broader aquaculture industry by optimising the timing of treatment administration, opening the door to chronotherapy to treat fish diseases.

27057834	Limited information is available regarding stroke-related out-of-hospital cardiac arrest (OHCA). We aimed to assess the clinical characteristics of stroke-related OHCA and to identify the factors associated with patient outcomes.We conducted a nationwide population-based study of adult OHCA patients in Japan from January 1, 2006 to December 31, 2009. We examined the epidemiology, risk factors, and outcomes of stroke-related OHCA compared with cardiogenic OHCA. The primary outcome was neurologically favorable survival.Of the 243,140 eligible patients, 18,682 (7.7%) were diagnosed with stroke-related OHCA. Compared to OHCA with a presumed cardiac etiology, stroke-related OHCA patients had a greater chance of prehospital return of spontaneous circulation (ROSC) (9.9% vs 5.9%, P < 0.0001) but a reduced chance of 1-month survival (3.6% vs 4.9%, P < 0.0001) or favorable neurological outcomes (1.2% vs 2.6%, P < 0.0001). After adjusting for a variety of confounding factors, the prehospital ROSC rates were higher (adjusted OR 2.47, 95% confidence interval [CI] 2.34-2.62), but the neurologically favorable survival rates were lower (adjusted OR 0.66, 95%CI 0.57-0.76), among the stroke-related OHCA patients. In stroke-related OHCA cases, having a younger age, witness, and shockable 1st documented rhythm were associated with improved outcomes. Men had more favorable neurological outcomes. Seasonal or circadian factors had no critical impact on favorable neurological outcomes. Prehospital advanced life support techniques (i.e., epinephrine administration or advanced airway management) were not associated with favorable neurological outcomes.Although stroke-related OHCA had lower 1-month survival rates and poorer neurological outcomes than cardiogenic OHCA, the rates were not considered to be medically futile. Characteristically, sex differences might impact neurologically favorable survival.
27057734	General anesthesia affects the expression of clock genes in various organs. Expression of Per2, a core component of the circadian clock, is markedly and reversibly suppressed by sevoflurane in the suprachiasmatic nucleus (SCN), and is considered to be a biochemical marker of anesthetic effect in the brain. The SCN contains various types of neurons, and this complexity makes it difficult to investigate the molecular mechanisms of anesthesia. Here, we established an in vitro experimental system using a cell line to investigate the mechanisms underlying anesthetic action. Development of the system comprised two steps: first, we developed a system for application of inhalational anesthetics and incubation; next, we established cultures of anesthetic-responsive cells expressing mPer2 promoter-dLuc. GT1-7 cells, derived from the mouse hypothalamus, responded to sevoflurane by reversibly decreasing mPer2-promoter-driven bioluminescence. Interestingly, the suppression of bioluminescence was found only in the serum-starved GT1-7 cells, which showed neuron-like morphology, but not in growing cells, suggesting that neuron-like characteristics are required for anesthetic effects in GT1-7 cells. 
27056296	The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question, we performed a combined functional, transcriptomic, and metabolomic analysis in mice with inducible conditional knockout (cKO) of BMAL1, which is critically involved in the circadian clock system, in renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Induction of cKO in adult mice did not produce obvious abnormalities in renal sodium, potassium, or water handling. Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport in cKO mice compared with control littermates. Furthermore, kidneys from cKO mice exhibited a significant decrease in the NAD+-to-NADH ratio, which reflects the oxidative phosphorylation-to-glycolysis ratio and/or the status of mitochondrial function. Metabolome profiling showed significant changes in plasma levels of amino acids, biogenic amines, acylcarnitines, and lipids. In-depth analysis of two selected pathways revealed a significant increase in plasma urea level correlating with increased renal Arginase II activity, hyperargininemia, and increased kidney arginine content as well as a significant increase in plasma creatinine concentration and a reduced capacity of the kidney to secrete anionic drugs (furosemide) paralleled by an approximate 80% decrease in the expression level of organic anion transporter 3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at the intrarenal and systemic levels and are involved in drug disposition.
27056252	To investigate autonomic nervous system function in enuretic children by performing ambulatory blood pressure monitor (ABPM) for 24 h.Twenty-eight children ranging in age from 6 to 15 years with primary nocturnal enuresis and 27 age-matched healthy controls were enrolled and they get 24 h ABPM. Hypertension was defined as standard deviation score (SDS) > 1.64 (i.e., >95th percentile) adjusted for gender and height. Urinalysis, urine electrolyte levels, urinary culture, and urinary system ultrasound were carried out in all children. They have also requested to have a diary about daily fluid intake and urine volume.	Although the mean 24-h and daytime diastolic blood pressure (BP) did not differ between the groups, systolic BP (SBP) was significantly higher in enuretic children (p < 0.05). The mean night-time SBP, DBP values, SDS and BP loads were found to be significantly higher than those in the controls (p < 0.01). A lack of nocturnal decrease was more prevalent in the enuretic children compared with the control subjects, the difference was statistically significant for DBP but not for SBP. Patients with elevated night-time BP load was found to have higher frequency of urinary incontinence per week as well as per night when compared with enuretic children with normal night-time BP load (r = 0.72, r = 0.69, p < 0.01, respectively).	Subtle abnormalities of circadian BP regulation in enuretic children indicated by a selective elevation of nocturnal SBP, DBP, and MAP, and attenuated nocturnal dipping may reflect sympathetic hyper activation and its possible role in pathogenesis of enuresis.	
27055591	Transcription factors primarily regulate gene expression by determining which genes are transcribed at initiation and the extent to which those genes are transcribed during elongation. Brain and muscle Arnt-like protein-1 (BMAL1, ARNTL) is a well-characterized key activator of genes related to circadian rhythm that can specifically bind promoter boxes (E-boxes), cis-acting DNA elements. Previous genetic and biochemical studies have shown that BMAL1 regulates the circadian clock feedback loop, but the role of BMAL1 in transcription is still unclear. BMAL1 is structurally and functionally similar to c-MYC, a canonical regulator of transcription elongation, and both proteins contain beta helix-loop-helix domains and bind to E-boxes. In the current study, we utilized POL2 and H3K4me3 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) in cells with BMAL1 gene knockout. The results demonstrate that, compared to wild type cells, both POL2 and H3K4me3 enrichment at transcription starting sites of clock-related genes are compromised in BMAL1 gene knockout cell. We also quantified nascent RNA production in wild type and BMAL1 gene knockout of clock-related genes. The results show that, compared to wild type cells, nascent RNA production is also reduced. In conclusion, these results suggest that BMAL1 is a major regulator of transcription initiation and activates circadian clock gene expression. 
27055099	A PCR array, based on expression of genes along the hypothalamic-pituitary-gonadal-liver (HPGL) axis of fish, has been suggested as a useful method for screening of endocrine-disrupting chemicals (EDCs). However, effects of circadian rhythm on responses of the HPGL axis to exposure to chemicals were unknown. In this study, profiles of expression of genes along the HPGL axis and concentrations of 17β-estradiol (E2) in blood plasma of female zebrafish were compared at two sampling times of day (8:00 AM and 7:00 PM). Prochloraz (PCZ) was selected as a model chemical to evaluate differences in responses of the HPGL axis at these two times of day. Profiles of responses of concentrations of E2 in plasma and expressions of genes along the HPGL axis genes were different between the two times of sampling. Concentrations of E2 were less, and abundances of mRNA for several genes along the HPGL axis were significantly greater or lesser when samples were collected at 7:00 PM than they were when samples were collected at 8:00 AM. Exposure to three concentrations of PCZ (3, 30 or 300μg/L) for 48h resulted in significantly lesser concentrations of plasma E2 and caused compensatory up-regulation of genes included in hypothalamus, pituitary and ovary. Expressions of genes along the HPGL were more responsive to PCZ at 8:00 AM than they were when samples were collected at 7:00 PM. Correlations among parameters in samples collected at the two times indicated the effects might be due to different concentrations of E2 in plasma due to exposure to PCZ. 
27053731	Circadian rhythms are generated by the autonomous circadian clock, the suprachiasmatic nucleus (SCN), and clock genes that are present in all tissues. The SCN times these peripheral clocks, as well as behavioral and physiological processes. Recent studies show that frequent violations of conditions set by our biological clock, such as shift work, jet lag, sleep deprivation, or simply eating at the wrong time of the day, may have deleterious effects on health. This infringement, also known as circadian desynchronization, is associated with chronic diseases like diabetes, hypertension, cancer, and psychiatric disorders. In this review, we will evaluate evidence that these diseases stem from the need of the SCN for peripheral feedback to fine-tune its output and adjust physiological processes to the requirements of the moment. This feedback can vary from neuronal or hormonal signals from the liver to changes in blood pressure. Desynchronization renders the circadian network dysfunctional, resulting in a breakdown of many functions driven by the SCN, disrupting core clock rhythms in the periphery and disorganizing cellular processes that are normally driven by the synchrony between behavior and peripheral signals with neuronal and humoral output of the hypothalamus. Consequently, we propose that the loss of synchrony between the different elements of this circadian network as may occur during shiftwork and jet lag is the reason for the occurrence of health problems. 
27051073	Fatigue has been associated with reductions in daily activity of older people. Summary measures of daily physical activity provide limited understanding of how fatigue affects physical activity behavior. This study examined the hour-by-hour energy expenditure estimated from accelerometry data to provide insight into physical activity behaviors of older people experiencing fatigue. Fatigued participants were matched to 'not fatigued' participants by age, sex, and BMI. Each group consisted of 86 people with a mean age 73.8 years (SD 2.0), BMI 26.5 kg⋅m-2 (SD 3.9) and 61% female. The phase-space plot, constructed to express rate of change of average vertical axis counts per hour as a time series, showed fatigued participants deviated from the not fatigued participants during the morning period, when hour-by-hour activity was increasing. Older people who feel fatigued have a different morning activity pattern, which appears to lead to the lower overall levels of physical activity.
27049729	BMAL1 and RORα are major regulators of the circadian molecular oscillator. Since previous work in other cell types has shown cross talk between circadian rhythm genes and hypoxic signaling, we investigated the role of BMAL1 and RORα in controlling HIF-1-dependent transcriptional responses in NP cells that exist in the physiologically hypoxic intervertebral disc. HIF-1-dependent HRE reporter activity was further promoted by co-transfection with either BMAL1 or RORα. In addition, stable silencing of BMAL1 or inhibition of RORα activity resulted in decreased HRE activation. Inhibition of RORα also modulated HIF1α-TAD activity. Interestingly, immunoprecipitation studies showed no evidence of BMAL1, CLOCK or RORα binding to HIF-1α in NP cells. Noteworthy, stable silencing of BMAL1 as well as inhibition of RORα decreased expression of select HIF-1 target genes including VEGF, PFKFB3 and Eno1. To delineate if BMAL1 plays a role in maintenance of disc health, we studied the spinal phenotype of BMAL1-null mice. The lumbar discs of null mice evidenced decreased height, and several parameters associated with vertebral trabecular bone quality were also affected in nulls. In addition, null animals showed a higher ratio of cells to matrix in NP tissue and hyperplasia of the annulus fibrosus. Taken together, our results indicate that BMAL1 and RORα form a regulatory loop in the NP and control HIF-1 activity without direct interaction. Importantly, activities of these circadian rhythm molecules may play a role in the adaptation of NP cells to their unique niche. 
27048996	BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion. 
27046809	While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems [3]. 
27046648	Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although rare genetically linked cases of PD have been reported, most incidences are sporadic in nature. Late-onset, sporadic PD is thought to result from the combined effects of genetic and environmental risk factors exposure. Sleep and circadian rhythm disorders are recurrent among PD patients and appear early in the disease. Although some evidence supports a relationship between circadian disruption (CD) and PD, whether this is secondary to the motor symptoms or, indeed, is a factor that contributes to the pathogenesis of the disease remains to be investigated. In the present paper, we studied the direct consequence of chronic CD on the development of the phenotype in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinen) model of PD. Pre-exposure to CD to mice treated with MPTP resulted in an exacerbation of motor deficit and a significant reduction in the capability of acquiring motor skills. These changes were associated with a greater loss of tyrosine hydroxylase cell content and intense neuroinflammation. Taken together, our findings demonstrate that CD by triggering a robust neuroinflammatory reaction and degeneration of the nigral-dopaminergic neuronal system exacerbates motor deficit. They support the novel hypothesis that circadian rhythm disorder is an environmental risk factor for developing PD.
27044085	In the mammalian suprachiasmatic nucleus (SCN), noisy cellular oscillators communicate within a neuronal network to generate precise system-wide circadian rhythms. Although the intracellular genetic oscillator and intercellular biochemical coupling mechanisms have been examined previously, the network topology driving synchronization of the SCN has not been elucidated. This network has been particularly challenging to probe, due to its oscillatory components and slow coupling timescale. In this work, we investigated the SCN network at a single-cell resolution through a chemically induced desynchronization. We then inferred functional connections in the SCN by applying the maximal information coefficient statistic to bioluminescence reporter data from individual neurons while they resynchronized their circadian cycling. Our results demonstrate that the functional network of circadian cells associated with resynchronization has small-world characteristics, with a node degree distribution that is exponential. We show that hubs of this small-world network are preferentially located in the central SCN, with sparsely connected shells surrounding these cores. Finally, we used two computational models of circadian neurons to validate our predictions of network structure. 
27044040	Yaks (Bos grunniens) are endemic species that can adapt well to thin air, cold temperatures, and high altitude. These species can survive in harsh plateau environments and are major source of animal production for local residents, being an important breed in the Qinghai-Tibet Plateau. However, compared with ordinary cattle that live in the plains, yaks generally have lower fertility. Investigating the basic physiological molecular features of yak ovary and identifying the biological events underlying the differences between the ovaries of yak and plain cattle is necessary to understand the specificity of yak reproduction. Therefore, RNA-seq technology was applied to analyze transcriptome data comparatively between the yak and plain cattle estrous ovaries.After deep sequencing, 3,653,032 clean reads with a total of 4,828,772,880 base pairs were obtained from yak ovary library. Alignment analysis showed that 16992 yak genes mapped to the yak genome, among which, 12,731 and 14,631 genes were assigned to Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, comparison of yak and cattle ovary transcriptome data revealed that 1307 genes were significantly and differentially expressed between the two libraries, wherein 661 genes were upregulated and 646 genes were downregulated in yak ovary. Functional analysis showed that the differentially expressed genes were involved in various Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. GO annotations indicated that the genes related to "cell adhesion," "hormonal" biological processes, and "calcium ion binding," "cation transmembrane transport" molecular events were significantly active. KEGG pathway analysis showed that the "complement and coagulation cascade" pathway was the most enriched in yak ovary transcriptome data, followed by the "cytochrome P450" related and "ECM-receptor interaction" pathways. Moreover, several novel pathways, such as "circadian rhythm," were significantly enriched despite having no evident associations with the reproductive function.	Our findings provide a molecular resource for further investigation of the general molecular mechanism of yak ovary and offer new insights to understand comprehensively the specificity of yak reproduction.	
27043528	Sleep disturbance is common in children with atopic dermatitis (AD). It is a major factor leading to impaired quality of life in these patients and could have negative effects on neurocognitive function and behavior. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. Pruritus and scratching could lead to sleep disruption but is unlikely the sole etiology. The circadian rhythm of cytokines, the immune system, and skin physiology such as transcutaneous water loss and skin blood flow might also play a role. Recent studies have suggested that melatonin could also be involved due to its multiple effects on sleep, immunomodulation, and anti-oxidant ability. Environmental factors should also be considered. In this review, we summarize the current understanding of the pathophysiology of sleep disturbance in children with AD, and discuss possible therapeutic implications. 
27043267	Retinoic acid receptor-related orphan receptors (RORs) are ligand-dependent transcriptional factors and members of the nuclear receptor superfamily. RORs regulate inflammation, metabolic disorders and circadian rhythm. RORγ is a promising therapeutic drug target for treating Th17-mediated autoimmune diseases. In our study, we performed structure-based virtual screening and ligand-based virtual screening targeting the RORγ ligand-binding domain and successfully identified N-phenyl-2-(N-phenylphenylsulfonamido) acetamides as a type of RORγ inverse agonist. Among the 28 purchased compounds, C11 was confirmed to be active with micromolar IC50 values in both an AlphaScreen assay (62.58 μM) and a cell-based reporter gene assay (4.54 μM). Structure-guided optimization of the compound C11 led to the identification of compound 39, which significantly enhanced RORγ inhibition with an IC50 value of 630 nM. The RORγ antagonism of 39 was 7-fold higher than that of hit compound C11. These results represent a promising starting point for developing potent small molecule RORγ inverse agonists for the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. 
27042395	Ctenophores (comb jellies) are emerging as important animals for investigating fundamental questions across numerous branches of biology (e.g., evodevo, neuroscience and biogeography). A few ctenophore species including, most notably, Mnemiopsis leidyi, are considered as invasive species, adding to the significance of studying ctenophore ecology. Despite the growing interest in ctenophore biology, relatively little is known about their reproduction. Like most ctenophores, M. leidyi is a simultaneous hermaphrodite capable of self-fertilization. In this study, we assess the influence of light on spawning, the effect of body size on spawning likelihood and reproductive output, and the cost of self-fertilization on egg viability in M. leidyi. Our results suggest that M. leidyi spawning is more strongly influenced by circadian rhythms than specific light cues and that body size significantly impacts spawning and reproductive output. Mnemiopsis leidyi adults that spawned alone produced a lower percentage of viable embryos versus those that spawned in pairs, suggesting that self-fertilization may be costly in this species. These results provide insight into the reproductive ecology of M. leidyi and provide a fundamental resource for researchers working with them in the laboratory. 
27040510	We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear.Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life.	Female mice were fed either a control (C, 7%kcal fat) or HF (45%kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, sirtuin expression (Sirt1, Sirt3), and the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erbα, Rev-Erbβ, RORα, and Srebp1c) were measured in offspring livers.	Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD(+)/NADH (p<0.05, HF/HF vs C/C), Sirt1 (p<0.001, HF/HF vs C/C), Sirt3 (p<0.01, HF/HF vs C/C), perturbed clock gene expression, and elevated expression of genes involved lipid metabolism, such as Srebp1c (p<0.05, C/HF and HF/HF vs C/C).	Our results suggest that exposure to excess dietary fat during early and post-natal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced sirtuin abundance, and desynchronized clock gene expression.	
27040465	Paradoxical increase in blood pressure (BP) during sleep, exceeding those of awake BP, is called the "riser" BP pattern, and known as an abnormal circadian BP rhythm, has been reported to be associated with adverse cardiovascular prognoses. However, the significance of ambulatory BP in heart failure patients with preserved ejection fraction (HFpEF) has never been reported. Here, we tested our hypothesis that abnormal circadian BP rhythm is associated with HFpEF. The authors enrolled 508 patients with hospitalized HF (age 68±13 years; 315 men, 193 women). There were 232 cases of HFpEF and 276 cases of heart failure with reduced ejection fraction (HFrEF). The riser BP pattern was significantly more frequent in the HFpEF (28.9%) group compared with the HFrEF group (19.9%). In a multivariable logistic regression analysis, the riser BP pattern was associated with HFpEF (odds ratio, 1.73; 95% confidence interval, 1.02-2.91; P=.041) independent of the other covariates. In conclusion, the riser BP pattern was associated with HFpEF.
27040118	Bio-mathematical models that predict fatigue and/or sleepiness have proved a useful adjunct in the management of what has been typically referred to as fatigue-related risk. Codifying what constitutes appropriate use of these models will be increasingly important over the next decade. Current guidelines for determining a safe working time arrangement based on model outputs generally use a single upper threshold and are, arguably, over-simplistic. These guidelines fail to incorporate explicitly essential aspects of the risk assessment process - namely, the inherent uncertainty and variability in human sleep-wake behavior; the non-linear relationship between fatigue, task performance and safety outcomes; the consequence of a fatigue-related error and its influence on overall risk; and the impact of risk mitigation or controls in reducing the likelihood or consequence of a fatigue-related error. As industry and regulatory bodies increasingly move toward performance-based approaches to safety management, any fatigue risk management system that includes a bio-mathematical model should specify what exactly is measured by the model, and how the model can be used in the context of a safety management system approach. This will require significant dialog between the various parties with an interest in bio-mathematical models, i.e. developers, vendors, end-users, and regulators.

27039027	You cannot escape time. Therefore, it seems wise to learn how to keep track of it and use it to your advantage. Circadian clocks are molecular circuits that allow organisms to temporally coordinate a plethora of processes, including gene expression, with a close to 24h rhythm, optimizing cellular function in synchrony with daily environmental cycles. The molecular bases of these clocks have been extensively studied in the fungus Neurospora crassa, providing a detailed molecular description. Surprisingly, there is scarce molecular information of clocks in fungi other than Neurospora, despite the existence of rhythmic phenomena in many fungal species, including pathogenic ones. This review will comment on the overall importance of clocks, what is known in Neurospora and what has been described in other fungi including new insights on the evolution of fungal clock components. The molecular description of the circadian system of the phytopathogenic fungus Botrytis cinerea will be revisited, as well as time-of-the-day variation in host-pathogen interaction dynamics, utilizing an Arabidopsis-Botrytis system, including also what is known regarding circadian regulation of defense mechanisms in the Arabidopsis thaliana plant model. Finally, this review will mention how little is known about circadian regulation of human pathogenic fungi, commenting on potential future directions and the overall perspective of fungal circadian studies. 
27038859	Melatonin is a hormone rhythmically secreted at night by the pineal gland in vertebrates. In diurnal mammals, melatonin is present during the inactive phase of the rest/activity cycle, and in primates it directly facilitates sleep and decreases body temperature. However, the role of the pineal gland for the promotion of sleep at night has not yet been studied in non-primate diurnal mammalian species. Here, the authors directly examined the hypothesis that the pineal gland contributes to diurnality in Nile grass rats by decreasing activity and increasing sleep at night, and that this could occur via effects on circadian mechanisms or masking, or both. Removing the pineal gland had no effect on the hourly distribution of activity across a 12:12 light-dark (LD) cycle or on the patterns of sleep-like behavior at night. Masking effects of light at night on activity were also not significantly different in pinealectomized and control grass rats, as 1h pulses of light stimulated increases in activity of sham and pinealectomized animals to a similar extent. In addition, the circadian regulation of activity was unaffected by the surgical condition of the animals. Our results suggest that the pineal gland does not contribute to diurnality in the grass rat, thus highlighting the complexity of temporal niche transitions. The current data raise interesting questions about how and why genetic and neural mechanisms linking melatonin to sleep regulatory systems might vary among mammals that reached a diurnal niche via parallel and independent pathways. 
27038650	There is a relationship between circadian rhythm and metabolic disorders. The active agent, SR8278, could competitively bind to and inhibit the nuclear receptor, Rev-erb (a major modulator of mammalian circadian clock system), to regulate the metabolism in organisms. However, we had limited knowledge of the pharmacokinetic (PK) characteristics of SR8278. Here, we describe a sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify SR8278 in vivo. The linearity range and the limit of quantification (LOQ) for SR8278 were 30-3000 ng/mL and 6 ng/mL, respectively. The inter-day and intra-day variability were within 10%. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of SR8278 in normal and diabetic rats after intravenous (i.v.) injection at a dosage of 2mg/kg. No significant differences were observed in the PK parameters of SR8278 in normal and diabetic rats. Specifically, the values of areas under plasma concentration time curves (AUC), initial plasma concentrations (C0), elimination half-lives (t1/2), and clearances (CL) were 608.33 ± 295.25 vs. 598.59 ± 276.92 ng·h/mL, 2410.25 ± 202.36 vs. 3742.11 ± 1300.21 ng/mL, 0.17 ± 0.08 vs. 0.11 ± 0.04 h, 3330.83 ± 1609.48 vs. 3364.81 ± 1111.38 mL/kg·h for SR8278 in normal rats vs. diabetic rats, respectively. In conclusion, a UPLC-MS/MS method was successfully developed and validated for the first time, with a wide linearity range, low LOQ, small sample volume (10 μL), rapid analysis (4 min) and excellent recoveries (>80%). It was also used to clarify the PK characteristics of SR8378 in rats. The same PK behaviors of SR8278 in normal and diabetic rats showed that diabetes may have little or no effect on the disposition, metabolism and/or elimination in vivo, which may be of great importance for future clinical studies.
27037592	Crocosphaera watsonii is a marine cyanobacterium that frequently inhabits low phosphate environments in oligotrophic oceans. While C. watsonii has the ability to fix atmospheric nitrogen, its growth may be limited by availability of phosphorus. Biomarkers that indicate cellular phosphorus status give insight into how P-limitation can affect the distribution of nitrogen-fixing cyanobacterial populations. However, adaptation to phosphorus stress is complex and one marker may not be sufficient to determine when an organism is P-limited. In this study, we characterized the transcription of key genes, activated during phosphorus stress in C. watsonii WH8501, to determine how transcription changed during the phosphorus stress response. Transcription of pstS, which encodes a high-affinity phosphate binding protein, was discovered to be quickly up-regulated in phosphorus-depleted cells as an immediate stress response; however, its transcription declined after a period of phosphorus starvation. In addition, diel regulation of pstS in C. watsonii WH8501 complicates the interpretation of this marker in field applications. Transcription of the gene coding for the arsenite efflux protein, arsB, was upregulated after pstS in phosphorus limited cells, but it remained upregulated at later stages of phosphorus limitation. These results demonstrate that a single molecular marker does not adequately represent the entire phosphorus stress response in C. watsonii WH8501. Using both markers, the variations in transcriptional response over a range of degrees of phosphorus limitation may be a better approach for defining cellular phosphorus status. 
27035936	Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push-pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene. 
27035655	Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of Clock(Δ19/Δ19) mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment. 
27033803	Disturbances of circadian rhythms have been suggested to be a causal factor in the development of major depressive disorder. However, the mechanisms underlying the association between circadian rhythm abnormalities and mood disorders are still unknown. In the current study the association between diurnal pattern of key phase markers (melatonin, corticosterone, and core body temperature) and anhedonic-like behavior was investigated using the highly validated rat chronic mild stress (CMS) model of depression. Phase marker measurements were done after 3.5 weeks of CMS in 48 control rats and 48 anhedonic-like rats at 6 time points within 24h. The results showed that anhedonic-like behavior associates with changes in all three phase markers: an increased dark phase melatonin secretion, an additional peak in corticosterone level in the beginning of the light phase, and hypothermia in the dark phase. The result adds to the validity of the CMS model in general and in particular to be adequate as a model for studying the chronobiology of depressive disorder. 
27033596	Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT. 
27032687	Hypertension is often associated with metabolic syndrome (MetS), and serves as a risk factor of MetS and its complications. Blood pressure circadian rhythm in hypertensive patients has been suggested to contribute to cardiovascular consequences and organ damage of hypertension. But circadian changes of BP and their response to drugs have not been clearly investigated in non-human primates (NHPs) of MetS with hypertension. Here, we identified 16 elderly, hypertensive MetS rhesus monkeys from our in-house cohort. With implanted telemetry, we investigate BP changes and its circadian rhythm, together with the effect of antihypertensive drugs on BP and its diurnal fluctuation. MetS hypertensive monkeys displayed higher BP, obesity, glucose intolerance, and dyslipidemia. We also confirmed impaired 24-h BP circadian rhythm in MetS hypertensive monkeys. Importantly, Eplerenone, a mineralocorticoid receptor blocker, exerts multiple beneficial effects in MetS hypertensive monkeys, including BP reduction, 24-h BP circadian rhythm restoration, and decreased plasma concentration of inflammation factors and advanced glycation end-products. In summary, we identified a naturally-developed hypertensive MetS NHP model, which is of great value in the studies on pathogenesis of MetS-associated hypertension and development of novel therapeutic strategies. We also provided multiple novel mechanistic insights of the beneficial effect of Eplerenone on MetS with hypertension. 
27032109	Rodent studies demonstrate that prolonged fasting during the sleep phase positively influences carcinogenesis and metabolic processes that are putatively associated with risk and prognosis of breast cancer. To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.To investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep.	Data were collected from 2413 women with breast cancer but without diabetes mellitus who were aged 27 to 70 years at diagnosis and participated in the prospective Women's Healthy Eating and Living study between March 1, 1995, and May 3, 2007. Data analysis was conducted from May 18 to October 5, 2015.	Nightly fasting duration was estimated from 24-hour dietary recalls collected at baseline, year 1, and year 4.	Clinical outcomes were invasive breast cancer recurrence and new primary breast tumors during a mean of 7.3 years of study follow-up as well as death from breast cancer or any cause during a mean of 11.4 years of surveillance. Baseline sleep duration was self-reported, and archived blood samples were used to assess concentrations of hemoglobin A1c and C-reactive protein.	The cohort of 2413 women (mean [SD] age, 52.4 [8.9] years) reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36; 95% CI, 1.05-1.76). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality (hazard ratio, 1.21; 95% CI, 0.91-1.60) or a statistically significant higher risk of all-cause mortality (hazard ratio, 1.22; 95% CI, 0.95-1.56). In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels (β = -0.37; 95% CI, -0.72 to -0.01) and a longer duration of nighttime sleep (β = 0.20; 95% CI, 0.14-0.26).	Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.	
27031999	Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (Bmal1, Per1-3, Cry1, RevErbα, Rora), clock-output genes (Dbp, E4bp4) and a glucocorticoid- and clock-controlled gene (Gilz) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT). Adrenalectomy did not affect the phase of clock gene rhythms but distinctly modulated clock gene mRNA levels, and this effect was partially tissue-dependent. Adrenalectomy had a significant inhibitory effect on the level of Per1 mRNA in VAT, liver and jejunum, but not in kidney and splenocytes. Similarly, adrenalectomy down-regulated mRNA levels of Per2 in splenocytes and VAT, Per3 in jejunum, RevErbα in VAT and Dbp in VAT, kidney and splenocytes, whereas the mRNA amounts of Per1 and Per2 in kidney and Per3 in VAT and splenocytes were up-regulated. On the other hand, adrenalectomy had minimal effects on Rora and E4bp4 mRNAs. Adrenalectomy also resulted in decreased level of Gilz mRNA but did not alter the phase of its diurnal rhythm. Collectively, these findings suggest that adrenalectomy alters the mRNA levels of core clock genes and clock-output genes in peripheral organs and may cause tissue-specific modulations of their circadian profiles, which are reflected in changes of the amplitudes but not phases. Thus, the circulating corticosteroids are necessary for maintaining the high-amplitude rhythmicity of the peripheral clocks in a tissue-specific manner.
27031879	To investigate the role of non-parametric light effects in entrainment, Djungarian hamsters of two different circadian phenotypes were exposed to skeleton photoperiods, or to light pulses at different circadian times, to compile phase response curves (PRCs). Wild-type (WT) hamsters show daily rhythms of locomotor activity in accord with the ambient light/dark conditions, with activity onset and offset strongly coupled to light-off and light-on, respectively. Hamsters of the delayed activity onset (DAO) phenotype, in contrast, progressively delay their activity onset, whereas activity offset remains coupled to light-on. The present study was performed to better understand the underlying mechanisms of this phenomenon. Hamsters of DAO and WT phenotypes were kept first under standard housing conditions with a 14:10 h light-dark cycle, and then exposed to skeleton photoperiods (one or two 15-min light pulses of 100 lx at the times of the former light-dark and/or dark-light transitions). In a second experiment, hamsters of both phenotypes were transferred to constant darkness and allowed to free-run until the lengths of the active (α) and resting (ρ) periods were equal (α:ρ = 1). At this point, animals were then exposed to light pulses (100 lx, 15 min) at different circadian times (CTs). Phase and period changes were estimated separately for activity onset and offset. When exposed to skeleton-photoperiods with one or two light pulses, the daily activity patterns of DAO and WT hamsters were similar to those obtained under conditions of a complete 14:10 h light-dark cycle. However, in the case of giving only one light pulse at the time of the former light-dark transition, animals temporarily free-ran until activity offset coincided with the light pulse. These results show that photic entrainment of the circadian activity rhythm is attained primarily via non-parametric mechanisms, with the "morning" light pulse being the essential cue. In the second experiment, typical photic PRCs were obtained with phase delays in the first half of the subjective night, phase advances in the second half, and a dead zone during the subjective day. ANOVA indicated no significant differences between WT and DAO animals despite a significantly longer free-running period (tau) in DAO hamsters. Considering the phase shifts induced around CT0 and the different period lengths, it was possible to model the entrainment patterns of both phenotypes. It was shown that light-induced phase shifts of activity offset were sufficient to compensate for the long tau in WT and DAO hamsters, thus enabling a stable entrainment of their activity offsets to be achieved. With respect to activity onsets, phase shifts were sufficient only in WT animals; in DAO hamsters, activity onset showed increasing delays. The results of the present paper clearly demonstrate that, under laboratory conditions, the non-parametric component of light and dark leads to circadian entrainment in Djungarian hamsters. However, a stable entrainment of activity onset can be achieved only if the free-running period does not exceed a certain value. With longer tau values, hamsters reveal a DAO phenotype. Under field conditions, therefore, non-photic cues/zeitgebers must obviously be involved to enable a proper circadian entrainment. 
27031035	Elite soccer players are at risk of reduced recovery following periods of sleep disruption, particularly following late-night matches. It remains unknown whether improving sleep quality or quantity in such scenarios can improve post-match recovery. Therefore, the aim of this study was to investigate the effect of an acute sleep hygiene strategy (SHS) on physical and perceptual recovery of players following a late-night soccer match. In a randomised cross-over design, two highly-trained amateur teams (20 players) played two late-night (20:45) friendly matches against each other seven days apart. Players completed an SHS after the match or proceeded with their normal post-game routine (NSHS). Over the ensuing 48 h, objective sleep parameters (sleep duration, onset latency, efficiency, wake episodes), countermovement jump (CMJ; height, force production), YoYo Intermittent Recovery test (YYIR2; distance, maximum heart rate, lactate), venous blood (creatine kinase, urea and c-reactive protein) and perceived recovery and stress markers were collected. Sleep duration was significantly greater in SHS compared to NSHS on match night (P = 0.002, d = 1.50), with NSHS significantly less than baseline (P < 0.001, d = 1.95). Significant greater wake episodes occurred on match night for SHS (P = 0.04, d = 1.01), without significant differences between- or within-conditions for sleep onset latency (P = 0.12), efficiency (P = 0.39) or wake episode duration (P = 0.07). No significant differences were observed between conditions for any physical performance or venous blood marker (all P > 0.05); although maximum heart rate during the YYIR2 was significantly higher in NSHS than SHS at 36 h post-match (P = 0.01; d = 0.81). There were no significant differences between conditions for perceptual "overall recovery" (P = 0.47) or "overall stress" (P = 0.17). Overall, an acute SHS improved sleep quantity following a late-night soccer match; albeit without any improvement in physical performance, perceptual recovery or blood-borne markers of muscle damage and inflammation.
27030964	Numerous cross-sectional studies report high prevalence rates of sleepiness and insomnia in shift workers, but few longitudinal studies exist. We investigated trajectories of sleepiness and insomnia symptoms in a sample of Norwegian nurses across four measurements, spanning a total of four years (sleepiness) and five years (insomnia). The participants completed the Epworth Sleepiness Scale and the Bergen Insomnia Scale at each measurement instance. Latent growth curve models were used to analyse the data. Separate models examined night work (night work, entering and leaving night work) and rotational work (rotational work, entering and leaving rotational work) as predictors for trajectories of sleepiness and insomnia symptoms, respectively. Baseline values of sleepiness and insomnia were higher among rotational shift workers than among workers with fixed shifts (day or night). The results showed that night work throughout the period and entering night work during the period were not associated with different trajectories of sleepiness or insomnia symptoms, compared to not having night work. The same results were found for rotational work and entering rotational work, compared to not having rotational work. Leaving night work and leaving rotational work were associated with a decrease in sleepiness and insomnia symptoms, compared to staying in such work.
27030770	InDrosophila, a transcriptional feedback loop that is activated by CLOCK-CYCLE (CLK-CYC) complexes and repressed by PERIOD-TIMELESS (PER-TIM) complexes keeps circadian time. The timing of CLK-CYC activation and PER-TIM repression is regulated post-translationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Although kinases that control PER, TIM, and CLK levels, activity, and/or subcellular localization have been identified, less is known about phosphatases that control clock protein dephosphorylation. To identify clock-relevant phosphatases, clock-cell-specific RNAi knockdowns ofDrosophilaphosphatases were screened for altered activity rhythms. One phosphatase that was identified, the receptor protein tyrosine phosphatase leukocyte-antigen-related (LAR), abolished activity rhythms in constant darkness (DD) without disrupting the timekeeping mechanism in brain pacemaker neurons. However, expression of the neuropeptide pigment-dispersing factor (PDF), which mediates pacemaker neuron synchrony and output, is eliminated in the dorsal projections from small ventral lateral (sLNv) pacemaker neurons whenLarexpression is knocked down during development, but not in adults. Loss ofLarfunction eliminates sLNvdorsal projections, but PDF expression persists in sLNvand large ventral lateral neuron cell bodies and their remaining projections. In contrast to the defects in lights-on and lights-off anticipatory activity seen in flies that lack PDF,LarRNAi knockdown flies anticipate the lights-on and lights-off transition normally. Our results demonstrate thatLaris required for sLNvdorsal projection development and suggest that PDF expression in LNvcell bodies and their remaining projections mediate anticipation of the lights-on and lights-off transitions during a light/dark cycle.In animals, circadian clocks drive daily rhythms in physiology, metabolism, and behavior via transcriptional feedback loops. Because key circadian transcriptional activators and repressors are regulated by phosphorylation, we screened for phosphatases that alter activity rhythms when their expression was reduced. One such phosphatase, leukocyte-antigen-related (LAR), abolishes activity rhythms, but does not disrupt feedback loop function. Rather,Lardisrupts clock output by eliminating axonal processes from clock neurons that release pigment-dispersing factor (PDF) neuropeptide into the dorsal brain, but PDF expression persists in their cell bodies and remaining projections. In contrast to flies that lack PDF, flies that lackLaranticipate lights-on and lights-off transitions normally, which suggests that the remaining PDF expression mediates activity during light/dark cycles.	
27030631	Aim Very few studies have investigated the temporal specificity of melatonin (MEL) ingestion upon short-term maximal athletic performances. The aim of the present study was to explore the effect of morning MEL ingestion on cognitive and physical performances measured in the afternoon. Methods Twelve soccer players from a Tunisian squad (17.9 ± 1.3 years, 1.74 ± 0.06 m and 62.0 ± 8.8 kg) participated in the present study. They performed two testing sessions at 08:00 h, 12:00 h and 16:00 h after either MEL (5mg) or placebo (PLA) ingestion, in a randomized order. During each period, the participants performed the following cognitive and physical tests: reaction time and vigilance tests, medicine-ball throw (MBT), five jumps, handgrip strength (HG), and agility tests. Results cognitive and physical performances were significantly higher at 16:00 h compared to 08:00 h during the two conditions (p < 0.05). Moreover, performances of MBT and HG were lower in the morning with MEL in comparison to PLA (p < 0.05). However, MEL ingestion did not affect physical and cognitive performances measured at 12:00 h and 16:00 h. Conclusion morning MEL ingestion has no unfavourable effect on afternoon physical and cognitive performances in soccer players. 
27030628	The objective of the present study was to compare differences between elderly rats and young obesity-induced rats in their activity/inactivity circadian rhythm. The investigation was motivated by the differences reported previously for the circadian rhythms of both obese and elderly humans (and other animals), and those of healthy, young or mature individuals. Three groups of rats were formed: a young control group which was fed a standard chow for rodents; a young obesity-induced group which was fed a high-fat diet for four months; and an elderly control group with rats aged 2.5 years that was fed a standard chow for rodents. Activity/inactivity data were registered through actimetry using infrared actimeter systems in each cage to detect activity. Data were logged on a computer and chronobiological analysis were performed. The results showed diurnal activity (sleep time), nocturnal activity (awake time), amplitude, acrophase, and interdaily stability to be similar between the young obesity-induced group and the elderly control group, but different in the young control group. We have concluded that obesity leads to a chronodisruption status in the body similar to the circadian rhythm degradation observed in the elderly. 
27030174	There is increasing evidence to suggest that late chronotypes are at increased risk for depression. The putative psychological mechanisms underpinning this risk, however, have not been fully explored. The aim of the present study was to examine whether, similar to acutely depressed patients and other "at risk" groups, late chronotype individuals display biases in tasks assaying emotional face recognition, emotional categorisation, recognition and recall and attention. Late chronotype was associated with increased recognition of sad facial expressions, greater recall and reduced latency to correctly recognise previously presented negative personality trait words and reduced allocation of attentional resources to happy faces. The current results indicate that certain negative biases in emotional processing are present in late chronotypes and may, in part, mediate the vulnerability of these individuals to depression. Prospective studies are needed to establish whether the cognitive vulnerabilities reported here predict subsequent depression. 
27030087	Cereus peruvianus (Peruvian apple cactus) is a large erect and thorny succulent cactus characterized by column-like (cereus [L]: column), that is, candle-shaped, appendages. For three successive years (1100 days), between early April and late November, we studied the flowering patterns of eight cacti growing in public gardens and rural areas of north and central Tunisia, far from nighttime artificial illumination, in relation to natural environmental light, temperature, relative humidity and precipitation parameters. Flower blooming was assessed nightly between 23:00 h and until at least 02:00 h, and additionally around-the-clock at ~1 h intervals for 30 consecutive days during the late summer of each year of study to quantify both nyctohemeral (day-night) and lunar patterns. During the summer months of prolonged daytime photoperiod, flower blooming of C. peruvianus exhibited predictable-in-time variation as "waves" with average period of 29.5 days synchronized by the light of the full moon. The large-sized flower (~16 cm diameter) opens almost exclusively at night, between sunset and sunrise, as a 24 h rhythm during a specific 3-4-day span of the lunar cycle (full moon), with a strong correlation between moon phase and number and proportion of flowers in bloom (ranging from r = +0.59 to +0.91). Black, blue and red cotton sheets were used to filter specific spectral bands of nighttime moonlight from illuminating randomly selected plant appendages as a means to test the hypothesis of a "gating" 24 h rhythm phenomenon of photoreceptors at the bud level. Relative to control conditions (no light filtering), black sheet covering inhibited flower bud induction by 87.5%, red sheet covering by 46.6% and blue sheet covering by 34%, and the respective inhibiting effects on number of flowers in bloom were essentially 100%, ~81% and ~44%. C. peruvianus is a unique example of a terrestrial plant that exhibits a circadian flowering rhythm (peak ~00:00 h) "gated" by 24 h, lunar 29.5-day (bright light of full moon) and annual 365.25-day (prolonged summertime day length) environmental photoperiod cycles. 
27029865	Brooding is a major breeding investment of parental birds during the early nestling stage, and has important effects on the development and survival of nestlings. Investigating brooding behavior can help to understand avian breeding investment strategies. From January to June in 2013 and 2014, we studied the brooding behaviors of long-tailed tits (Aegithalos caudatus glaucogularis) in Dongzhai National Nature Reserve, Henan Province, China. We analyzed the relationships between parental diurnal brooding duration and nestling age, brood size, temperature, relative breeding season, time of day and nestling frequencies during brooding duration. Results showed that female and male long-tailed tit parents had different breeding investment strategies during the early nestling stage. Female parents bore most of the brooding investment, while male parents performed most of the nestling feedings. In addition, helpers were not found to brood nestlings at the two cooperative breeding nests. Parental brooding duration was significantly associated with the food delivered to nestlings (F=86.10, df=1, 193.94, P<0.001), and was longer when the nestlings received more food. We found that parental brooding duration declined significantly as nestlings aged (F=5.99, df=1, 50.13, P=0.018). When nestlings were six days old, daytime parental brooding almost ceased, implying that longtailed tit nestlings might be able to maintain their own body temperature by this age. In addition, brooding duration was affected by both brood size (F=12.74, df=1, 32.08, P=0.001) and temperature (F=5.83, df=1, 39.59, P=0.021), with it being shorter in larger broods and when ambient temperature was higher.
27029286	The circadian rhythms found in almost all organisms are driven by molecular oscillators, including transcription/translation feedback loops (TTFLs). However, TTFL-independent oscillators can drive rhythms in both eukaryotes and prokaryotes. The fungus Neurospora crassa is a model organism for studying the molecular mechanism of the circadian clock. Although a circadian TTFL involving the proteins FRQ, WC-1, and WC-2 is well-characterized in N. crassa, rhythms can still be observed in the absence of this feedback loop. These rhythms are said to be driven by 1 or more FRQ-less oscillator(s) (FLOs). The prd-1 mutation lengthens the period in frq wild type and was previously shown to severely disrupt FRQ-less rhythms in frq null mutants under several different conditions; therefore, the prd-1 gene product is a candidate for a component of a FLO. We report here that prd-1 also disrupts free-running rhythms in wc-1 null mutants, confirming its effects on FRQ-less rhythms. We have now mapped and identified the prd-1 gene as NCU07839, a DEAD-box RNA helicase dbp-2 Complementation with the wild-type gene corrects the rhythm defects of the prd-1 mutant in the complete circadian system (when the FRQ-based TTFL is intact) and also the free-running FRQ-less rhythm on low choline. A PRD-1-GFP fusion protein localizes to the nucleus. The prd-1 mutant has a single base pair change in the first base of an intron that results in abnormally spliced transcripts. FRQ-less rhythms on low choline, or entrained to heat pulses, were only marginally affected in strains carrying deletions of 2 other RNA helicases (prd-6 and msp-8). We conclude that PRD-1 is a member of an RNA helicase family that may be specifically involved in regulating rhythmicity in N. crassa in both the complete circadian system and FLO(s). 

27028761	Bipolar disorder, also known as manic-depressive illness, causes swings in mood and activity levels at irregular intervals. Such changes are difficult to predict, and their molecular basis remains unknown. Here, we use infradian (longer than a day) cyclic activity levels in αCaMKII (Camk2a) mutant mice as a proxy for such mood-associated changes. We report that gene-expression patterns in the hippocampal dentate gyrus could retrospectively predict whether the mice were in a state of high or low locomotor activity (LA). Expression of a subset of circadian genes, as well as levels of cAMP and pCREB, possible upstream regulators of circadian genes, were correlated with LA states, suggesting that the intrinsic molecular circuitry changes concomitant with infradian oscillatory LA. Taken together, these findings shed light onto the molecular basis of how irregular biological rhythms and behavior are controlled by the brain. 
27028468	Residency training requires work in clinical settings for extended periods of time, resulting in altered sleep patterns, sleep deprivation, and potentially deleterious effects on safe performance of daily activities, including driving a motor vehicle.Twenty-nine anesthesiology resident physicians in postgraduate year 2 to 4 drove for 55 min in the Virginia Driving Safety Laboratory using the Driver Guidance System (MBFARR, LLC, USA). Two driving simulator sessions were conducted, one experimental session immediately after the final shift of six consecutive night shifts and one control session at the beginning of a normal day shift (not after call). Both sessions were conducted at 8:00 AM. Psychomotor vigilance task testing was employed to evaluate reaction time and lapses in attention.	After six consecutive night shifts, residents experienced significantly impaired control of all the driving variables including speed, lane position, throttle, and steering. They were also more likely to be involved in collisions. After six consecutive night shifts, residents had a significant increase in reaction times (281.1 vs. 298.5 ms; P = 0.001) and had a significant increase in the number of both minor (0.85 vs. 1.88; P = 0.01) and major lapses (0.00 vs. 0.31; P = 0.008) in attention.	Resident physicians have greater difficulty controlling speed and driving performance in the driving simulator after six consecutive night shifts. Reaction times are also increased with emphasis on increases in minor and major lapses in attention after six consecutive night shifts.	
27027506	How animals achieve evolutionary adaptation to different thermal environments is an important issue for evolutionary biology as well as for biodiversity conservation in the context of recent global warming. In Cuba, three sympatric species of Anolis lizards (Anolis allogus, A. homolechis and A. sagrei) inhabit different thermal microhabitats, thereby providing an excellent opportunity to examine how they have adapted to different environmental temperatures. Here, we performed RNA-seq on the brain, liver and skin tissues from these three species to analyse their transcriptional responses at two different temperatures. In total, we identified 400, 816 and 781 differentially expressed genes (DEGs) between the two temperatures in A. allogus, A. homolechis and A. sagrei, respectively. Only 62 of these DEGs were shared across the three species, indicating that global transcriptional responses have diverged among these species. Gene ontology (GO) analysis showed that large numbers of ribosomal protein genes were DEGs in the warm-adapted A. homolechis, suggesting that the upregulation of protein synthesis is an important physiological mechanism in the adaptation of this species to hotter environments. GO analysis also showed that GO terms associated with circadian regulation were enriched in all three species. A gene associated with circadian regulation, Nr1d1, was detected as a DEG with opposite expression patterns between the cool-adapted A. allogus and the hot-adapted A. sagrei. Because the environmental temperature fluctuates more widely in open habitats than in forests throughout the day, the circadian thermoregulation could also be important for adaptation to distinct thermal habitats. 
27026262	The effects of diurnal variation of photosynthetically active radiation (PAR; 400-700 nm) and ultraviolet-B (UV-B; 280-315 nm) radiation on phycobiliproteins (PBPs) and photosynthetic pigments (PP) have been studied in the hot-spring cyanobacterium Nostoc sp. strain HKAR-2. The variations in PBPs and PP were monitored by alternating light and dark under PAR, UV-B, and PAR + UV-B radiations over a period of 25 h. There was a decline in the amount of Chl a and PBPs during light periods of UV-B and PAR + UV-B and an increase during dark periods showing a circadian rhythm by destruction and resynthesis of pigment-protein complex. However, a marked induction in carotenoids was recorded during light periods of the same radiations. Moreover, the ratio of Chl a/PE and Chl a/PC was increased in dark periods showing the resynthesis of bleached Chl a. The wavelength shift in emission fluorescence of PBPs toward shorter wavelengths further indicated the bleaching and destruction of PBPs during light periods. Oxidative damage upon exposure to PAR, UV-B, and PAR + UV-B was alleviated by induction of antioxidative enzymes such as superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX). The studied cyanobacterium exhibits a significant increase in the activities of SOD, CAT, and APX upon exposure to UV-B and PAR + UV-B radiations. The results indicate that pigment-protein composition of Nostoc sp. stain HKAR-2 was significantly altered during diurnal variation of light/radiation, which might play an important role in optimization for their productivity in a particular cyanobacterium.
27023572	The two main components of the stress system are the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes. While cortisol has been commonly used as a biomarker of HPA functioning, much less attention has been paid to the role of the SAM in this context. Studies have shown that long-term breast cancer survivors display abnormal reactive cortisol patterns, suggesting a dysregulation of their HPA axis. To fully understand the integrity of the stress response in this population, this paper explored the diurnal and acute alpha-amylase profiles of 22 breast cancer survivors and 26 women with no history of cancer. Results revealed that breast cancer survivors displayed identical but elevated patterns of alpha-amylase concentrations in both diurnal and acute profiles relative to that of healthy women, F (1, 39) = 17.95, p < 0.001 and F (1, 37) = 7.29, p = 0.010, respectively. The average area under the curve for the diurnal and reactive profiles was 631.54 ± 66.94 SEM and 1238.78 ± 111.84 SEM, respectively. This is in sharp contrast to their cortisol results, which showed normal diurnal and blunted acute patterns. The complexity of the stress system necessitates further investigation to understand the synergistic relationship of the HPA and SAM axes. 
27023464	The purpose of this study was to evaluate the measurement of heart rate undertaken in clinical studies by (1) assessing the repeatability and reproducibility of heart rate measurements by various methods and under various conditions and (2) determining whether a single heart rate measurement at rest is representative of the circadian and inter-day variation of heart rate.Prospective cohort study in 102 patients with various types of heart disease at Duisburg Heart Center, Germany between 2011 and 2012. The heart rate measurements were based on self-assessment, ECG tracings at rest, and bicycle stress ECG in the office as well as 24-h Holter ECG.	Office measurements and self-assessment at rest as well as 24-h Holter ECG and self-assessment at rest are highly correlated, but no correlation between self-assessment and office recordings/24 h recordings under exercise conditions was seen. Coefficient of variability was below 10 % for the self-assessment and for office measurements at rest. There were no differences in coefficient of variability during the day and within the 6 days for self-assessment of heart rate at rest and circadian variation was normal.	At rest heart rate measurements by various methods agree sufficiently and inter-day/circadian variation is adequately represented. Under exercise conditions self-assessment of heart rate is not valuable and use of 24 h Holter as well as stress ECG recordings is necessary. Thus, self-reported heart rate measurements by the patient at rest seem to be reliable, but should be used in clinical studies only for heart rate assessment at rest.	
27022680	The circadian rhythm generated by circadian clock underlies a molecular mechanism of rhythmic transcriptional regulation by transcription factor BMAL1/CLOCK. Importantly, the circadian clock is coordinated by exogenous cues to accommodate to changes in the external environment. However, the molecular mechanisms by which intracellular-signaling pathways mediate the adjustments of the circadian transcriptional rhythms remain unclear. In this study, we found that pharmacological inhibition or shRNA-mediated knockdown of phosphatidylinositol 3-kinase (PI3K) blocked upregulation of Dbp mRNA induced by serum shock in NIH 3T3 cells. Moreover, the inhibition of PI3K significantly reduced the promoter activity of the Dbp gene, as well as decreased the recruitment of BMAL1/CLOCK to the E-box in the Dbp promoter. Interestingly, the inhibition of PI3K blocked heterodimerization of BMAL1 and CLOCK. Our findings suggest that PI3K signaling plays a modulatory role in the regulation of the transcriptional rhythm of the Dbp gene by targeting BMAL1 and CLOCK. 
27021954	Patients with Alzheimer's disease (AD) have circadian rhythm disorders, which are mimicked in 3xTg-AD and 5xFAD mouse models. The deposition of β-amyloid protein (Aβ) is an important pathological characteristic of AD, however, its role in inducing alterations in biological rhythms and in the expression of circadian clock-related genes remains elusive. The Per1 and Per2 play complex regulatory roles in biological clocks and are diffusely expressed in the suprachiasmatic nucleus (SCN), hippocampus and heart. In the present study, wheel-running behavioral experiments showed that Aβ31-35, which was administered into the hippocampus, resulted in the disruption of the circadian rhythm of C57BL/6 mice. Furthermore, real-time PCR and western blot analysis showed that Aβ31-35 altered the expression of the Per1 and Per2 in the SCN, hippocampus and heart. These findings provide experimental evidence for circadian rhythm disturbances in patients with AD. 

27021453	The objective of this study was to assess the effects of age, sex, and the age-sex interaction on mean pain trajectories and individual variations in the pain experienced by adolescents after orthodontic separator placement.We included 115 subjects (mean age, 14.99 years; SD, ±1.90 years; 56 boys, 48.7%; 59 girls, 51.3%) in this study. Orthodontic separators were placed in the mesial and distal contact points of the maxillary and mandibular first molars. A 100-mm visual analog scale was used for pain assessment at 11 prespecified times: 1 hour and 2, 4, 12, 24, 36, 48, 72, 96, 120, and 144 hours. A mixed-effects location scale model was used for the data analysis to directly model between-subject and within-subject variabilities in pain in addition to the usual modeling of mean pain as a function of age, sex, and time.	Mean initial pain after 1 hour of separator placement for the 12- to 15-year-old male group was 13.52 mm on the visual analog scale, which initially increased rapidly (linear estimate, 9.16; P = 0.000; 95% confidence interval [CI], -8.65 to 9.67) but decelerated with time (quadratic estimate, -0.95; P = 0.000; 95% CI, -1.0 to -0.90), suggesting an inverted U-shaped mean pain trajectory. Age, sex, and age-sex interaction effects did not significantly influence initial pain. Compared with the 12- to 15-year-old male group, the 15- to 18-year-old female group reported the steepest rise in pain (estimate, 8.55; P = 0.00; 95% CI, 7.40 to 9.70) and, as a result, experienced the most overall pain. The 12- to 15-year-old male group reported minimum between-subjects variations (SD, ±4.6 mm) as well as within-subjects variations (SD, ±5.5 mm). The between-subjects variations were highest for the 12- to 15-year-old female group (SD, ±9.8 mm), whereas the within-subjects variations were highest for the 15- to 18-year-old female group (SD, ±10.1 mm).	The 12- to 15-year-old boys reported the lowest mean average pain intensity and a minimum subjective variation in between-subject and within-subject variances. The 15- to 18-year-old girls experienced maximum mean pain intensity and the highest daily fluctuations in pain intensity. The 12- to 15-year-old girls were the most different from one another in their overall pain experience.	
27020850	Stress and recovery from stress significantly affect interactions between the central nervous system, endocrine pathways, and the immune system. However, the influence of acute stress on circulating immune-endocrine mediators in humans is not well known. Using a double-blind, randomized study design, we administered a CO2 stress test to n = 143 participants to identify the effects of acute stress, and recovery from stress, on serum levels of several mediators with immune function (IL-6, TNF-α, leptin, and somatostatin), as well as on noradrenaline, and two hypothalamic-pituitary-adrenal axis hormones (ACTH and cortisol). Moreover, during a 1 h-recovery period, we repeatedly measured these serum parameters, and administered an auditory mood-induction protocol with positive music and a neutral control stimulus. The acute stress elicited increases in noradrenaline, ACTH, cortisol, IL-6, and leptin levels. Noradrenaline and ACTH exhibited the fastest and strongest stress responses, followed by cortisol, IL-6 and leptin. The music intervention was associated with more positive mood, and stronger cortisol responses to the acute stressor in the music group. Our data show that acute (CO2) stress affects endocrine, immune and metabolic functions in humans, and they show that mood plays a causal role in the modulation of responses to acute stress.
27020314	The purpose of the current study was to examine the influence of "time" on isometric elbow flexion torque, body temperature and muscle size without interrupting the sleep wake cycle in college aged males. Two hours following the participants normal wake time, oral temperature was measured, followed by muscle thickness of the upper and lower body using ultrasound, as well as elbow flexor torque via a maximal voluntary contraction (MVC). Measurements were repeated every 2h for 12h (Time points 1-7). To examine the repeatability of the rhythm, participants returned and completed the same procedures as before within 14days of their first circadian visit (Circadian visit 2). There was no time×day interaction for body temperature (p=0.29), nor were there main effects for time (p=0.15) or day (p=0.74). For MVC, there was no time×day interaction (p=0.93) or main effect for day (p=0.50), however, there was a main effect for time (p=0.01). MVC at time points 1 (86.4±6.4Nm) and 2 (87.1±6.2Nm) was greater than time points 4 (84.2±6.6Nm) and 6 (83.4±6.8Nm, p<0.05). Additionally, time point 5 MVC was greater than time point 4. For upper body muscle thickness, there was no time×day interaction (p=0.34), nor was there a main effect for day (p=0.38), or time (p=0.06). For lower body muscle thickness, there was no time×day interaction (p=0.57), nor was there a main effect for day (p=0.75), or time (p=0.13). Cosinor analyses revealed no group level rhythms for oral temperature, muscle thickness or strength (p>0.05), however, there were some individual rhythms noted for muscle thickness and strength. Results suggest that, when accounting for an individuals normal wake time, circadian rhythms of strength, temperature and muscle thickness are not apparent in most individuals. 
27019373	Peripheral clocks are essential for driving cell differentiation. In osteoarthritis, loss of the normal differentiated chondrocyte (cartilage cell) phenotype is causative of disease. We investigated whether clock gene expression differed in osteoarthritic compared to "healthy" chondrocytes and used RNAi to determine whether the differences observed could affect chondrocyte phenotype. Following serum shock, PER2 expression was significantly higher, whereas BMAL1 expression was significantly lower, in osteoarthritic chondrocytes. Knockdown of BMAL1 in "healthy" chondrocytes was associated with higher cell proliferation and MMP13 expression, features characteristic of the osteoarthritic chondrocyte phenotype. Chondrocyte-intrinsic clock disruption may be a critical early step in osteoarthritis development.
27019304	Biological rhythmicity is presumed to be an advantageous genetic adaptation of fitness and survival value resulting from evolution of life forms in an environment that varies predictably-in-time during the 24 h, month, and year. The 24 h light/dark cycle is the prime synchronizer of circadian periodicities, and its modulation over the course of the year, in terms of daytime photoperiod length, is a prime synchronizer of circannual periodicities. Circadian and circannual rhythms have been the major research focus of most scientists. Circa-monthly rhythms triggered or synchronized by the 29.5 day lunar cycle of nighttime light intensity, or specifically the light of the full moon, although explored in waterborne and certain other species, have received far less study, perhaps because of associations with ancient mythology and/or an attitude naturalistic studies are of lesser merit than ones that entail molecular mechanisms. In this editorial, we cite our recent discovery through multidisciplinary naturalistic investigation of a highly integrated circadian, circa-monthly, and circannual time structure, synchronized by the natural ambient nyctohemeral, lunar, and annual light cycles, of the Peruvian apple cactus (C. peruvianus) flowering and reproductive processes that occur in close temporal coordination with like rhythms of the honey bee as its pollinator. This finding led us to explore the preservation of this integrated biological time structure, synchronized and/or triggered by environmental light cues and cycles, in the reproduction of other species, including Homo sapiens, and how the artificial light environment of today in which humans reside may be negatively affecting human reproduction efficiency. 
27019198	Sleep restriction causes impaired cognitive performance that can result in adverse consequences in many occupational settings. Individuals may rely on self-perceived alertness to decide if they are able to adequately perform a task. It is therefore important to determine the relationship between an individual's self-assessed alertness and their objective performance, and how this relationship depends on circadian phase, hours since awakening, and cumulative lost hours of sleep. Healthy young adults (aged 18-34) completed an inpatient schedule that included forced desynchrony of sleep/wake and circadian rhythms with twelve 42.85-hour "days" and either a 1:2 (n = 8) or 1:3.3 (n = 9) ratio of sleep-opportunity:enforced-wakefulness. We investigated whether subjective alertness (visual analog scale), circadian phase (melatonin), hours since awakening, and cumulative sleep loss could predict objective performance on the Psychomotor Vigilance Task (PVT), an Addition/Calculation Test (ADD) and the Digit Symbol Substitution Test (DSST). Mathematical models that allowed nonlinear interactions between explanatory variables were evaluated using the Akaike Information Criterion (AIC). Subjective alertness was the single best predictor of PVT, ADD, and DSST performance. Subjective alertness alone, however, was not an accurate predictor of PVT performance. The best AIC scores for PVT and DSST were achieved when all explanatory variables were included in the model. The best AIC score for ADD was achieved with circadian phase and subjective alertness variables. We conclude that subjective alertness alone is a weak predictor of objective vigilant or cognitive performance. Predictions can, however, be improved by knowing an individual's circadian phase, current wake duration, and cumulative sleep loss. 
27017734	Renal sympathetic denervation (RSD) could be an effective antihypertensive treatment of resistant hypertension that triggers additional positive effects on glucose metabolism and insulin sensitivity in type 2 diabetes mellitus. We report the effects of RSD in a patient with chronic kidney disease, type 2 diabetes mellitus and resistant hypertension, manifesting as blood pressure reduction with dipping pattern restoration, followed by nephrotic proteinuria alleviation. The non-dipping blood pressure pattern and proteinuria increase the risk of cardiovascular complications and accelerate kidney disease progression. Thus, further research documenting the frequency and investigating the mechanisms of these effects reported after RSD in chronic kidney disease patients with type 2 diabetes mellitus and resistant hypertension is necessary for the benefit of this high-risk patient population.
27016480	In adipose tissue mTOR complex 2 (mTORC2) contributes to the regulation of glucose/lipid metabolism and inflammatory molecule expression. Both processes display diurnal variations during the course of the day. RICTOR and mSIN1 are unique and essential components of mTORC2, which is activated by growth factors including insulin. To assess whether mTORC2 components display diurnal variations, we analyzed steady state mRNA expression levels of Rictor, mSin1, and mTor in various adipose tissues during a 24 h period. Diurnally regulated expression of Rictor was detected in brown adipose tissues displaying highest mRNA expression levels at the beginning of the 12 h light period (zeitgeber time 2, ZT2). Gene expression patterns of mSin1 and mTor displayed a similar diurnal regulation as Rictor in PVAT while smaller changes were detected for these genes in aorta during the course of the day. Basal mTORC2 activity was measured by phosphorylation of protein kinase C (PKC) α at serine 657 was higher at ZT14 as compared with ZT2 in PVAT. In line, gene expression of inflammatory molecules nitric oxide synthase 2 and tumor necrosis factor α was lower at ZT 14 compared to ZT2. Our findings provide evidence for a diurnal regulation of expression of mTORC2 components and activity. Hence, mTORC2 is possibly an integral part of diurnally regulated signaling pathways in PVAT and possibly in other adipose tissues.
27015421	Increasing ozone concentrations have been known to damage human health and ecosystems. Although ozone tends to display diurnal variation, most studies have reported only on the association between daily ozone concentrations and ischemic stroke occurrence on the same day, or with a 1-day lag. We investigated the effect of the diurnal variation of ozone on ischemic stroke occurrence during the same day.We included a consecutive series of 1,734 patients from January 1, 2008, to December 31, 2014, at a single tertiary hospital in Seoul, South Korea. We evaluated differences between temperature and pollutants at the time of stroke onset for each time interval and averaged those parameters across the 7-year study period.	During the interval from 13:00 to 16:59, we found a positive association between ischemic stroke occurrence and ozone concentration relative to other time periods. Upper median ozone levels from 13:00 to 16:59 were positively correlated with ischemic stroke (odds ratio, 1.550; 95% confidence intervals, 1.220 to 1.970; P = <0.001) when compared with lower median levels.	The results show diurnal patterns of ischemic stroke occurrence based on upper and lower median ozone levels for a 24-hour period, which extends understanding of the association between stroke occurrence and environmental influences.	
27014564	The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Disruption of this transcriptional program leads to a variety of pathologies, including insomnia, depression and metabolic disorders. Circadian rhythms in gene expression rely on specific chromatin transitions which are ultimately coordinated by the molecular clock. As a consequence, a highly plastic and dynamic circadian epigenome can be delineated across different tissues and cell types. Intriguingly, genome topology appears to coordinate cyclic transcription at circadian interactomes, in which circadian genes are in physical contact within the cell nucleus in a time-specific manner. Moreover, the clock machinery shows functional interplays with key metabolic regulators, thereby connecting the circadian epigenome to cellular metabolism. Unraveling the molecular aspects of such interplays is likely to reveal new therapeutic strategies towards the treatment of metabolic disorders.
27014288	I summarize my scientific journey from my first interest in science to my career investigating how plants use the phytochrome photoreceptor to regulate what genes they express. I then describe how this work led to an understanding of how circadian rhythms function in plants and to the discovery of CCA1, a component of the plant central oscillator. 
27014255	Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota-gut-brain axis and the role of microbiota as a "peacekeeper" in the brain health. Here, we review recent discoveries on the role of the gut microbiota in central nervous system-related diseases. We also discuss the emerging concept of the bidirectional regulation by the circadian rhythm and gut microbiota, and the potential role of the epigenetic regulation in neuronal cell function. Microbiome studies are also highlighted as crucial in the development of targeted therapies for neurodevelopmental disorders. 
27013671	Circadian clocks enable organisms to anticipate and adapt to fluctuating environmental conditions. Despite substantial knowledge of central clock machineries, we have less understanding of how the central clock's behavioral outputs are regulated. Here, we identify Drosophila miR-124 as a critical regulator of diurnal activity. During normal light/dark cycles, mir-124 mutants exhibit profoundly abnormal locomotor activity profiles, including loss of anticipatory capacities at morning and evening transitions. Moreover,mir-124 mutants exhibited striking behavioral alterations in constant darkness (DD), including a temporal advance in peak activity. Nevertheless, anatomical and functional tests demonstrate a normal circadian pacemaker in mir-124 mutants, indicating this miRNA regulates clock output. Among the extensive miR-124 target network, heterozygosity for targets in the BMP pathway substantially corrected the evening activity phase shift in DD. Thus, excess BMP signaling drives specific circadian behavioral output defects in mir-124 knock-outs.Circadian clocks control rhythmic behaviors of most life-forms. Despite extensive knowledge of the central clock, there is less understanding of how its behavioral outputs are regulated. Here, we identify a conserved neural microRNA as a critical regulator of diurnal behavior. We find Drosophila mir-124 mutants exhibit robust activity abnormalities during normal light/dark cycles and during constant darkness. Nevertheless, as the central pacemaker is functional in these mutants, miR-124 regulates clock output. We provide mechanistic insight by showing deregulation of miR-124 targets in BMP signaling drives specific mir-124 defects. In summary,Drosophila mir-124 mutants reveal post-transcriptional control of circadian activities, and impact of BMP signaling in behavioral output.	
27012888	The reduction of predation risk is widely considered a major factor affecting the nocturnal activity of mammals. Furthermore, on precipitous mountain terrain, moving in very poor light conditions should be avoided by animals with no special eyesight adaptation to darkness. The Northern chamois Rupicapra rupicapra has been for long considered as a diurnal species, with occasional nocturnal movements. For the first time, we have quantified the nocturnal activity of 21 radiotagged female chamois from the Italian Eastern Alps (Paneveggio-Pale di San Martino Natural Park), continuously monitored for two years from sunset to sunrise, with 24h tracking sessions carried out for six months. Large predators were not present in the study site. Despite their mainly diurnal activity pattern, peaks of nocturnal movements were detected throughout the year. The least proportion of active night fixes occurred in January and in July, while the most were in April and in October. The greater nocturnal activity in the warm months compared to cold periods, was probably due to frozen snow cover reducing nocturnal movements. Movements were mainly concentrated in bright moonlight nights, possibly because of the absence of large predators, but more likely because of increased visibility. Changes in activity levels throughout the year may also reflect changes in energy requirements of Northern chamois. 
27012868	Seasonal timing is assumed to involve the circadian clock, an endogenous mechanism to track time and measure day length. Some debate persists, however, and aphids were among the first organisms for which circadian clock involvement was questioned. Inferences about links to phenology are problematic, as the clock itself is little investigated in aphids. For instance, it is unknown whether aphids possess diurnal rhythms at all. Possibly, the close interaction with host plants prevents independent measurements of rhythmicity. We reared the pea aphid Acyrthosiphon pisum(Harris) on an artificial diet, and recorded survival, moulting, and honeydew excretion. Despite their plant-dependent life style, aphids were independently rhythmic under light-dark conditions. This first demonstration of diurnal aphid rhythms shows that aphids do not simply track the host plant's rhythmicity.
27012691	This study was designed to examine diurnal variations in tear film break-up time (BUT) and maximum blink interval (MBI) and to assess two different ways of calculating these variables on video recordings of the BUT test interpreted with the help of especially designed software. The repeatability of interpreting BUT video recordings was also addressed.Twenty-six healthy young adults were enrolled after ruling out dry eye according to a battery of tests (ocular surface disease index, McMonnies questionnaire, Schirmer test, phenol red test and corneal staining). BUT and maximum blink interval were determined on video-recordings of the BUT test conducted over a day in four sessions (9.30 am, 12.30 pm, 3.30 pm and 6.30 pm). In each session, the test was repeated three times to give three videos in which three BUT and MBI values were obtained by a masked observer. BUT and MBI were determined by averaging the three measurements and by averaging only the two closest measurements. Finally, two further experienced observers re-examined the videos to assess the repeatability of the BUT measurements made.	No diurnal variation in BUT was observed regardless of whether three or two video measurements were averaged. Significant correlation was detected between BUT and MBI. Inter-observer repeatability was better when BUT times were no longer than 15 seconds.	Tear film BUT was not influenced by the time of day and moderate to strong correlation with MBI was observed in all four sessions. The software-assisted method proved useful and identified the need to clarify the BUT end-point and to limit the test to 15 seconds to improve observer repeatability.	
27012281	As most organisms age, their appearance, physiology, and behaviour alters as part of a life history strategy that maximizes their fitness over their lifetime. The passage of time is measured by organisms and is used to modulate these age-related changes. Organisms have an endogenous time measurement system called the circadian clock. This endogenous clock regulates many physiological responses throughout the life history of organisms to enhance their fitness. However, little is known about the relation between ageing and the circadian clock in plants. Here, we investigate the association of leaf ageing with circadian rhythm changes to better understand the regulation of life-history strategy in Arabidopsis. The circadian periods of clock output genes were approximately 1h shorter in older leaves than younger leaves. The periods of the core clock genes were also consistently shorter in older leaves, indicating an effect of ageing on regulation of the circadian period. Shortening of the circadian period with leaf age occurred faster in plants grown under a long photoperiod compared with a short photoperiod. We screened for a regulatory gene that links ageing and the circadian clock among multiple clock gene mutants. Only mutants for the clock oscillator TOC1 did not show a shortened circadian period during leaf ageing, suggesting that TOC1 may link age to changes in the circadian clock period. Our findings suggest that age-related information is incorporated into the regulation of the circadian period and that TOC1 is necessary for this integrative process. 
27012036	Plasma PTH levels are normally high during the night and early morning and lowest at approximately 10 am (the PTH circadian rhythm). Our objective was to examine the relationship between the PTH circadian rhythm and calcium-phosphorus metabolism in non-dialyzed, chronic kidney disease (CKD) patients.The characteristics of twenty-eight subjects comprised: male, 23; diabetic patients, 16; mean age, 71.1 +/- 10.5 years; mean eGFR, 18.3 +/- 8.1 mL/min/1.73 m2. Under a protein-restricted diet, plasma intact PTH (iPTH) was measured at 7 am (iPTH7), 10 am (iPTH10), and 10 pm (iPTH22). Serum concentrations of calcium (Ca), phosphate (Pi), 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25[OH]2D), and fibroblast growth factor (FGF)-23 were measured at 7 am. A normal iPTH rhythm was defined as when both iPTH7 and iPTH22 exceeded iPTH10. When iPTH10 was equal to, or exceeded either iPTH7 or iPTH22, or both, the rhythm was considered abnormal.	Median levels of iPTH7, iPTH10, and iPTH22 were 92.5 [IQR: 60.8-152.01, 85.5 [61.0-144.5], and 95.5 164.3-160.5] pg/mL, respectively. Sixteen subjects showed an abnormal iPTH rhythm. There was no significant difference between groups in age, eGFR, iPTH7, iPTH10, iPTH22, Pi, 25-OH1D, 1,25(OH)2D, or FGF-23. However, the abnormal group showed significantly higher mean levels of corrected Ca as compared to the normal group (9.50 +/- 0.42 vs. 9.18 +/- 0.28; p = 0.032).	Abnormal diurnal patterns of PTH are associated with sustained mild hypercalcemia in nondialyzed chronic kidney disease patients. This abnormal rhythm was not associated with Pi or FGF-23, and this may be an independent risk factor for CKD-mineral and bone disorder.	
27011178	Chronic pruritus is a debilitating condition with numerous etiologies. Many patients suffer from nocturnal pruritus, which can decrease quality of life and affect mortality in hemodialysis patients. Nocturnal pruritus may occur in all sleep stages but is most prevalent in stages N1 and N2. Further research is needed to elucidate the pathophysiology of nocturnal itch, which will aid in the development of tailored management strategies. 
27010676	It seems that seeing others in slow-motion by heroes does not belong only to movies. When Lionel Messi plays football, you can hardly see anything from him that other players cannot do. Then why he is not stoppable really? It seems the answer may be that opponents do not have enough time to do what they want; because in Messi's neural system, time passes slower. In differential equations that model a single neuron, this speed can be generated by multiplying an equal term in all equations. Or maybe interactions between neurons and the structure of neural networks play this role. 
27010605	Cancer cells have broken circadian clocks when compared to their normal tissue counterparts. Moreover, it has been shown in breast cancer that disruption of common circadian oscillations is associated with a more negative prognosis. Numerous studies, focused on canonical circadian genes in breast cancer cell lines, have suggested that there are no mRNA circadian-like oscillations. Nevertheless, cancer cell lines have not been extensively characterized and it is unknown to what extent the circadian oscillations are disrupted. We have chosen representative non-cancerous and cancerous breast cell lines (MCF-10A, MCF-7, ZR-75-30, MDA-MB-231 and HCC-1954) in order to determine the degree to which the circadian clock is damaged. We used serum shock to synchronize the circadian clocks in culture. Our aim was to initially observe the time course of gene expression using cDNA microarrays in the non-cancerous MCF-10A and the cancerous MCF-7 cells for screening and then to characterize specific genes in other cell lines. We used a cosine function to select highly correlated profiles. Some of the identified genes were validated by quantitative polymerase chain reaction (qPCR) and further evaluated in the other breast cancer cell lines. Interestingly, we observed that breast cancer and non-cancerous cultured cells are able to generate specific circadian expression profiles in response to the serum shock. The rhythmic genes, suggested via microarray and measured in each particular subtype, suggest that each breast cancer cell type responds differently to the circadian synchronization. Future results could identify circadian-like genes that are altered in breast cancer and non-cancerous cells, which can be used to propose novel treatments. Breast cell lines are potential models for in vitro studies of circadian clocks and clock-controlled pathways. 
27010525	Light is the strongest synchronizer of human circadian rhythms, and exposure to residential light at night reportedly causes a delay of circadian rhythms. The present study was conducted to investigate the association between color temperature of light at home and circadian phase of salivary melatonin in adults and children. Twenty healthy children (mean age: 9.7 year) and 17 of their parents (mean age: 41.9 years) participated in the experiment. Circadian phase assessments were made with dim light melatonin onset (DLMO). There were large individual variations in DLMO both in adults and children. The average DLMO in adults and in children were 21:50 ± 1:12 and 20:55 ± 0:44, respectively. The average illuminance and color temperature of light at eye level were 139.6 ± 82.7 lx and 3862.0 ± 965.6 K, respectively. There were significant correlations between color temperature of light and DLMO in adults (r = 0.735, p < 0.01) and children (r = 0.479, p < 0.05), although no significant correlations were found between illuminance level and DLMO. The results suggest that high color temperature light at home might be a cause of the delay of circadian phase in adults and children. 
27010449	Calbindin-D(28K) (Calb1), a high-affinity calcium buffer/sensor, shows abundant expression in neurons and has been associated with a number of neurobehavioral diseases, many of which are sexually dimorphic in incidence. Behavioral and physiological end points are affected by experimental manipulations of calbindin levels, including disruption of spatial learning, hippocampal long-term potentiation, and circadian rhythms. In this study, we investigated novel aspects of calbindin function on social behavior, anxiety-like behavior, and fear conditioning in adult mice of both sexes by comparing wild-type to littermate Calb1 KO mice. Because Calb1 mRNA and protein are sexually dimorphic in some areas of the brain, we hypothesized that sex differences in behavioral responses of these behaviors would be eliminated or revealed in Calb1 KO mice. We also examined gene expression in the amygdala and prefrontal cortex, two areas of the brain intimately connected with limbic system control of the behaviors tested, in response to sex and genotype. Our results demonstrate that fear memory and social behavior are altered in male knockout mice, and Calb1 KO mice of both sexes show less anxiety. Moreover, gene expression studies of the amygdala and prefrontal cortex revealed several significant genotype and sex effects in genes related to brain-derived neurotrophic factor signaling, hormone receptors, histone deacetylases, and γ-aminobutyric acid signaling. Our findings are the first to directly link calbindin with affective and social behaviors in rodents; moreover, the results suggest that sex differences in calbindin protein influence behavior. 
27010443	The circadian timing system regulates key aspects of mammalian physiology. Here, we analyzed the effect of the endogenous antioxidant paraoxonase 1 (PON1), a high-density lipoprotein-associated lipolactonase that hydrolyses lipid peroxides and attenuates atherogenesis, on circadian gene expression in C57BL/6J and PON1KO mice fed a normal chow diet or a high-fat diet (HFD). Expression levels of core-clock transcripts Nr1d1, Per2, Cry2 and Bmal1 were altered in skeletal muscle in PON1-deficient mice in response to HFD. These findings were supported by circadian bioluminescence reporter assessments in mouse C2C12 and human primary myotubes, synchronized in vitro, where administration of PON1 or pomegranate juice modulated circadian period length. 
27010376	Month of birth (MOB) has been linked to a variety of health conditions in adulthood. This study examined the association between MOB and mortality among the healthy elderly in Japan, where a practice of traditional age reckoning was employed up until the late 1940s. The results showed male participants born in December were more likely to die earlier while those born in January had lower mortality. It is possible that social factors in early life, such as the time period when a birth is officially registered, may have implications for health that stretch across the life course. 
27010328	As in general, technological inventions also drive the development in the field of toxicology and ecotoxicology. In the past decade, gene expression analysis has become a universally applied technology allowing many insights into toxicological pathways of environmental contaminants. Due to the novel technologies, including quantitative determination of mRNA by quantitative reverse transcription analysis (qRT-PCR), and semiquantitative methods, such as microarrays and RNA-sequencing technologies, toxicological profiles of contaminants could be identified. For instance, gene expression analysis of genes associated with the hypothalamic-pituitary-gonadal axis (HPG axis) in fish had become a conventional end point for endocrine disrupting chemicals. While these gene expression data provide novel insights into identifying potential toxicological end points and molecular mechanisms, often not enough attention is given to the question of mRNA stabilities and reliabilities of transcriptional data, in particular when links to physiological effects are difficult to make. A crucial factor in this issue is the endogenous circadian oscillations of genes during sampling. 
27009620	Recent literature suggests that blood pressure variability (BPV) predicts outcome beyond blood pressure level (BPL) and that antihypertensive drug classes differentially influence BPV. We compared calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockade for effects on changes in self-measured home BPL and BPV and for their prognostic significance in newly treated hypertensive patients.We enrolled 2484 patients randomly allocated to first-line treatment with a calcium channel blocker (n=833), an angiotensin-converting enzyme inhibitor (n=821), or angiotensin receptor blockade (n=830). Home blood pressures in the morning and evening were measured for 5 days off treatment before randomization and for 5 days after 2 to 4 weeks of randomized drug treatment. We assessed BPL and BPV changes as estimated by variability independent of the mean and compared cardiovascular outcomes. Home BPL response in each group was significant (P≤0.0001) but small in the angiotensin-converting enzyme inhibitor group (systolic/diastolic: 4.6/2.8 mm Hg) compared with the groups treated with a calcium channel blocker (systolic/diastolic: 8.3/3.9 mm Hg) and angiotensin receptor blockade (systolic/diastolic: 8.2/4.5 mm Hg). In multivariable adjusted analyses, changes in home variability independent of the mean did not differ among the 3 drug classes (P≥0.054). Evening variability independent of the mean before treatment significantly predicted hard cardiovascular events independent of the corresponding home BPL (P≤0.022), whereas BPV did not predict any cardiovascular outcome based on the morning measurement (P≥0.056). Home BPV captured after monotherapy had no predictive power for cardiovascular outcome (P≥0.22).	Self-measured home evening BPV estimated by variability independent of the mean had prognostic significance, whereas antihypertensive drug classes had no significant impact on BPV changes. Home BPL should remain the primary focus for risk stratification and treatment.	URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000137.	
27008901	Many patients with depressive disorders experience symptoms in relation to sleep behavior and daily rhythmicity. However, the multifaceted associations between sleep, depression and circadian rhythms are not fully understood. During the past years, the concept of chronotypehas become increasingly popular in research. The Munich Chronotype Questionnaire (MCTQ) derives chronotype from sleep timing on work-free days and therefore represents a biological measure for the circadian clock, whereas the Morningness-Eveningness-Questionnaire(MEQ) assesses chronotype as a subjective preference for different activities at specific times of day. Chronotype changes with age, with adolescents and young adults being especially late types. We conducted a systematic literature research and identified studies that explore the association between chronotype (MEQ, MCTQ) and depressive symptoms or depressive disorders. Most of the studies showed an association between a late chronotype and depressive symptomatology. However, it is still unclear what is cause and effect. We propose a bidirectional relationship: On the one hand, due to reduced social and physical activity, depressed patients get less daylight which causes their chronotype to delay. On the other hand, a discrepancy between internal time (directed by the circadian clock) and external time (such as early school- or works tarting times) can cause problems
27008791	The diversity-stability relationship has been under intense scrutiny for the past decades, and temporal asynchrony is recognized as an important aspect of ecosystem stability. In contrast to relatively well-studied interannual and seasonal asynchrony, few studies investigate the role of circadian cycles for ecosystem stability. Here, we studied multifunctional redundancy of diurnal and nocturnal ant communities in four tropical rain forest sites. We analyzed how it was influenced by species richness, functional performance, and circadian asynchrony. In two neotropical sites, species richness and functional redundancy were lower at night. In contrast, these parameters did not differ in the two paleotropical sites we studied. Circadian asynchrony between species was pronounced in the neotropical sites, and increased circadian functional redundancy. In general, species richness positively affected functional redundancy, but the effect size depended on the temporal and spatial breadth of the species with highest functional performance. Our analysis shows that high levels of trophic performance were only reached through the presence of such high-performing species, but not by even contributions of multiple, less-efficient species. Thus, these species can increase current functional performance, but reduce overall functional redundancy. Our study highlights that diurnal and nocturnal ecosystem properties of the very same habitat can markedly differ in terms of species richness and functional redundancy. Consequently, like the need to study multiple ecosystem functions, multiple periods of the circadian cycle need to be assessed in order to fully understand the diversity-stability relationship in an ecosystem.
27008404	The hypocretin/orexin neuropeptides (hcrt) are key players in the control of sleep and wakefulness evidenced by the fact that lack of hcrt leads to the sleep disorder Narcolepsy Type 1. Sleep disturbances are common in mood disorders, and hcrt has been suggested to be poorly regulated in depressed subjects. To study seasonal variation in hcrt levels, we obtained data on hcrt-1 levels in the cerebrospinal fluid (CSF) from 227 human individuals evaluated for central hypersomnias at a Danish sleep center. The samples were taken over a 4 year timespan, and obtained in the morning hours, thus avoiding impact of the diurnal hcrt variation. Hcrt-1 concentration was determined in a standardized radioimmunoassay. Using biometric data and sleep parameters, a multivariate regression analysis was performed. We found that the average monthly CSF hcrt-1 levels varied significantly across the seasons following a sine wave with its peak in the summer (June-July). The amplitude was 19.9 pg hcrt/mL [12.8-26.9] corresponding to a 10.6% increase in midsummer compared to winter. Factors found to significantly predict the hcrt-1 values were day length, presence of snow, and proximity to the Christmas holiday season. The hcrt-1 values from January were much higher than predicted from the model, suggestive of additional factors influencing the CSF hcrt-1 levels such as social interaction. This study provides evidence that human CSF hcrt-1 levels vary with season, correlating with day length. This finding could have implications for the understanding of winter tiredness, fatigue, and seasonal affective disorder. This is the first time a seasonal variation of hcrt-1 levels has been shown, demonstrating that the hcrt system is, like other neurotransmitter systems, subjected to long term modulation. 
27007274	Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with diverse adverse health outcomes, making it an important therapeutic target. Measurement of the diurnal rhythm of cortisol secretion provides a window into this system. At present, no guidelines exist for the optimal use of this biomarker within randomised controlled trials (RCTs).The aim of this study is to describe the ways in which salivary diurnal cortisol has been measured within RCTs of health or behavioural interventions in adults.	Six electronic databases (up to May 21, 2015) were systematically searched for RCTs which used salivary diurnal cortisol as an outcome measure to evaluate health or behavioural interventions in adults. A narrative synthesis was undertaken of the findings in relation to salivary cortisol methodology and outcomes.	From 78 studies that fulfilled the inclusion criteria, 30 included healthy participants (38.5 %), 27 included patients with physical disease (34.6 %) and 21 included patients with psychiatric disease (26.9 %). Psychological therapies were most commonly evaluated (n = 33, 42.3 %). There was substantial heterogeneity across studies in relation to saliva collection protocols and reported cortisol parameters. Only 39 studies (50 %) calculated a rhythm parameter such as the diurnal slope or the cortisol awakening response (CAR). Patterns of change in cortisol parameters were inconsistent both within and across studies and there was low agreement with clinical findings.	Salivary diurnal cortisol is measured inconsistently across RCTs, which is limiting the interpretation of findings within and across studies. This indicates a need for more validation work, along with consensus guidelines.	
27007073	Sex differences in glucocorticoid production are associated with increased responsiveness of the adrenal gland in females. However, the adrenal-intrinsic mechanisms that establish sexual dimorphic function remain ill defined. Glucocorticoid production is gated at the molecular level by the circadian clock, which may contribute to sexual dimorphic adrenal function. Here we examine sex differences in the adrenal gland using an optical reporter of circadian clock function. Adrenal glands were cultured from male and female Period2::Luciferase (PER2::LUC) mice to assess clock function in vitro in real time. We confirm that there is a pronounced sex difference in the intrinsic capacity to sustain PER2::LUC rhythms in vitro, with higher amplitude rhythms in adrenal glands collected from males than from females. Changes in adrenal PER2::LUC rhythms over the reproductive life span implicate T as an important factor in driving sex differences in adrenal clock function. By directly manipulating hormone levels in adult mice in vivo, we demonstrate that T increases the amplitude of PER2::LUC rhythms in adrenal glands of both male and female mice. In contrast, we find little evidence that ovarian hormones modify adrenal clock function. Lastly, we find that T in vitro can increase the amplitude of PER2::LUC rhythms in male adrenals but not female adrenals, which suggests the existence of sex differences in the mechanisms of T action in vivo. Collectively these results reveal that activational effects of T alter circadian timekeeping in the adrenal gland, which may have implications for sex differences in stress reactivity and stress-related disorders. 
27003747	The melanopsin system consists of intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (mRGCs). These mRGCs mediate several non-image-forming visual functions, including light entrainment of circadian rhythms. Here we evaluate age-related alterations of the melanopsin system and circadian rhythms in P23H line 1 (P23H-1) rats, a rodent model of retinitis pigmentosa (RP). In homozygous P23H-1 rats and wild-type control rats from the same genetic background (Sprague-Dawley), body temperature and locomotor activity were continuously monitored at 10-min intervals for 7 days, once every 4-5 weeks, between 2 and 24 months of age, using a telemetry transmitter. The distribution and number of mRGCs were assessed in control rats at 12, 18, and 24 months of age and in P23H-1 rats aged 12, 18, 24, and 30 months by immunostaining whole-mount retinas with antibodies against melanopsin. The mean density of mRGCs in control rats showed no significant variations when evaluated at 12 and 18 months of age, and fell by approximately 56% between 18 and 24 months of age. Meanwhile, a significant decrease in the mean number of mRGCs was found in 18-month-old P23H-1 rats as compared to 18-month-old control rats (81% decrease). Parametric and non-parametric analyses of the records showed a gradual age-dependent weakening of body temperature and locomotor activity circadian rhythms robustness in both control and P23H-1 rats from 2 to 24 months of age. However, body temperature and locomotor activity circadian patterns were less robust throughout the experiment in P23H-1 as compared to control rats, with lower amplitude, weaker coupling strength to environmental zeitgebers and higher fragmentation of the rhythms. The present study shows that the degeneration of photoreceptors and inner retinal neurons, characteristic of RP, has age-related degenerative effects on the melanopsin system and is associated with weaker circadian patterns. 
27003694	Tasimelteon (Hetlioz(®)) is a dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) (free-running disorder). In two randomized, double-masked, multicentre, phase III trials, totally blind individuals with Non-24 who received oral tasimelteon 20 mg once nightly were significantly more likely than those receiving placebo to entrain the circadian pacemaker (the SET trial) and maintain entrainment (the RESET trial). Sleep/wake parameters and functioning were also improved with tasimelteon. Oral tasimelteon was generally well tolerated in totally blind patients with Non-24. In conclusion, tasimelteon is a useful drug for the treatment of Non-24 in totally blind individuals. 
27003630	The organizing committee of the 2016 Rio Olympic Games recently announced that some of the preliminary and final competitions will be held at night. The present article discusses the potential harmful effects of these late-night competitions on sleep, circadian rhythms and athletic performance during the Olympic Games. Specifically, night-time competition could lead to injury and may compromise an athlete's decision-making, attentional, physiological and other processes. Consequently, these impacts could negatively affect the performance of athletes and their teams. Thus, it is suggested that technical commissions take special care when creating strategies to minimize harm to the athletes by considering factors such as light exposure, melatonin intake, sleep hygiene and scheduled naps, and training at local competition time. Furthermore, it is necessary for specialists in chronobiology and sleep to engage with members of the national teams to develop an activity schedule for physical, technical, tactical and psychological preparation that accounts for circadian rhythms, thereby creating the best possible environment for the athletes to achieve their ideal performance. 
27003509	Bipolar disorder (BD) is a severe and common psychiatric disorder. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. Lithium (Li) is the first-line treatment in BD, and its therapeutic action has been related to its ability to alter circadian rhythms. We systematically searched the PubMed database until January 2016, aiming to critically examine published studies investigating direct and indirect effects of Li on circadian rhythms. The results, from the 95 retained studies, indicated that Li: acts directly on the molecular clocks; delays the phase of sleep-wakefulness rhythms and the peak elevation of diurnal cycle body temperature; reduces the amplitude and shortens the duration of activity rhythms and lengthens free-running rhythms. Chronic Li treatment stabilizes free-running activity rhythms, by improving day-to-day rhythmicity of the activity, with effects that appear to be dose related. Pharmacogenetics demonstrate several associations of Li's response with circadian genes (NR1D1, GSK3β, CRY1, ARNTL, TIM, PER2). Finally, Li acts on the retinal-hypothalamic pineal pathway, influencing light sensitivity and melatonin secretion. Li is a highly investigated chronobiologic agent, and although its chronobiological effects are not completely understood, it seems highly likely that they constitute an inherent component of its therapeutic action in the treatment of mood disorders. 
27003385	Sleep and its impact on physiology and pathophysiology are researched at an accelerating pace and from many different angles. Experiments provide evidence for chronobiologically plausible links between chronodisruption and sleep and circadian rhythm disruption (SCRD), on the one hand, and the development of cancer, on the other. Epidemiological evidence from cancer incidence among some 1 500 000 study individuals in 13 countries regarding associations with sleep duration, napping or "poor sleep" is variable and inconclusive. Combined adjusted relative risks (meta-RRs) for female breast cancer, based on heterogeneous data, were 1.01 (95% CI: 0.97-1.06). Meta-RRs for cancers of the colorectum and of the lung in women and men and for prostate cancer were 1.08 (95% CI: 1.03-1.13), 1.11 (95% CI: 1.00-1.22) and 1.05 (95% CI: 0.83-1.33), respectively. The significantly increased meta-RRs for colorectal cancer, based on homogeneous data, warrant targeted study. However, the paramount epidemiological problem inhibiting valid conclusions about the associations between sleep and cancer is the probable misclassification of the exposures to facets of sleep over time. Regarding the inevitable conclusion that more research is needed to answer How are sleep and cancer linked in humans? we offer eight sets of recommendations for future studies which must take note of the complexity of multidirectional relationships. 
27002152	The circadian system in Neurospora is based on the transcriptional/translational feedback loops and rhythmic frequency (frq) transcription requires the WHITE COLLAR (WC) complex. Our previous paper has shown that frq could be transcribed in a WC-independent pathway in a strain lacking the histone H3K36 methyltransferase, SET-2 (su(var)3-9-enhancer-of-zeste-trithorax-2) (1), but the mechanism was unclear. Here we disclose that loss of histone H3K36 methylation, due to either deletion of SET-2 or H3K36R mutation, results in arrhythmic frq transcription and loss of overt rhythmicity. Histone acetylation at frq locus increases in set-2(KO) mutant. Consistent with these results, loss of H3K36 methylation readers, histone deacetylase RPD-3 (reduced potassium dependence 3) or EAF-3 (essential SAS-related acetyltransferase-associated factor 3), also leads to hyperacetylation of histone at frq locus and WC-independent frq expression, suggesting that proper chromatin modification at frq locus is required for circadian clock operation. Furthermore, a mutant strain with three amino acid substitutions (histone H3 lysine 9, 14, and 18 to glutamine) was generated to mimic the strain with hyperacetylation state of histone H3. H3K9QK14QK18Q mutant exhibits the same defective clock phenotype as rpd-3(KO) mutant. Our results support a scenario in which H3K36 methylation is required to establish a permissive chromatin state for circadian frq transcription by maintaining proper acetylation status at frq locus. 
27001715	Illumina-based RNA-seq was used to determine the short-term transcriptomic responses of Paralichthys olivaceus gill to an environmentally relevant level of water accommodated fraction (WAF) of crude oil. 213,979 transcripts and 128,482 unigenes were obtained. Differential expression analysis revealed that 1641 and 2142 genes were significantly up- and down-regulated. Enrichment analysis identified a set of GO terms and putative pathways involved in the response of P. olivaceus to WAF exposure. Analysis of the transcripts revealed the effective protective mechanisms of P. olivaceus to reduce the toxic effects of WAF. Moreover, WAF exposure induced the metabolism of energy substrates, and downstream pathway genes were modified to provide protection against toxic damage. Transcripts analysis demonstrated that the genes involved in circadian rhythm signaling were regulated in gills of P. olivaceus exposed to WAF. These results provide insights into the mechanisms of WAF-induced toxicity in fishes and into the WAF-sensitive biomarkers in P. olivaceus. 
27001299	Patients often have lower (white coat effect) or higher (masked effect) ambulatory/home blood pressure readings compared with clinic measurements, resulting in misdiagnosis of hypertension. The present study assessed whether blood pressure and patient characteristics from a single clinic visit can accurately predict the difference between ambulatory/home and clinic blood pressure readings (the home-clinic difference). A linear regression model predicting the home-clinic blood pressure difference was derived in 2 data sets measuring automated clinic and ambulatory/home blood pressure (n=991) using candidate predictors identified from a literature review. The model was validated in 4 further data sets (n=1172) using area under the receiver operator characteristic curve analysis. A masked effect was associated with male sex, a positive clinic blood pressure change (difference between consecutive measurements during a single visit), and a diagnosis of hypertension. Increasing age, clinic blood pressure level, and pulse pressure were associated with a white coat effect. The model showed good calibration across data sets (Pearson correlation, 0.48-0.80) and performed well-predicting ambulatory hypertension (area under the receiver operator characteristic curve, 0.75; 95% confidence interval, 0.72-0.79 [systolic]; 0.87; 0.85-0.89 [diastolic]). Used as a triaging tool for ambulatory monitoring, the model improved classification of a patient's blood pressure status compared with other guideline recommended approaches (93% [92% to 95%] classified correctly; United States, 73% [70% to 75%]; Canada, 74% [71% to 77%]; United Kingdom, 78% [76% to 81%]). This study demonstrates that patient characteristics from a single clinic visit can accurately predict a patient's ambulatory blood pressure. Usage of this prediction tool for triaging of ambulatory monitoring could result in more accurate diagnosis of hypertension and hence more appropriate treatment. 
27000098	Recent findings revealed negative effects of deregulated molecular circadian rhythm in coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). Physical exercise training (ET) has been shown to promote anti-diabetic and anti-atherogenic responses in skeletal muscle of these patients, but the role of the circadian clock-machinery remains unknown. This study investigated whether mRNA expression of clock genes in skeletal muscle of CAD and T2DM patients is influenced by physical ET intervention.Nineteen patients with CAD and T2DM (age 64 ± 5 years) were randomised to either six months of ET (four weeks of in-hospital ET followed by a five-month ambulatory programme) or usual care. At the beginning of the study, after four weeks and after six months parameters of metabolic and cardiovascular risk factors, and physical exercise capacity were assessed. Gene expression was measured in skeletal muscle biopsies by quantitative real-time polymerase chain reaction (PCR).	A selection of clock genes and associated components (circadian locomoter output cycle kaput protein (CLOCK), period (PER) 1, cryptochrome (CRY) 2 and aminolevulinate-deltA-synthase-1 (ALAS1)) was reliably measured and used for further analysis. A time-dependent effect in gene expression was observed in CLOCK (p = 0.013) and a significant interaction between time and intervention was observed for ALAS1 (p = 0.032; p = 0.014) as a result of ET.	This is the first study to analyse clock gene expression in skeletal muscles of patients with CAD and T2DM participating in a long-lasting exercise intervention. ET, as one of the cornerstones in prevention and rehabilitation of CAD and T2DM, exerts no effects on CLOCK genes but meaningful effects on the clock-associated gene ALAS1.	
26999106	The limited effects of currently available antidepressants are becoming an urgent issue in depression research. It takes a long time to determine treatment effects, and the overall remission rate is low. Although we expect the development of non-monoamine antidepressants in the near future, efforts in this regard over the past several decades have not yet been compensated. Thus, researchers and clinicians should clarify the neurobiological mechanisms of integrated modulators that regulate changes in genes, cells, the brain, and behaviors associated with depression. In this study, we review molecular neurobiological theories and new treatments for depression. Beyond neuroanatomy and monoamine theory, we discuss cells and molecules, neural plasticity, neurotrophisms, endocrine mechanisms, immunological mechanisms, genetics, circadian rhythms, and metabolic regulation in depression. In addition, we introduce the possibility of new antidepressant drug development using protein translation signaling (mTOR) pathways. 
26998345	Insects show daily behavioral rhythms controlled by an endogenous oscillator, the circadian clock. The rhythm synchronizes to daily light-dark cycles (LD) and changes waveform in association with seasonal change in photoperiod.To explore the molecular basis of the photoperiod-dependent changes in circadian locomotor rhythm, we investigated the role of a chromatin modifier, Enhancer of zeste (Gb'E(z)), in the cricket, Gryllus bimaculatus. Under a 12 h:12 h LD (LD 12:12), Gb'E(z) was constitutively expressed in the optic lobe, the site of the biological clock; active phase (α) and rest phase (ρ) were approximately 12 h in duration, and α/ρ ratio was approximately 1.0. When transferred to LD 20:4, the α/ρ ratio decreased significantly, and the Gb'E(z) expression level was significantly reduced at 6 h and 10 h after light-on, as was reflected in the reduced level of trimethylation of histone H3 lysine 27. This change was associated with change in clock gene expression profiles. The photoperiod-dependent changes in α/ρ ratio and clock gene expression profiles were prevented by knocking down Gb'E(z) by RNAi.	These results suggest that histone modification by Gb'E(z) is involved in photoperiodic modulation of the G. bimaculatus circadian rhythm.	
26996255	During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.
26994616	Fasting is one of the recommended worships of several great religions in the world. During the month of Ramadan, circadian rhythm and pattern of eating changes result in physiological, biochemical and hormonal changes in the body. Many Muslims with medical conditions ask their physicians about the feasibility and safety of fasting during Ramadan. In this study, we aim to assess the effect of Ramadan fasting on the quality of life and fatigue in multiple sclerosis (MS) patients. Relapsing-remitting MS (RRMS) patients according to McDonald's criteria who had mild disability (EDSS score ≤3) were included in this study. Fatigue and quality of life were were assessed using the validated Persian versions of modified fatigue impact scale (MFIS) and multiple sclerosis quality of life-54 (MSQOL-54) questionnaires, respectively. 218 patients (150 females and 68 males) were enrolled in our study. There was no statistically significant difference between the mean total score of MSIF before and after fasting (25.50 ± 13.81 versus 26.94 ± 16.65; p = 0.58). The mean physical health and mental health composites of quality of life increased significantly after fasting (p = 0.008 and p = 0.003 respectively). Despite the observed lack of favorable effects on fatigue, our results showed increased quality of life of MS patients once Ramadan has ended. Whether this is specifically related to Ramadan-related fasting deserves further testing in appropriately designed larger prospective clinical studies. 
26994450	Review the literature on excessive crying in young infants, also known as infantile colic, and its effects on family dynamics, its pathophysiology, and new treatment interventions.The literature review was carried out in the Medline, PsycINFO, LILACS, SciELO, and Cochrane Library databases, using the terms "excessive crying," and "infantile colic," as well technical books and technical reports on child development, selecting the most relevant articles on the subject, with emphasis on recent literature published in the last five years.	Excessive crying is a common symptom in the first 3 months of life and leads to approximately 20% of pediatric consultations. Different prevalence rates of excessive crying have been reported, ranging from 14% to approximately 30% in infants up to 3 months of age. There is evidence linking excessive crying early in life with adaptive problems in the preschool period, as well as with early weaning, maternal anxiety and depression, attention deficit hyperactivity disorder, and other behavioral problems. Several pathophysiological mechanisms can explain these symptoms, such as circadian rhythm alterations, central nervous system immaturity, and alterations in the intestinal microbiota. Several treatment alternatives have been described, including behavioral measures, manipulation techniques, use of medication, and acupuncture, with controversial results and effectiveness.	Excessive crying in the early months is a prevalent symptom; the pediatrician's attention is necessary to understand and adequately manage the problem and offer support to exhausted parents. The prescription of drugs of questionable action and with potential side effects is not a recommended treatment, except in extreme situations. The effectiveness of dietary treatments and use of probiotics still require confirmation. There is incomplete evidence regarding alternative treatments such as manipulation techniques, acupuncture, and use of the herbal supplements and behavioral interventions.	
26993958	The internal or biological clock which is located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by clock genes and environmental factors which are able to synchronize the clock to 24h. Rhythm desynchronization (shiftwork and nightwork, transmeridian flights, aging, some psychiatric diseases, blindness, intake of some drugs…) occurs when the internal clock does no longer work in harmony with the astronomical time i.e. our watch. The circadian system consists of three major elements, which are the clock, the retinohypothalamic tract and melatonin which is secreted by the pineal gland and considered as the arrow of the clock. Both light and melatonin present a phase response curve useful for the treatment of sleep circadian disorders. 
26993661	Photoperiodic regulation of the circadian rhythms in insect locomotor activity has been studied in several species, but seasonal entrainment of these rhythms is still poorly understood. We have traced the entrainment of activity rhythm of northern Drosophila montana flies in a climate chamber mimicking the photoperiods and day and night temperatures that the flies encounter in northern Finland during the summer. The experiment was started by transferring freshly emerged females into the chamber in early and late summer conditions to obtain both non-diapausing and diapausing females for the studies. The locomotor activity of the females and daily changes in the expression levels of two core circadian clock genes, timeless and period, in their heads were measured at different times of summer. The study revealed several features in fly rhythmicity that are likely to help the flies to cope with high variation in the day length and temperature typical to northern summers. First, both the non-diapausing and the diapausing females showed evening activity, which decreased towards the short day length as observed in the autumn in nature. Second, timeless and period genes showed concordant daily oscillations and seasonal shifts in their expression level in both types of females. Contrary to Drosophila melanogaster, oscillation profiles of these genes were similar to each other in all conditions, including the extremely long days in early summer and the cool temperatures in late summer, and their peak expression levels were not locked to lights-off transition in any photoperiod. Third, the diapausing females were less active than the non-diapausing ones, in spite of their younger age. Overall, the study showed that D. montana clock functions well under long day conditions, and that both the photoperiod and the daily temperature cycles are important zeitgebers for seasonal changes in the circadian rhythm of this species. 
26989605	Normal blood pressure (BP) follows a circadian rhythm, with dipping of BP at night. However, little has been done to show how the dipping groups vary amongst the White and Asian population at different periods of the year. This study aims to examine the pattern of nocturnal dipping between the White and Asian population, as well as to compare it to the different timings of the year, between summer and winter.Ambulatory Blood Pressure Monitor recordings were obtained from 220 patients, half were White patients obtained from Mercy University Hospital, Cork, Ireland and half were Asian patients from National Heart Centre, Singapore during the summer period from May to June and the winter period from October to December.	Both the Irish and Singaporeans exhibit a decrease in total number of reverse dipper from summer to winter. However, the redistribution of reverse dipper was mainly to the dippers in Singapore, while in Ireland it was to both the extreme dipper and dipper. Irish seasonal changes also resulted in an increase in nocturnal diastolic pressure (95% CI, 0.72 to 6.03, 3.37 mm Hg; p<0.05) and a change in the duration of dipping at night (95% CI, 0.045 to 1.01, 0.53 Hours; p<0.05).	Regardless of race or temperature, reverse dippers seem to decrease in winter. However, the racial differences dictate the redistribution of the fall in number of dippers. This has implications on how reverse dippers should be treated at different periods of the year.	
26987267	In order to identify daily changes in digestive physiology in developing gilthead seabream larvae, the enzyme activity (trypsin, lipases and α-amylase) and gene expression (trypsinogen-try, chymotrypsinogen-ctrb, bile salt-activated lipase-cel1b, phospholipase A2-pla2 and α-amylase-amy2a) were measured during a 24h cycle in larvae reared under a 12h light/12h dark photoperiod. Larvae were sampled at 10, 18, 30 and 60days post-hatch. In each sampling day, larvae were sampled every 3h during a complete 24h cycle. The enzyme activity and gene expression exhibited a marked dependent behavior to the light/darkness cycle in all tested ages. The patterns of activity and expression of all tested enzymes were compared to the feeding pattern found in the same larvae, which showed a rhythmic feeding pattern with a strong light synchronization. In the four tested ages, the activities of trypsin, and to a lesser extent lipases and amylase, were related to feeding activity. Molecular expression of the pancreatic enzymes tended to increase during the night, probably as an anticipation of the forthcoming ingestion of food that will take place during the next light period. It follows that the enzymatic activities are being regulated at translational and/or post-translational level. The potential variability of enzyme secretion along the whole day is an important factor to take into account in future studies. A particularly striking consequence of the present results is the reliability of studies based in only one daily sample taken at the same hour of the day, as those focused to assess ontogeny of digestive enzymes. 
26987067	Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL-receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be grouped under "pleiotropic functions" of the protein. This includes PCSK9's role in: trafficking of epithelial sodium channel; hepatic regeneration; pancreatic integrity and glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signalling pathways; cortical neural differentiation; neuronal apoptosis and Alzheimer's disease. The question that needs to be investigated in depth is "How will the pleotropic functions of PCSK9, be affected by the therapeutic intervention of the protease's LDL-receptor lowering activity?" In this review, we appraise the different lipid lowering strategies targeting PCSK9 in light of the protein's different pleiotropic functions. Additionally, we delineate the key areas that require further examination, to ensure the long-term safety of the above lipid-lowering strategies. 
26985106	Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms.In this study, 30 members of close-knit family with SAD, 30 age- and sex-matched controls of the same caste with no prior history of psychiatric illness and 30 age- and sex-matched controls belonging to 17 different castes with no prior history of psychiatric illness were genotyped for five different single nucleotide polymorphisms (SNPs) in ARNTL gene by TaqMan allele-specific genotyping assay.	Statistical significance was assessed by more powerful quasi-likelihood score test-XM.	Most of the family members carried the risk alleles and we observed a highly significant SNP rs2279287 (A/G) in ARNTL gene with an allelic frequency of 0.75.	Polymorphisms in ARNTL gene disrupt circadian rhythms causing SAD and genetic predisposition becomes more deleterious in the presence of adverse environment.	
26985030	Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity.Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day-specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet-induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns.	
26984377	The initial examination of a male subject's body temperature revealed that it was highest during the evening. Based on this observation, I measured grasping power, calculation speed, performance time on a light sensory task and body temperature, all of which were highest or best during the evening. The time of this subject's best physical condition shifted from the evening to morning hours when the subject executed hard physical labor in the morning, and the shifted phase was maintained after the termination of the labor period. 
26984272	Melatonin is a neurohormone secreted by epiphysis and extrapineal structures. It performs several functions including chronobiotic, antioxidant, oncostatic, immune modulating, normothermal, and anxiolytic functions. Melatonin affects the cardiovascular system and gastrointestinal tract, participates in reproduction and metabolism, and body mass regulation. Moreover, recent studies have demonstrated melatonin efficacy in relation to pain syndromes. The present paper reviews the studies on melatonin use in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The paper discusses the possible mechanisms of melatonin analgesic properties. On one hand, circadian rhythms normalization results in sleep improvement, which is inevitably disordered in chronic pain syndromes, and activation of melatonin adaptive capabilities. On the other hand, there is evidence of melatonin-independent analgesic effect involving melatonin receptors and several neurotransmitter systems. 
26982486	Circadian (daily) rhythms are a fundamental and ubiquitous property of eukaryotic organisms. However, cyanobacteria are the only prokaryotic group for which bona fide circadian properties have been persuasively documented, even though homologs of the cyanobacterial kaiABC central clock genes are distributed widely among Eubacteria and Archaea. We report the purple non-sulfur bacterium Rhodopseudomonas palustris (that harbors homologs of kaiB and kaiC) only poorly sustains rhythmicity in constant conditions-a defining characteristic of circadian rhythms. Moreover, the biochemical characteristics of the Rhodopseudomonas homolog of the KaiC protein in vivo and in vitro are different from those of cyanobacterial KaiC. Nevertheless, R. palustris cells exhibit adaptive kaiC-dependent growth enhancement in 24-h cyclic environments, but not under non-natural constant conditions. Therefore, our data indicate that Rhodopseudomonas does not have a classical circadian rhythm, but a novel timekeeping mechanism that does not sustain itself in constant conditions. These results question the adaptive value of self-sustained oscillatory capability for daily timekeepers and establish new criteria for circadian-like systems that are based on adaptive properties (i.e., fitness enhancement in rhythmic environments), rather than upon observations of persisting rhythms in constant conditions. We propose that the Rhodopseudomonas system is a "proto" circadian timekeeper, as in an ancestral system that is based on KaiC and KaiB proteins and includes some, but not necessarily all, of the canonical properties of circadian clocks. These data indicate reasonable intermediate steps by which bona fide circadian systems evolved in simple organisms. 
26982441	In insects, olfaction plays a crucial role in many behavioral contexts, such as locating food, sexual partners, and oviposition sites. To successfully perform such behaviors, insects must respond to chemical stimuli at the right moment. Insects modulate their olfactory system according to their physiological state upon interaction with their environment. Here, we review the plasticity of behavioral responses to different odor types according to age, feeding state, circadian rhythm, and mating status. We also summarize what is known about the underlying neural and endocrinological mechanisms, from peripheral detection to central nervous integration, and cover neuromodulation from the molecular to the behavioral level. We describe forms of olfactory plasticity that have contributed to the evolutionary success of insects and have provided them with remarkable tools to adapt to their ever-changing environment.
26982485	To estimate the prevalence of inflammatory back pain (IBP) characteristics and analyse the discriminative value of IBP relative to axial spondyloarthritis (SpA) according to the Assessment of SpondyloArthritis international Society (ASAS) criteria.Patients who had low back pain for > 3 months were selected from a cohort of secondary care patients aged 18-40 years. Data included information on SpA features, human leucocyte antigen (HLA)-B27 typing, C-reactive protein (CRP) level, magnetic resonance imaging (MRI) of the sacroiliac joints, and self-reported IBP questions covering the pain characteristics included in the Calin, Berlin, and ASAS IBP definitions.	Of the 759 included patients, 99% [95% confidence interval (CI) 98-100] had at least one IBP characteristic. The prevalence of the single IBP characteristics ranged from 10% (95% CI 7-12) for 'pain worst in the morning' to 79% (95% CI 76-82) for 'morning stiffness'. Two-thirds of the patients (67%, 95% CI 63-70), met at least one of the three IBP definitions. In all, 86 (11%) were classified as 'SpA according to ASAS'. All three IBP definitions were significantly associated with 'SpA according to ASAS'; however, the discriminative value was low, with sensitivity, specificity, and balanced accuracy values of 64, 50, and 57% for Calin, 59, 60, and 60% for Berlin, and 35, 79, and 57% for ASAS IBP definitions, respectively.	In this study population, IBP characteristics were in general common and the discriminative value was low, as IBP could not differentiate patients with SpA according to ASAS criteria from patients with other causes of back pain.	
26982381	Experiments were carried out to investigate whether diuretics (hydrochlorothiazide + furosemide) impact on the effects of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor on glucose metabolism and blood pressure (BP) in metabolic syndrome SHR/NDmcr-cp(+/+) rats (SHRcp).Male 13-week-old SHRcp were treated with: vehicle; the SGLT2-inhibitor luseogliflozin (10 mg/kg per day); diuretics (hydrochlorothiazide; 10 mg/kg/day + furosemide; 5 mg/kg per day); or luseogliflozin + diuretics (n = 5-8 for each group) daily by oral gavage for 5 weeks. BP and glucose metabolism were evaluated by a telemetry system and oral glucose tolerance test, respectively.	Vehicle-treated SHRcp developed nondipper type hypertension (dark vs. light-period mean arterial pressure: 148.6 ± 0.7 and 148.0 ± 0.7 mmHg, respectively, P = 0.2) and insulin resistance. Compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4000-fold increase in urinary excretion of glucose and improved glucose metabolism. Luseogliflozin also significantly decreased BP and turned the circadian rhythm of BP from a nondipper to dipper pattern (dark vs. light-period mean arterial pressure: 138.0 ± 1.6 and 132.0 ± 1.3 mmHg, respectively, P < 0.01), which were associated with a significant increase in urinary excretion of sodium. Addition of diuretics did not influence luseogliflozin-induced improvement of glucose metabolism and circadian rhythm of BP in SHRcp.	These data suggest that a SGLT2 inhibitor elicits its beneficial effects on glucose metabolism and hypertension in study participants with metabolic syndrome undergoing treatment with diuretics.	
26980824	Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. 
26980725	The biological hard-wiring of 24-hour rhythmicity relies on the circadian clock circuitry, made of peripheral oscillators operated by molecular clockworks and synchronized through humoral and neural outputs by central oscillators located in the hypothalamic suprachiasmatic nuclei. Metabolically active tissues, such as the liver, are entrained also by local cues represented by metabolic flux related to feeding. The mechanics of the molecular clockwork have been explored by studies using cell lines and wild type or genetically engineered mouse models. There is a compelling need to reduce the use of animals in experimental settings. The aim of our study was to evaluate the periodicity and dynamics of functioning of the hepatic clock gene machinery in human and mouse hepatic models. We compared the results obtained in human hepatoma cells (HepG2 cells) and in mouse liver, and a significant 24-hour rhythmic component was found for five clock genes in the HepG2 cells (Bmal1, Cry1, Per1, Per2, NR1D1) and for six clock genes in the mouse liver (Bmal1, Clock, Cry1, Per1, Per2, NR1D1). The amplitude of oscillation rendered by the cosine curve and the dynamics of expression rendered by the rate of change (the derivative of gene expression level with respect to time) were greater in the mouse liver than in the HepG2 cells for Bmal1, Per1, Per2 and NR1D1, and the cosine curve phase was different for many of them. In conclusion, the periodicity of expression of the clock genes showed similar patterns when the two experimental models were compared, whereas the dynamics of transcription in human hepatoma cells cultured in vitro were less vigorous and phased in a different way when compared to mouse hepatic tissue. The results support the reliability of the human hepatic in vitro model as an alternative to animal models only to study the periodicity of function of the molecular clockwork, but not to evaluate the dynamics of clock gene expression. 
26980087	Evidence suggests that patients with bipolar disorder (BD) experience biological rhythm disturbances; however, no studies have examined the impact of this disruption on quality of life (QOL). The aim of this study is to investigate the influence of biological rhythm, depressive symptoms, sleep quality, and sleep medication use on QOL in BD.Eighty BD subjects (44 depressed and 36 euthymic) completed questionnaires assessing QOL (WHOQOL-BREF), biological rhythm disruption (BRIAN), depressive symptoms (MADRS), and sleep quality (PSQI). The impact of biological rhythm disturbance, depressive symptoms severity, sleep quality, and sleep medication use on QOL was determined with multiple regression analyses.	BRIAN (β = -0.31, t = -2.73, p < 0.01), MADRS (β = -0.30, t = -2.93, p < 0.01), and sleep medication use (β = -0.45, t = -2.55, p < 0.05) were significant predictors of QOL in this model (F 4, 75 = 20.28; p < 0.0001). The relationship of these factors with subdomains of QOL showed that poorer social QOL was associated with greater biological rhythm disturbance (β = -0.43, t = -3.66, p < 0.01) and sleep medication use (β = -0.49, t = -2.35, p < 0.01), providing support for the social rhythm theory of BD. Physical QOL was associated with depression (β = -0.30, t = -2.93, p < 0.01) and biological rhythm disruption (β = -0.31, t = -2.73, p < 0.01). Main limitations include the cross-sectional assessment and the lack of objective measures of biological rhythms in relation to QOL.	Disruption in biological rhythm is associated with poor QOL in BD, independent of sleep disturbance, sleep medication use, and severity of depression. Treatment strategies targeting regulation of biological rhythms, such as sleep/wake cycles, eating patterns, activities, and social rhythms, are likely to improve QOL in this population.	

26978881	The present paper aims to highlight the role of arterial hypotension in the progression of glaucoma. The data analyzed in this study was collected in a prospective manner for a period of one year, from september 2013 to august 2014. It includes newly diagnosed glaucoma patients treated with prostaglandin analogues and who have presented within normal range values of intraocular pressure during the study. In spite of good control of intraocular pressure, there was recorded a progression of glaucoma lesions documented using the visual field . All patients were evaluated through 24 h outpatient holter monitoring of systemic blood pressure (BP) and were consequently divided into three groups: Group A--non-dipper (within normal range of both diurnal and nocturnal BP values and no significant drop during the night). Group B--dipper (patients with nocturnal hypotension recording BP drops of more the X mmHg). Group C--patients with arterial hypertension (defined as diurnal values of more than 150 mmHg for systolic BP and 110 mmHg for dyastolic BP). After through statistical analysis of the patients data, we noticed that the most important progression of glaucoma changes objectified by visual field and OCT examinations was recorded in group B, which illustrates the importance of careful monitoring and strict control of blood pressure in order to eliminate this risk factor in the progress of glaucoma.
26978703	Light-dark cycles mimicking natural settings in a zebrafish facility are crucial for maintaining fish with an entrained circadian clock making them an ideal vertebrate model to study such rhythms. However, failure to provide optimal conditions to include complete darkness can lead to a disturbed circadian pacemaker affecting physiology and behavior in zebrafish. To meet building code requirements, the aquatics facility in use was outfitted with EXIT signs emitting a constant light. To determine if light radiating from the EXIT sign has an effect on zebrafish embryo production, 100 fish (1:1 m/f ratio) were split and housed at 10 fish/L. Half were housed directly in front of the EXIT sign, whereas the other half (control) were housed under a true 14-h light-10-h dark cycle. Reproductive success was evaluated by recording fecundity and viability from 10 weekly matings under two light colors: red (640 nm) and green (560 nm). On average the control group spawned twice as many embryos compared to those housed in front of a red EXIT sign, whereas green EXIT sign showed no difference. This suggests the importance of providing a complete dark environment within the night cycle and a recommendation toward dim green EXIT signs to avoid a decline in reproductive performance. 
26978182	Disturbances in sleep and circadian rest-activity rhythms are key features of depression. Actigraphy, a non-invasive method for monitoring motor activity, can be used to objectively assess circadian rest-activity rhythms and sleep patterns. While recent studies have measured sleep and daytime activity of depressed patients using wrist-worn actigraphy, the actigraphic 24-h rest-activity rhythm in depression has not been well documented. We aimed to examine actigraphically measured sleep and circadian rest-activity rhythms in depressed outpatients. Twenty patients with DSM-IV major depressive episode and 20 age- and sex-matched healthy controls participated in this study. Participants completed 7 consecutive days of all-day actigraphic activity monitoring while engaging in usual activities. For sleep parameters, total sleep time, wake after sleep onset, and sleep fragmentation index were determined. Circadian rhythms were estimated by fitting individual actigraphy data to a cosine curve of a 24-h activity rhythm using the cosinor method, which generated three circadian activity rhythm parameters, i.e., MESOR (rhythm-adjusted mean), amplitude, and acrophase. Subjective sleep was also assessed using a sleep diary and the Pittsburgh Sleep Quality Index. Patients showed significantly lower MESOR and more dampened amplitude along with significant sleep disturbances. Logistic regression analysis revealed that lower MESOR and more fragmented sleep emerged as the significant predictors of depression. Correlations between subjectively and actigraphically measured parameters demonstrated the validity of actigraphic measurements. These results indicate marked disturbances in sleep and circadian rest-activity rhythms of depression. By simultaneously measuring sleep and rest-activity rhythm parameters, actigraphy might serve as an objective diagnostic aid for depression. 
26977390	While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders.This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations.	Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.	
26976740	Williams-Beuren syndrome (WBS), a neurodevelopmental disorder caused by a microdeletion on chromosomic region 7q11.23, presents with peculiar behavioral and neurocognitive phenotypes that are marked by apparently preserved social and communicative abilities, which contrasts with low overall cognitive and particularly visuospatial performance. In addition, parents often report complaints of sleep disorders and behavioral problems of unknown cause. Sleep is a biological phenomenon that is modulated by the plasma concentration of melatonin and with influence on behavioral aspects and memory. Thus, this study sought to investigate the behavior, memory and the presence of sleep disorders in WBS and to correlate these factors with each other and with the plasma melatonin content. We used the Child Behavior Checklist for ages 6-18 (CBCL), the digit subtest of the Wechsler scale for auditory memory, the visual sequential memory subtest of the Illinois Test of Psycholinguistic Abilities (ITPA) and the Sleep Disturbance Scale for Children (SDSC). Determination of urinary aMT6s, an indirect measure of plasma melatonin content, was held for 72h by ELISA, and the analysis of the circadian rhythm of this content was performed by the Cosinor method. The results of the CBCL showed that 87% of the WBS group presented with a clinical score on the overall competence and total behavioral problems. Furthermore, the behavioral problems that were most frequently reported by parents were anxiety and problems of thought. All individuals with WBS presented with impairments in auditory memory and 47% with impairments in visual sequential memory; 65% of the WBS group presented with an indicative of at least one sleep disorder, where respiratory, initiation and maintenance of sleep (DIMS) and hyperhidrosis were the most frequent disorders. The night time aMT6s levels were lower in individuals with WBS when compared with controls; 53% of the WBS group did not present with circadian rhythm variations in aMT6s levels. In addition, there was a negative correlation between the scores of auditory memory and the total score of sleep disorders and between the DIMS and nocturnal aMT6s content. In conclusion, in the present study, individuals with WBS showed a high frequency of behavioral and memory problems, sleep disturbances and no rhythm variation in aMT6s levels. The low melatonin content may be related with sleep disorders in this population, which, in turn, can have an adverse effect on specific cognitive skills such as memory. 
26975828	To study the changes of miRNA expression in the pineal gland of neonatal rats with hypoxic-ischemic brain damage (HIBD) and the possible roles of miRNA in the pathogenesis of circadian rhythm disturbance after HIBD.Seven-day-old Sprague-Dawley (SD) rats were randomly divided into 2 groups: HIBD and sham-operated. HIBD was induced according to the Rice-Vannucci method. The pineal glands were obtained 24 hours after the HIBD event. The expression profiles of miRNAs were determined using GeneChip technigue and quantitative real-time PCR (RT-PCR). Then the miRNA which was highly expressed was selected. The expression levels of the chosen miRNA were detected in different tissues (lungs, intestines, stomach, kidneys, cerebral cortex, pineal gland). RT-PCR analysis was performed to measure the expression profiles of the chosen miRNA and the targeted gene Clock mRNA in the pineal gland at 0, 24, 48 and 72 hours after HIBD.	miRNA-182 that met the criteria was selected by GeneChip and RT-PCR. miRNA-182 was highly expressed in the pineal gland. Compared with the sham-operated group, the expression of miRNA-182 was significantly up-regulated in the pineal gland at 24 and 48 hours after HIBD (P<0.05). Compared with the sham-operated group, Clock mRNA expression in the HIBD group increased at 0 hour after HIBD, decreased at 48 hours after HIBD and increased at 72 hours after HIBD (P<0.05).	miRNA-182 may be involved in the pathogenesis of circadian rhythm disturbance after HIBD.	
26975540	Peripheral clock genes show a circadian rhythm is correlated with the timing of feeding in peripheral tissues. It was reported that these clock genes are strongly regulated by insulin action and that a high-fat diet (HFD) intake in C57BL/6J mice for 21days induced insulin secretion during the dark phase and reduced the circadian rhythm of clock genes. In this study, we examined the circadian expression patterns of these clock genes in insulin-resistant animal models with excess secretion of insulin during the day.We examined whether insulin resistance induced by a HFD intake for 80days altered blood parameters (glucose and insulin concentrations) and expression of mRNA and proteins encoded by clock and functional genes in the liver using male ICR mice.	Serum insulin concentrations were continuously higher during the day in mice fed a HFD than control mice. Expression of lipogenesis-related genes (Fas and Accβ) and the transcription factor Chrebp peaked at zeitgeber time (ZT)24 in the liver of control mice. A HFD intake reduced the expression of these genes at ZT24 and disrupted the circadian rhythm. Expression of Bmal1 and Clock, transcription factors that compose the core feedback loop, showed circadian variation and were synchronously associated with Fas gene expression in control mice, but not in those fed a HFD.	These results indicate that the disruption of the circadian rhythm of insulin secretion by HFD intake is closely associated with the disappearance of circadian expression of lipogenic and clock genes in the liver of mice.	

26973695	Sinapis alba is an important condiment crop and can also be used as a phytoremediation plant. Though it has important economic and agronomic values, sequence data, and the genetic tools are still rare in this plant. In the present study, a de novo transcriptome based on the transcriptions of leaves, stems, and roots was assembled for S. alba for the first time. The transcriptome contains 47,972 unigenes with a mean length of 1185 nt and an N50 of 1672 nt. Among these unigenes, 46,535 (97%) unigenes were annotated by at least one of the following databases: NCBI non-redundant (Nr), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology (GO), and Clusters of Orthologous Groups of proteins (COGs). The tissue expression pattern profiles revealed that 3489, 1361, and 8482 unigenes were predominantly expressed in the leaves, stems, and roots of S. alba, respectively. Genes predominantly expressed in the leaf were enriched in photosynthesis- and carbon fixation-related pathways. Genes predominantly expressed in the stem were enriched in not only pathways related to sugar, ether lipid, and amino acid metabolisms but also plant hormone signal transduction and circadian rhythm pathways, while the root-dominant genes were enriched in pathways related to lignin and cellulose syntheses, involved in plant-pathogen interactions, and potentially responsible for heavy metal chelating, and detoxification. Based on this transcriptome, 14,727 simple sequence repeats (SSRs) were identified, and 12,830 pairs of primers were developed for 2522 SSR-containing unigenes. Additionally, the glucosinolate (GSL) and phytochelatin metabolic pathways, which give the characteristic flavor and the heavy metal tolerance of this plant, were intensively analyzed. The genes of aliphatic GSLs pathway were predominantly expressed in roots. The absence of aliphatic GSLs in leaf tissues was due to the shutdown of BCAT4, MAM1, and CYP79F1 expressions. Glutathione was extensively converted into phytochelatin in roots, but it was actively converted to the oxidized form in leaves, indicating the different mechanisms in the two tissues. This transcriptome will not only benefit basic research and molecular breeding of S. alba but also be useful for the molecular-assisted transfer of beneficial traits to other crops. 
26973668	The goal of the study was to determine circadian movements of silver birch (Petula Bendula) branches and foliage detected with terrestrial laser scanning (TLS). The study consisted of two geographically separate experiments conducted in Finland and in Austria. Both experiments were carried out at the same time of the year and under similar outdoor conditions. Experiments consisted of 14 (Finland) and 77 (Austria) individual laser scans taken between sunset and sunrise. The resulting point clouds were used in creating a time series of branch movements. In the Finnish data, the vertical movement of the whole tree crown was monitored due to low volumetric point density. In the Austrian data, movements of manually selected representative points on branches were monitored. The movements were monitored from dusk until morning hours in order to avoid daytime wind effects. The results indicated that height deciles of the Finnish birch crown had vertical movements between -10.0 and 5.0 cm compared to the situation at sunset. In the Austrian data, the maximum detected representative point movement was 10.0 cm. The temporal development of the movements followed a highly similar pattern in both experiments, with the maximum movements occurring about an hour and a half before (Austria) or around (Finland) sunrise. The results demonstrate the potential of terrestrial laser scanning measurements in support of chronobiology. 
26973592	The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development of circadian rhythm sleep disorders (CRSD). Non-24-hour sleep-wake disorders (N24HSWD) is a CRSD affecting up to 50% of totally blind patients and characterized by the inability to maintain a stable entrainment of the typically long circadian rhythm (tau > 24.5 h) to the LD cycle. The disease is rare in sighted individuals and the pathophysiology less well understood. Here, we present the case of a 40-year-old sighted male, who developed a misalignment of the internal clock with the external LD cycle following the treatment for Hodgkin's lymphoma (ABVD regimen, four cycles and AVD regimen, four cycles). A thorough clinical assessment, including actigraphy, melatonin profiles and polysomnography led to the diagnosis of non-24-hour sleep-wake disorders (N24HSWD) with a free-running rhythm of tau = 25.27 h. A therapeutic intervention with bright light therapy (30 min, 10,000 lux) in the morning and melatonin administration (0.5-0.75 mg) in the evening failed to entrain the free-running rhythm, although a longer treatment duration and more intense therapy might have been successful. The sudden onset and close timely connection led us to hypothesize that the chemotherapy might have caused a mutation of the molecular clock components leading to the observed elongation of the circadian period. 
26973261	The time rate of blood pressure (BP) variation indicates the speed of BP fluctuations. Previous studies have demonstrated that the time rate of BP variation was associated with target organ damage. However, the association between time rate of BP variation and endothelial function has not been evaluated.24-hour ambulatory blood pressure monitoring (ABPM) was performed in 61 patients with metabolic syndrome. Time rate of BP variation was calculated from BP recordings of ABPM. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI) by EndoPat2000. Multiple linear regression models were used to detect the association between time rate of BP variation and RHI.Among all the subjects (n = 61), the multiple linear regression models revealed that the daytime rate of systolic blood pressure (SBP) variation was independently associated with RHI (β = -0.334, P = 0.008). A 0.1 mmHg/minute increase in the daytime rate of SBP variation correlated with a decline of 0.20 in RHI. The same effect was also found in the subjects with eGFR ≥ 60 mL/ (minute*1.73 m(2)). A greater association was found in those who were not taking a statin, β-blocker, ACEI/ARB, or diuretic and those without diabetes compared with those with any antihypertensive medication or with diabetes. Other ambulatory blood pressure parameters and central hemodynamics were not found to be associated with RHI.Our findings have shown that the daytime rate of SBP variation was associated with endothelial function in patients with metabolic syndrome, independent of other BP parameters and central hemodynamics.
26972823	High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes. 
26972685	Light is the major stimulus for the synchronization of circadian clocks with day-night cycles. The light-driven entrainment of the clock that controls rest-activity rhythms in Drosophila relies on different photoreceptive molecules. Cryptochrome (CRY) is expressed in most brain clock neurons, whereas six different rhodopsins (RH) are present in the light-sensing organs. The compound eye includes outer photoreceptors that express RH1 and inner photoreceptors that each express one of the four rhodopsins RH3-RH6. RH6 is also expressed in the extraretinal Hofbauer-Buchner eyelet, whereas RH2 is only found in the ocelli. In low light, the synchronization of behavioral rhythms relies on either CRY or the canonical rhodopsin phototransduction pathway, which requires the phospholipase C-β encoded by norpA (no receptor potential A). We used norpA(P24) cry(02) double mutants that are circadianly blind in low light and restored NORPA function in each of the six types of photoreceptors, defined as expressing a particular rhodopsin. We first show that the NORPA pathway is less efficient than CRY for synchronizing rest-activity rhythms with delayed light-dark cycles but is important for proper phasing, whereas the two light-sensing pathways can mediate efficient adjustments to phase advances. Four of the six rhodopsin-expressing photoreceptors can mediate circadian entrainment, and all are more efficient for advancing than for delaying the behavioral clock. In contrast, neither RH5-expressing retinal photoreceptors nor RH2-expressing ocellar photoreceptors are sufficient to mediate synchronization through the NORPA pathway. Our results thus reveal different contributions of rhodopsin-expressing photoreceptors and suggest the existence of several circuits for rhodopsin-dependent circadian entrainment. J. Comp. Neurol. 524:2828-2844, 2016. © 2016 Wiley Periodicals, Inc. 
26972478	Neuronal coupling contributes to circadian rhythms formation in the suprachiasmatic nucleus (SCN). While the neurotransmitter vasoactive intestinal polypeptide (VIP) is considered essential for synchronizing the oscillations of individual neurons, γ-aminobutyric acid (GABA) does not have a clear functional role despite being highly concentrated in the SCN. While most studies have examined the role of either GABA or VIP, our mathematical modeling approach explored their interplay on networks of SCN neurons. Tuning the parameters that control the release of GABA and VIP enabled us to optimize network synchrony, which was achieved at a peak firing rate during the subjective day of about 7Hz. Furthermore, VIP and GABA modulation could adjust network rhythm amplitude and period without sacrificing synchrony. We also performed simulations of SCN networks to phase shifts during 12h:12h light-dark cycles and showed that GABA networks reduced the average time for the SCN model to re-synchronize. We hypothesized that VIP and GABA balance cell coupling in the SCN to promote synchronization of heterogeneous oscillators while allowing flexibility for adjustment to environmental changes. 
26972473	Inflammatory pain exhibits circadian rhythmicity. Recently, a distinct diurnal pattern has been described for peripheral neuropathic conditions. This diurnal variation has several implications: advancing understanding of chronobiology may facilitate identification of new and improved treatments; developing pain-contingent strategies that maximize treatment at times of the day associated with highest pain intensity may provide optimal pain relief as well as minimize treatment-related adverse effects (e.g., daytime cognitive dysfunction); and consideration of the impact of chronobiology on pain measurement may lead to improvements in analgesic study design that will maximize assay sensitivity of clinical trials. Recent and ongoing chronobiology studies are thus expected to advance knowledge and treatment of neuropathic pain. 
26972320	Increasing ambient temperature reorganizes the Drosophila sleep pattern in a way similar to the human response to heat, increasing daytime sleep while decreasing nighttime sleep. Mutation of core circadian genes blocks the immediate increase in daytime sleep, but not the heat-stimulated decrease in nighttime sleep, when animals are in a light:dark cycle. The ability of per(01) flies to increase daytime sleep in light:dark can be rescued by expression of PER in either LNv or DN1p clock cells and does not require rescue of locomotor rhythms. Prolonged heat exposure engages the homeostat to maintain daytime sleep in the face of nighttime sleep loss. In constant darkness, all genotypes show an immediate decrease in sleep in response to temperature shift during the subjective day, implying that the absence of light input uncovers a clock-independent pro-arousal effect of increased temperature. Interestingly, the effects of temperature on nighttime sleep are blunted in constant darkness and in cry(OUT) mutants in light:dark, suggesting that they are dependent on the presence of light the previous day. In contrast, flies of all genotypes kept in constant light sleep more at all times of day in response to high temperature, indicating that the presence of light can invert the normal nighttime response to increased temperature. The effect of temperature on sleep thus reflects coordinated regulation by light, the homeostat, and components of the clock, allowing animals to reorganize sleep patterns in response to high temperature with rough preservation of the total amount of sleep.
26972038	In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed. 
26972037	The intensive care unit (ICU) environment is not propitious for restoring sleep and many studies have reported that critically ill patients have severe sleep disruptions. However, sleep alterations in critically ill patients are specific and differ significantly from those in ambulatory patients. Polysomnographic patterns of normal sleep are frequently lacking in critically ill patients and the neurobiology of sleep is important to consider regarding alternative methods to quantify sleep in the ICU. This article discusses elements of sleep neurobiology affecting the specificity of sleep patterns and sleep alterations in patients admitted to the ICU. 
26972034	Sleep and circadian rhythms significantly impact almost all aspects of human behavior and are therefore relevant to occupational sleep medicine, which is focused predominantly around workplace productivity, safety, and health. In this article, 5 main factors that influence occupational functioning are reviewed: (1) sleep deprivation, (2) disordered sleep, (3) circadian rhythms, (4) common medical illnesses that affect sleep and sleepiness, and (5) medications that affect sleep and sleepiness. Consequences of disturbed sleep and sleepiness are also reviewed, including cognitive, emotional, and psychomotor functioning and drowsy driving. 
26970497	Changes in ocular growth that lead to myopia or hyperopia are associated with alterations in the circadian rhythms in eye growth, choroidal thickness and intraocular pressure in animal models of emmetropization. Recent studies have shown that light at night has deleterious effects on human health, acting via "circadian disruptions" of various diurnal rhythms, including changes in phase or amplitude. The purpose of this study was to determine the effects of brief, 2-h episodes of light in the middle of the night on the rhythms in axial length and choroidal thickness, and whether these alter eye growth and refractive error in the chick model of myopia. Starting at 2 weeks of age, birds received 2 h of light between 12:00 am and 2:00 am for 7 days (n = 12; total hours of light: 14 h). Age-matched controls had a continuous dark night (n = 14; 14L/10D). Ocular dimensions were measured using high-frequency A-scan ultrasonography on the first day of the experiment, and again on day 7, at 6-h intervals, starting at noon (12 pm, 6 pm, 12 am, 6 am, 12 pm). Measurements during the night were done under a photographic safe-light. These data were used to determine rhythm parameters of phase and amplitude. 2 groups of birds, both experimental (light at night) and control, were measured with ultrasound at various intervals over the course of 4 weeks to determine growth rates. Refractive errors were measured in 6 experimental and 6 control birds at the end of 2 weeks. Eyes of birds in a normal L/D cycle showed sinusoidal 24-h period diurnal rhythms in axial length and choroid thickness. Light in the middle of the night caused changes in both the rhythms in axial length and choroidal thickness, such that neither could be fit to a sine function having a period of 24 h. Light caused an acute, transient stimulation in ocular growth rate in the subsequent 6-h period (12 am-6 am), that may be responsible for the increased growth rate seen 4 weeks later, and the more myopic refractive error. It also abolished the increase in choroidal thickness that normally occurs between 6 pm and 12 am. We conclude that light at night alters the rhythms in axial length and choroidal thickness in an animal model of eye growth, and that these circadian disruptions might lead to the development of ametropias. These results have implications for the use of light during the night in children. 
26970404	Esomeprazole is one of the most commonly used drugs to treat gastroesophageal reflux disease and peptic ulcers, but the quantitative relationships among the pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics (PG) of the drug are not fully understood in special patient populations. A clinical PK/PD/PG study of intravenous (IV) esomeprazole in 5 dosing regimens was conducted in 20 healthy Chinese volunteers, who were categorized into Helicobacter pylori (HP)-negative and HP-positive subgroups. Plasma esomeprazole concentration and intragastric H(+) concentration were monitored for 24 hours postdosing. Population PK (PopPK) models were tested based on elimination characteristics and other data. For a single-dose IV esomeprazole regimen, a 2-compartment model with nonlinear elimination characteristics fitted the PK data well. The elimination of esomeprazole was found to be significantly linked to CYP2C19 genotype by 11% to 29%. A mechanism-based PD model was first tested to mimic the irreversible inhibition of H(+) /K(+) -ATPase by esomeprazole using a cell-killing mechanism and models of gastric H(+) secretion that included the effects of an asymmetric circadian rhythm and food effects. Results from this PD model showed that the turnover rate of H(+) /K(+) -ATPase was significantly different between HP-negative and HP-positive subgroups. In conclusion, the PopPK model quantitatively identified the effects of the CYP2C19 genotype on esomeprazole elimination in healthy subjects for the first time. In addition, the effects of HP status on drug effect, H(+) /K(+) -ATPase turnover, and circadian rhythm amplitude were preliminarily explored using a mechanism-based PD model. 
26969584	Sleep-disordered breathing is a common and serious feature of many paediatric conditions and is particularly a problem in children with Down syndrome. Overnight pulse oximetry is recommended as an initial screening test, but it is unclear how overnight oximetry results should be interpreted and how many nights should be recorded.This retrospective observational study evaluated night-to-night variation using statistical measures of repeatability for 214 children referred to a paediatric respiratory clinic, who required overnight oximetry measurements. This included 30 children with Down syndrome. We measured length of adequate trace, basal SpO2, number of desaturations (>4% SpO2 drop for >10 s) per hour ('adjusted index') and time with SpO2<90%. We classified oximetry traces into normal or abnormal based on physiology.	132 out of 214 (62%) children had three technically adequate nights' oximetry, including 13 out of 30 (43%) children with Down syndrome. Intraclass correlation coefficient for adjusted index was 0.54 (95% CI 0.20 to 0.81) among children with Down syndrome and 0.88 (95% CI 0.84 to 0.91) for children with other diagnoses. Negative predictor value of a negative first night predicting two subsequent negative nights was 0.2 in children with Down syndrome and 0.55 in children with other diagnoses.	There is substantial night-to-night variation in overnight oximetry readings among children in all clinical groups undergoing overnight oximetry. This is a more pronounced problem in children with Down syndrome. Increasing the number of attempted nights' recording from one to three provides useful additional clinical information.	
26969345	Sleep and its disorders are known to affect the functions of essential organs and systems in the body. However, very little is known about how the blood-brain barrier (BBB) is regulated. A few years ago, we launched a project to determine the impact of sleep fragmentation and chronic sleep restriction on BBB functions, including permeability to fluorescent tracers, tight junction protein expression and distribution, glucose and other solute transporter activities, and mediation of cellular mechanisms. Recent publications and relevant literature allow us to summarize here the sleep-BBB interactions in five sections: (1) the structural basis enabling the BBB to serve as a huge regulatory interface; (2) BBB transport and permeation of substances participating in sleep-wake regulation; (3) the circadian rhythm of BBB function; (4) the effect of experimental sleep disruption maneuvers on BBB activities, including regional heterogeneity, possible threshold effect, and reversibility; and (5) implications of sleep disruption-induced BBB dysfunction in neurodegeneration and CNS autoimmune diseases. After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind-body crosstalk. The pharmaceutical industry should take into consideration that sleep disruption alters the pharmacokinetics of BBB permeation and CNS drug delivery, being attentive to the chrono timing and activation of co-transporters in subjects with sleep disorders.
26968929	An efficient inverse problem approach for parameter estimation, state and structure identification from dynamic data by embedding training functions in a genetic algorithm methodology (ETFGA) is proposed for nonlinear dynamical biosystems using S-system canonical models. Use of multiple shooting and decomposition approach as training functions has been shown for handling of noisy datasets and computational efficiency in studying the inverse problem. The advantages of the methodology are brought out systematically by studying it for three biochemical model systems of interest. By studying a small-scale gene regulatory system described by a S-system model, the first example demonstrates the use of ETFGA for the multifold aims of the inverse problem. The estimation of a large number of parameters with simultaneous state and network identification is shown by training a generalized S-system canonical model with noisy datasets. The results of this study bring out the superior performance of ETFGA on comparison with other metaheuristic approaches. The second example studies the regulation of cAMP oscillations in Dictyostelium cells now assuming limited availability of noisy data. Here, flexibility of the approach to incorporate partial system information in the identification process is shown and its effect on accuracy and predictive ability of the estimated model are studied. The third example studies the phenomenological toy model of the regulation of circadian oscillations in Drosophila that follows rate laws different from S-system power-law. For the limited noisy data, using a priori information about properties of the system, we could estimate an alternate S-system model that showed robust oscillatory behavior with predictive abilities. 
26966234	The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells. 
26966073	Although a deficiency in CRY1 or CRY2 correlates with a shorter or longer circadian period, the regulation of CRY proteins in the circadian period has not been well studied. In this study, we found that both CRY1 and CRY2 were able to rescue oscillation in CRY null cells and that they displayed different periods. Furthermore, we demonstrated that protein nuclear import rates, not protein stability, regulate the period-length at the cellular level. Co-transfection of CRY1 and CRY2 in various ratios in the same cells gives rise to the predicted period length in a dose-dependent manner. Given the distinct characteristics of the C-terminal tails of the CRY1 and CRY2 proteins, our study addresses a long-standing hypothesis that the ratio of these two CRY molecules affects the clock period. 
26966017	The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that new representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable␣rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems.
26963516	The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression. 
26961881	In mammals, circadian rhythms in physiological function are generated by a molecular oscillator driven by transcriptional-translational feedback loop consisting of negative and positive regulators. Disruption of this circadian clock machinery is thought to increase the risk of cancer development, but the potential contributions of each component of circadian clock to oncogenesis have been little explored. Here we reported that negative and positive transcriptional regulators of circadian feedback loop had different roles in oncogene-induced neoplastic transformation. Mouse embryonic fibroblasts prepared from animals deficient in negative circadian clock regulators, Period2 (Per2) or Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression of H-ras(V12) and SV40 large T antigen (SV40LT). In contrast, mouse embryonic fibroblasts prepared from mice deficient in positive circadian clock regulators, Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence. Although genetic ablation of either negative or positive transcriptional regulators of the circadian clock leads to disrupted rhythms in physiological functions, our findings define their different contributions to neoplastic cellular transformation. 
26959472	Nurses are accustomed to helping others with their sleep problems and dealing with issues such as pain that may delay or interrupt sleep. However, they may be less familiar with what constitutes a healthy night's sleep. This article examines what is known about the process and purpose of sleep, and examines the ways in which factors that promote wakefulness and sleep combine to help establish a normal circadian rhythm. Theories relating to the function of sleep are discussed and research is considered that suggests that sleep deficit may lead to metabolic risks, including heart disease, obesity, type 2 diabetes mellitus and several types of cancer. 
26959185	Organismal homeostasis relies on coherent interactions among tissues, specifically between brain-driven functions and peripheral metabolic organs. Hypothalamic circuits compute metabolic information to optimize energetic resources, but the role of the circadian clock in these pathways remains unclear. We have generated mice with targeted ablation of the core-clock gene Bmal1 within Sf1-neurons of the ventromedial hypothalamus (VMH). While this mutation does not affect the central clock in the suprachiasmatic nucleus (SCN), the VMH clock controls cyclic thermogenesis in brown adipose tissue (BAT), a tissue that governs energy balance by dissipating chemical energy as heat. VMH-driven control is exerted through increased adrenergic signaling within the sympathetic nervous system, without affecting the BAT's endogenous clock. Moreover, we show that the VMH circadian clock computes light and feeding inputs to modulate basal energy expenditure. Thus, we reveal a previously unsuspected circuit where an SCN-independent, hypothalamic circadian clock controls BAT function, energy expenditure, and thermogenesis.
26958101	There is a growing interest in the photosynthetic carbon fixation by microalgae for the production of valuable products from carbon dioxide (CO2). Microalgae are capable of transporting bicarbonate (HCO3 (-)), the most abundant form of inorganic carbon species in the water, as a source of CO2 for photosynthesis. Despite the importance of HCO3 (-) as the carbon source, little is known about the chemotactic response of microalgae to HCO3 (-). Here, we showed the chemotaxis of a model alga, Chlamydomonas reinhardtii, towards HCO3 (-) using an agarose gel-based microfluidic device with a flow-free and stable chemical gradient during the entire assay period. The device was validated by analyzing the chemotactic responses of C. reinhardtii to the previously known chemoattractants (NH4Cl and CoCl2) and chemotactically neutral molecule (NaCl). We found that C. reinhardtii exhibited the strongest chemotactic response to bicarbonate at the concentration of 26 mM in a microfluidic device. The chemotactic response to bicarbonate showed a circadian rhythm with a peak during the dark period and a valley during the light period. We also observed the changes in the chemotaxis to bicarbonate by an inhibitor of bicarbonate transporters and a mutation in CIA5, a transcriptional regulator of carbon concentrating mechanism, indicating the relationship between chemotaxis to bicarbonate and inorganic carbon metabolism in C. reinhardtii. To the best of our knowledge, this is the first report of the chemotaxis of C. reinhardtii towards HCO3 (-), which contributes to the understanding of the physiological role of the chemotaxis to bicarbonate and its relevance to inorganic carbon utilization. 
26955885	Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment. 
26955841	Several tools use prior biological knowledge to interpret gene expression data. However, existing enrichment tools assume that variables are monotonic and incorrectly measure the distance between periodic phases. As a result, these tools are poorly suited for the analysis of the cell cycle, circadian clock, or other periodic systems. Here, we develop Phase Set Enrichment Analysis (PSEA) to incorporate prior knowledge into the analysis of periodic data. PSEA identifies biologically related gene sets showing temporally coordinated expression. Using synthetic gene sets of various sizes generated from von Mises (circular normal) distributions, we benchmarked PSEA alongside existing methods. PSEA offered enhanced sensitivity over a broad range of von Mises distributions and gene set sizes. Importantly, and unlike existing tools, the sensitivity of PSEA is independent of the mean expression phase of the set. We applied PSEA to 4 published datasets. Application of PSEA to the mouse circadian atlas revealed that several pathways, including those regulating immune and cell-cycle function, demonstrate temporal orchestration across multiple tissues. We then applied PSEA to the phase shifts following a restricted feeding paradigm. We found that this perturbation disrupts intraorgan metabolic synchrony in the liver, altering the timing between anabolic and catabolic pathways. Reanalysis of expression data using custom gene sets derived from recent ChIP-seq results revealed circadian transcriptional targets bound exclusively by CLOCK, independently of BMAL1, differ from other exclusive circadian output genes and have well-synchronized phases. Finally, we used PSEA to compare 2 cell-cycle datasets. PSEA increased the apparent biological overlap while also revealing evidence of cell-cycle dysregulation in these cancer cells. To encourage its use by the community, we have implemented PSEA as a Java application. In sum, PSEA offers a powerful new tool to investigate large-scale, periodic data for biological insight. 
26953959	Generalized anxiety disorder (GAD) is a chronic and disabling disorder which is characterized by worrisome mentation about future outcomes. Because the evocative stimuli in GAD are largely internally derived, the feared outcomes contained in worry episodes can be invoked--and responded to--regardless of external context. We hypothesized that individuals with GAD would be entrained to internally-regulated, fixed patterns of anxiety on a day-to-day basis and that successful therapeutic intervention would serve to mitigate this entrainment. Thus, the present study examined the constructs of flexibility and rigidity as they apply to the daily fluctuation of anxious symptoms in individuals with GAD. We aimed to demonstrate that an apparently variable system can be conceptualized as rigid when the variability maps onto stable and predictable periodic oscillations. Sixty-nine individuals completed cognitive-behavioral treatment for GAD. Average age was 36.62 years (SD = 11.56), and participants were mostly Caucasian (89.5%) and female (68.4%). Daily-diary data indicating level of anxiety on a 0 to 100-point scale and collected four times per day were subjected to spectral analysis in order to determine the spectral power attributable to daily oscillations--which was related to the degree of rigidity in daily anxiety. Diurnal rigidity decreased throughout therapy and the degree to which rigidity was reduced significantly predicted reliable change at post-treatment. Thus, symptom rigidity can be conceptualized as stable periodic fluctuation and is discernible from other metrics of volatility in repeated measures data. Moreover, diurnal rigidity is significantly reduced during treatment, facilitating flexible responding to environmental demands.
26953792	Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5μL. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, we measured SMN protein in whole blood from SMA patients and healthy controls and found that SMN protein levels were associated with SMN2 copy number and were greater in SMA patients with 4 copies, relative to those with 2 and 3 copies. SMN protein levels did not vary significantly in healthy individuals over a four-week period and were not affected by circadian rhythms. Almost half of the SMN protein was found in platelets. We show that SMN protein levels in C/C-allele mice, which model a mild form of SMA, were high in neonatal stage, decreased in the first few weeks after birth, and then remained stable throughout the adult stage. Importantly, SMN protein levels in the CNS correlated with SMN levels measured in whole blood of the C/C-allele mice. These findings have implications for the measurement of SMN protein induction in whole blood in response to SMN-upregulating therapy. 
26953619	Our daily lives are influenced by three different daily timers: the solar clock, our endogenous circadian clock and the societal clock. The way an individual's endogenous clock synchronises to the solar clock, through either advances or delays relative to sunrise and sunset, results in a phenomenon known as diurnal preference or chronotype. South Africa uses just one time zone, but in the most easterly regions of the country, the sun rises and sets up to an hour earlier than in the most westerly regions throughout the year. It was hypothesised first that South Africans living in the east of the country may have a greater preference for mornings (more morning chronotypes) than those living in the west; and second, that this difference would not be due to genetic differences in the populations, particularly a genetic polymorphism previously shown to influence chronotype. Here, we describe and compare the distribution of chorotype and PERIOD3 variable number tandem repeat (VNTR) polymorphism frequency in eastern (n = 129) and western (n = 175) sample populations. Using the Horne-Östberg Morningness, Eveningness Questionnaire we found that there was a significantly higher proportion of morning-types in the eastern population (56.6%) than in the western population (39.4%), and there were higher proportions of neither-types and evening-types in the western population (51.4% and 9.1%, respectively) than in the eastern population (37.2% and 6.2%, respectively) (p = 0.009). There were no significant differences in distribution of the PER3 genotype (p = 0.895) and allele (p = 0.636) frequencies. Although previous studies have shown associations between chronotype and PER3 VNTR genotypes, no significant associations were observed in either the eastern (p = 0.695) or the western (p = 0.630) populations. These findings indicate that, in South African populations, longitude influences chronotype independently of PER3 genotype. The impacts of the differences in chronotype whilst maintaining the same societal temporal organisation in the eastern and western regions were not assessed. 
26953322	Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.
26951421	There is currently no questionnaire-based pre-screening tool available to detect non-24-hour sleep-wake rhythm disorder (N24HSWD) among blind patients. Our goal was to develop such a tool, derived from gold standard, objective hormonal measures of circadian entrainment status, for the detection of N24HSWD among those with visual impairment.We evaluated the contribution of 40 variables in their ability to predict N24HSWD among 127 blind women, classified using urinary 6-sulfatoxymelatonin period, an objective marker of circadian entrainment status in this population. We subjected the 40 candidate predictors to 1,000 bootstrapped iterations of a logistic regression forward selection model to predict N24HSWD, with model inclusion set at the p < 0.05 level. We removed any predictors that were not selected at least 1% of the time in the 1,000 bootstrapped models and applied a second round of 1,000 bootstrapped logistic regression forward selection models to the remaining 23 candidate predictors. We included all questions that were selected at least 10% of the time in the final model. We subjected the selected predictors to a final logistic regression model to predict N24SWD over 1,000 bootstrapped models to calculate the concordance statistic and adjusted optimism of the final model. We used this information to generate a predictive model and determined the sensitivity and specificity of the model. Finally, we applied the model to a cohort of 1,262 blind women who completed the survey, but did not collect urine samples.	The final model consisted of eight questions. The concordance statistic, adjusted for bootstrapping, was 0.85. The positive predictive value was 88%, the negative predictive value was 79%. Applying this model to our larger dataset of women, we found that 61% of those without light perception, and 27% with some degree of light perception, would be referred for further screening for N24HSWD.	Our model has predictive utility sufficient to serve as a pre-screening questionnaire for N24HSWD among the blind.	

26949880	The aim of this study was to investigate the prevalence and severity of firefighter sleep quality across department shift schedules.Sleep quality was assessed using a Pittsburgh Sleep Quality Index in a sample of 109 male career firefighters from six fire departments in three Southwestern US states. The three shift schedules studied were 24on/48off, 48on/96off, and Kelly.	Seventy-three percent of firefighters report poor sleep quality. The 24on/48off shift schedule is associated with the best sleep quality and Kelly is associated with the worst sleep quality. Firefighters working second jobs report significantly poorer sleep quality than those who do not.	Shift schedules that disrupt normal circadian rhythms more result in poorer sleep quality, which can lead to less effective emergency response and increased risk to firefighter health and safety.	
26949521	Plants use the circadian clock as a timekeeping mechanism to regulate photoperiodic flowering in response to the seasonal changes. CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1), initially identified as a central repressor of seedling photomorphogenesis, was recently shown to be involved in the regulation of light input to the circadian clock, modulating the circadian rhythm and flowering. COP1 encodes a RING-finger E3 ubiquitin ligase and works in concert with SUPPRESSOR of phyA-105 (SPA) proteins to repress photoperiodic flowering by regulating proteasome-mediated degradation of CONSTANS (CO), a central regulator of photoperiodic flowering. In addition, COP1 and EARLY FLOWERING 3 (ELF3) indirectly modulate CO expression via the degradation of GIGANTEA (GI). Here, we summarize the current understanding of the molecular mechanisms underlying COP1's role in controlling of photoperiodic flowering. 
26948972	There is a complex bidirectional relationship between sleep and epilepsy. Sleep/wake timing of seizures has been investigated for several individual seizure types and syndromes, but few large-scale studies of the timing of seizures exist in people with varied epilepsy types. In addition, the genetic contributions to seizure timing have not been well studied.Sleep/wake timing of seizures was determined for 1,395 subjects in 546 families enrolled in the Epilepsy Phenome/Genome Project (EPGP). We examined seizure timing among subjects with different epilepsy types, seizure types, epilepsy syndromes, and localization. We also examined the familial aggregation of sleep/wake occurrence of seizures.	Seizures in nonacquired focal epilepsy (NAFE) were more likely to occur during sleep than seizures in generalized epilepsy (GE), for both convulsive (odds ratio [OR] 5.2, 95% confidence interval [CI] 3.59-7.52) and nonconvulsive seizures (OR 4.2, 95% CI 2.48-7.21). Seizures occurring within 1 h of awakening were more likely to occur in patients with GE than with NAFE for both convulsive (OR 2.3, 95% CI 1.54-3.39) and nonconvulsive (OR 1.7, 95% CI 1.04-2.66) seizures. Frontal onset seizures were more likely than temporal onset seizures to occur during sleep. Sleep/wake timing of seizures in first-degree relatives predicted timing of seizures in the proband.	We found that sleep/wake timing of seizures is associated with both epilepsy syndrome and seizure type. In addition, we provide the first evidence for a genetic contribution to sleep/wake timing of seizures in a large group of individuals with common epilepsy syndromes.	
26947521	Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. 
26945906	Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. We found that the graded CR manipulation resulted in upregulation of core circadian rhythm genes, which correlated negatively with circulating levels of leptin, insulin-like growth factor 1 (IGF-1), insulin, and tumor necrosis factor alpha (TNF-α). In addition, key components in the hunger signaling pathway were expressed in a manner reflecting elevated hunger at greater levels of restriction, and which also correlated negatively with circulating levels of insulin, TNF-α, leptin and IGF-1. Lastly, phenotypes, such as food anticipatory activity and body temperature, were associated with expression levels of both hunger genes and core clock genes. Our results suggest modulation of the hunger and circadian signaling pathways in response to altered levels of circulating hormones, that are themselves downstream of morphological changes resulting from CR treatment, may be important elements in the response to CR, driving some of the key phenotypic outcomes. 
26945648	Seasonality in daily locomotor activity pattern was investigated in the subtropical tree sparrow by exposing a group of birds to natural day lengths (NDL) for 30days and another group to 12L/12D for 14days followed by transfer to constant dim light (LLdim) for another 15days in four different seasons of the year. Serum testosterone levels were also measured during different seasons. Sparrows, under NDL, exhibited distinct circadian rhythmicity in their locomotor activity with almost similar general pattern in different seasons that restricted mainly to the light hours. However, they showed season-dependent differences in the characteristics of circadian locomotor activity rhythm. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. Though, tau (τ) under free run conditions did not show any significant difference, the activity period varied significantly in different seasons. The highest level of testosterone was recorded in the spring season that corresponded with the maximum locomotor activity in spring months. The seasonality in daily locomotor activity correlates with the seasonal changes in testosterone levels suggesting the influence of gonadal steroids on endogenous circadian system which is indicative of adaptation of tree sparrow to local photoperiodic conditions. 
26945058	Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1(-/-)) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1(-/-)mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1(-/-)(also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.
26941366	Shift work-related carcinogenesis is hypothesized to be mediated by melatonin; however, few studies have considered the potential effect modification of this underlying pathway by chronotype or specific aspects of shift work such as the number of consecutive nights in a rotation. In this study, we examined melatonin patterns in relation to shift status, stratified by chronotype and number of consecutive night shifts, and cumulative lifetime exposure to shift work.Melatonin patterns of 261 female personnel (147 fixed-day and 114 on rotations, including nights) at Kingston General Hospital were analyzed using cosinor analysis. Urine samples were collected from all voids over a 48-hour specimen collection period for measurement of 6-sulfatoxymelatonin concentrations using the Buhlmann ELISA Kit. Chronotypes were assessed using mid-sleep time (MSF) derived from the Munich Chronotype Questionnaire (MCTQ). Sociodemographic, health, and occupational information were collected by questionnaire.	Rotational shift nurses working nights had a lower mesor and an earlier time of peak melatonin production compared to day-only workers. More pronounced differences in mesor and acrophase were seen among later chronotypes, and shift workers working ≥3 consecutive nights. Among nurses, cumulative shift work was associated with a reduction in mesor.	These results suggest that evening-types and/or shift workers working ≥3 consecutive nights are more susceptible to adverse light-at-night effects, whereas long-term shift work may also chronically reduce melatonin levels.	Cumulative and current exposure to shift work, including nights, affects level and timing of melatonin production, which may be related to carcinogenesis and cancer risk. Cancer Epidemiol Biomarkers Prev; 25(5); 830-8. ©2016 AACR.	
26941083	A significant proportion of the labor force works irregular hours during harvest, summer, or holiday work surges. Unfortunately such workers are often uninformed about the importance of sleep and fatigue management. Seasonally timed worker training can improve health and safety outcomes during work surges. 
26940770	Inactivation is an intrinsic property of several voltage-dependent ion channels, closing the conduction pathway during membrane depolarization and dynamically regulating neuronal activity. BK K(+) channels undergo N-type inactivation via their β2 subunit, but the physiological significance is not clear. Here, we report that inactivating BK currents predominate during the day in the suprachiasmatic nucleus, the brain's intrinsic clock circuit, reducing steady-state current levels. At night inactivation is diminished, resulting in larger BK currents. Loss of β2 eliminates inactivation, abolishing the diurnal variation in both BK current magnitude and SCN firing, and disrupting behavioural rhythmicity. Selective restoration of inactivation via the β2 N-terminal 'ball-and-chain' domain rescues BK current levels and firing rate, unexpectedly contributing to the subthreshold membrane properties that shift SCN neurons into the daytime 'upstate'. Our study reveals the clock employs inactivation gating as a biophysical switch to set the diurnal variation in suprachiasmatic nucleus excitability that underlies circadian rhythm. 
26938751	Diurnal frequent urination is a common condition in elementary school children who are especially at risk for associated somatic and behavioral problems. Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that has been used in both partial and generalized seizures and less commonly adverse effects including psychiatric and behavioral problems. Diurnal frequent urination is not a well-known adverse effect of LEV. Here, we reported 2 pediatric cases with epilepsy that developed diurnal frequent urination after LEV administration. Case 1 was a 6-year-old male patient who presented urinary frequency and urgency in the daytime since the third day after LEV was given as adjunctive therapy. Symptoms increased accompanied by the raised dosage of LEV. Laboratory tests and auxiliary examinations did not found evidence of organic disease. Diurnal frequent urination due to LEV was suspected, and then the drug was discontinued. As expected, his frequency of urination returned to normal levels. Another 13-year-old female patient got similar clinical manifestations after oral LEV monotherapy and the symptoms became aggravated while in stress state. Since the most common causes of frequent micturition had been ruled out, the patient was considered to be diagnosed with LEV-associated psychogenic frequent urination. The dosage of LEV was reduced to one-third, and the frequency of urination was reduced by 60%. Both patients got the Naranjo score of 6, which indicated that LEV was a "probable" cause of diurnal frequent urination. Although a definite causal link between LEV and diurnal urinary frequency in the 2 cases remains to be established, we argue that diurnal frequent urination associated with LEV deserves clinician's attention. 
26938655	The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRα) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxrα(-/-) males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxrα(-/-) males which display a female-like phenotype. We also show that circadian expression patterns of liver 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxrα(-/-) animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxα(-/-) females and could be explained by the change in corticosterone profile. Together this data indicates that LXRα is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRα in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRα targeted therapies.
26938057	Organisms quickly learn about their surroundings and display synaptic plasticity which is thought to be critical for their survival. For example, fruit flies Drosophila melanogaster exposed to highly enriched social environment are found to show increased synaptic connections and a corresponding increase in sleep. Here we asked if social environment comprising a pair of same-sex individuals could enhance sleep in the participating individuals. To study this, we maintained individuals of D. melanogaster in same-sex pairs for a period of 1 to 4 days, and after separation, monitored sleep of the previously socialized and solitary individuals under similar conditions. Males maintained in pairs for 3 or more days were found to sleep significantly more during daytime and showed a tendency to fall asleep sooner as compared to solitary controls (both measures together are henceforth referred to as "sleep-enhancement"). This sleep phenotype is not strain-specific as it is observed in males from three different "wild type" strains of D. melanogaster. Previous studies on social interaction mediated sleep-enhancement presumed 'waking experience' during the interaction to be the primary underlying cause; however, we found sleep-enhancement to occur without any significant increase in wakefulness. Furthermore, while sleep-enhancement due to group-wise social interaction requires Pigment Dispersing Factor (PDF) positive neurons; PDF positive and CRYPTOCHROME (CRY) positive circadian clock neurons and the core circadian clock genes are not required for sleep-enhancement to occur when males interact in pairs. Pair-wise social interaction mediated sleep-enhancement requires dopamine and olfactory signaling, while visual and gustatory signaling systems seem to be dispensable. These results suggest that socialization alone (without any change in wakefulness) is sufficient to cause sleep-enhancement in fruit fly D. melanogaster males, and that its neuronal control is context-specific. 
26937781	Biobank saliva sample quality depends on specific criteria applied to collection, processing, and storage. In spite of the growing interest in saliva as a diagnostic fluid, few biobanks currently store large collections of such samples. The development of a standard operating procedure (SOP) for saliva collection and quality control is fundamental for the establishment of a new saliva biobank, which stores samples to be made available to the saliva research community. Different collection methods were tested regarding total volume of protein obtained, protein content, and protein profiles, and the results were used to choose the best method for protein studies. Furthermore, the impact of the circadian variability and inter- and intraindividual differences, as well as the saliva sample stability at room temperature, were also evaluated. Considering our results, a sublingual cotton roll method for saliva collection proved to produce saliva with the best characteristics and should be applied in the morning, whenever possible. In addition, there is more variability in salivary proteins between individuals than in the same individual for a 5-month period. According to the electrophoretic protein profile, protein stability is guaranteed for 24 hours at room temperature and the protein degradation profile and protein identification were characterized. All this information was used to establish an SOP for saliva collection, processing, and storage in a biobank. We conclude that it is possible to collect saliva using an easy and inexpensive protocol, resulting in saliva samples for protein analysis with sufficient quality for biobanking purposes. 
26936778	Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.

26934362	Our goal was to model the temporal dynamics of sleep-wake transitions, represented by transitions between rest and activity obtained from actigraphic data, in patients with bipolar disorder using a probabilistic state transition approach.We collected actigraphic data for 14 days from 20 euthymic patients with bipolar disorder, who had been characterized clinically, demographically, and with respect to their circadian preferences (chronotype). We processed each activity record to generate a series of transitions in both directions between the states of rest (R) and activity (A) and plotted the estimated transition probabilities (pRA and pAR). Each 24-hour period was also divided into a rest phase consisting of the eight consecutive least active hours in each day and an active phase consisting of the 16 consecutive most active hours in each day. We then calculated separate transition probabilities for each of these phases for each participant. We subsequently modeled the rest phase data to find the best fit for rest-activity transitions using maximum likelihood estimation. We also examined the association of transition probabilities with clinical and demographic variables.	The best-fit model for rest-activity transitions during the rest phase was a mixture (bimodal) of exponential functions. Of those patients with rapid cycling, 75% had an evening-type chronotype. Patients with bipolar II disorder taking antidepressants had a lower probability of transitioning back to rest than those not on antidepressants [mean ± SD = 0.050 ± 0.006 versus 0.141 ± 0.058, F(1,15) = 3.40, p < 0.05].	The dynamics of transitions between rest and activity in bipolar disorder can be accounted for by a mixture (bimodal) of exponential functions. Patients taking antidepressants had a reduced probability of sustaining and returning to sleep.	

26930624	Lithium is widely used as a treatment of bipolar disorder, a neuropsychiatric disorder associated with disrupted circadian rhythms. Lithium is known to lengthen period and increase amplitude of circadian rhythms. One possible pathway for these effects involves inhibition of glycogen synthase kinase-3β (GSK-3β), which regulates degradation of CRY2, a canonical clock protein determining circadian period. CRY1 is also known to play important roles in regulating circadian period and phase, although there is no evidence that it is similarly phosphorylated by GSK-3β. In this paper, we tested the hypothesis that lithium affects circadian rhythms through CRYs. We cultured fibroblasts and slices of the suprachiasmatic nucleus (SCN), the master circadian pacemaker of the brain, from Cry1-/-, Cry2-/-, or wild-type (WT) mice bearing the PER2:LUC circadian reporter. Lithium was applied in the culture medium, and circadian rhythms of PER2 expression were measured. In WT and Cry2-/- fibroblasts, 10mM lithium increased PER2 expression and rhythm amplitude but not period, and 1mM lithium did not affect either period or amplitude. In non-rhythmic Cry1-/- fibroblasts, 10mM lithium increased PER2 expression. In SCN slices, 1mM lithium lengthened period ∼1h in all genotypes, but did not affect amplitude except in Cry2-/- SCN. Thus, the amplitude-enhancing effect of lithium in WT fibroblasts was unaffected by Cry2 knockout and occurred in the absence of period-lengthening, whereas the period-lengthening effect of lithium in WT SCN was unaffected by Cry1 or Cry2 knockout and occurred in the absence of rhythm amplification, suggesting that these two effects of lithium on circadian rhythms are independent of CRYs and of each other. 
26930260	In birds, circadian control of tissue level communication is not well understood. The present study investigated this, by monitoring daily oscillation of genes coding for peptides (neuropeptide Y, NPY; vasoactive intestinal peptide, VIP; somatostatis, SST) and intermediary enzymes of amine and amino acid neurotransmitters (dopamine [tyrosine hydroxylase, TH]; glutamate [glutaminase, GLS; glutamate oxaloacetate transaminase 2, GOT2]; gamma amino butyric actid, GABA [glutamic acid decarboxylase 65, GAD65]) biosynthetic pathway, along with c-FOS as an activation marker, in different tissues of migratory redheaded buntings, Emberiza bruniceps. We cloned a partial sequence of these genes, and measured their mRNA expression in the 'central' clock (retina, hypothalamus) and peripheral (heart, stomach, gut, liver) tissues, collected at six times (ZT 2, 6, 11, 13, 18 and 23; ZT 0 = lights on) from birds (n = 4/ ZT) in the 12 h:12 h light-dark cycle. There were daily mRNA oscillations of all genes, although with a tissue-specific expression pattern as well as with the differential phase relationships in genes within and between tissues. These results support a conserved tissue level circadian regulation of genes coding for peptide, amine and amino acid neurotransmitters, and substantiate the expression and plausible role of neurotransmitters in the peripheral tissues. We suggest a tissue-specific contribution of neurotransmitters in the circadian regulation of physiology and behaviour in a seasonal migratory species, the redheaded bunting. 
26930172	Research on chronotypic differences has been conducted for many years, however, until recently, little attention has been paid to young children. The current study examined the influence of morningness-eveningness in the daily lives of 2 to 4 year olds (291 females, 230 males, 8 gender not given) via an online survey completed by 529 mothers from across the United States. The results replicated previous findings on chronotypic differences in sleep-wake patterns and the development of morningness-eveningness in early childhood. The influence of chronotype on sleep habits, daily routines and schedules was also explored. At both bed and wake times, mothers of evening type (E-type) children were more likely to report challenges. For a while, morning type (M-type) children tended to fall asleep easily and wake themselves up in the morning, E-types were more likely to show bedtime resistance, wake in a negative mood and have conflicts with their parents. In the morning, mothers of M-type children often stuck to their normal routine on days when the child had to be somewhere at 7:00 am, whereas mothers of E-type children employed different strategies to get their child up and out the door. Bedtime routines and daily schedules also differed by chronotype. Individual differences in morningness-eveningness and their impact on sleep-wake patterns and social interactions are evident early on. A greater understanding of how they affect the lives of young children and their future development is needed. 
26930129	Growth factors in vertebrates display daily rhythms, which, while widely described in mammals, are still poorly understood in teleost fish. Here, we investigated the existence of daily rhythms in the somatotropic axis of the flatfish Solea senegalensis. In a first experiment, daily rhythms of the expression of pituitary adenylate cyclase-activating polypeptide (pacap), growth hormone (gh), insulin-like growth factor 1 (igf1) and its receptor (igf1r) were analyzed under a 12:12 h light:dark cycle. All genes displayed daily rhythms with the acrophases of pacap, gh and igf1 located in the second half of the dark phase (ZT 20:28-0:04 h), whereas the acrophase of igf1r was located around mid-light (ZT 5:33 h). In a second experiment, the influence of the time of day (mid-light, ML, versus mid-darkness, MD) of GH administration on the expression of these factors and on plasma glucose levels was tested. The response observed depended on the time of injection: the strongest effects were observed at MD, when GH administration significantly reduced pituitary gh and enhanced liver igf1 expression. These results provide the first evidence of daily rhythms and differential day/night effects in growth factors in S. senegalensis, suggesting new insights for investigating the physiology of growth and possible applications to improve fish aquaculture. 
26928887	We aimed to explore the association between family conflict and HPA axis activity, especially with respect to the potential modulating effect of puberty. A total of 205 adolescents and 244 adult parents were recruited. Family conflict was assessed by the family conflict subscale of the Family Environmental Scale and serial salivary cortisol was measured in all participants. A marginally lower AUCg at 30 minutes after wake up in the morning and a significant lower AUCg at 60 minutes and 90 minutes in adult parents with high family conflict was found when compared to those with low family conflict. In adolescents, there were significant interaction effects between pubertal status and family conflict on AUCg (interaction p values <0.05). Among the adolescents with low family conflict, those at late/post pubertal status had higher AUCg than their pre/early pubertal counterparts but this difference was not observed in the adolescents with high family conflict. Adverse family environment is associated with HPA axis dysfunction in adults and late/post pubertal adolescents and pubertal maturation plays a critical role in modulating the association between family environment and HPA axis function. 
26928065	Twenty-four hour rhythms in behavior are organized by a network of circadian pacemaker neurons. Rhythmic activity in this network is generated by intrinsic rhythms in clock neuron physiology and communication between clock neurons. However, it is poorly understood how the activity of a small number of pacemaker neurons is translated into rhythmic behavior of the whole animal. To understand this, we screened for signals that could identify circadian output circuits in Drosophila melanogaster. We found that leucokinin neuropeptide (LK) and its receptor (LK-R) were required for normal behavioral rhythms. This LK/LK-R circuit connects pacemaker neurons to brain areas that regulate locomotor activity and sleep. Our experiments revealed that pacemaker neurons impose rhythmic activity and excitability on LK- and LK-R-expressing neurons. We also found pacemaker neuron-dependent activity rhythms in a second circadian output pathway controlled by DH44 neuropeptide-expressing neurons. We conclude that rhythmic clock neuron activity propagates to multiple downstream circuits to orchestrate behavioral rhythms. 
26927666	Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT. 
26927164	Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988-1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%-12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles. 
26927084	Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future. 
26926884	An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK and hPER3 proteins, respectively. In addition, hCLOCK expression is affected by glucocorticoids, consistent with the sex-dependency of the genetic associations and the modulation of glucocorticoid-mediated stress response, providing a mechanism by which the circadian clock controls outputs that may affect psychiatric disorders. We conclude that genetic polymorphisms in circadian genes (especially hClock and hPer3, where functional assays could be tested) influence risk of developing depression in a sex- and stress-dependent manner. These studies support a genetic connection between circadian disruption and mood disorders, and confirm a key connection between circadian gene variation and major depression. 
26926165	The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells. 
26926115	Circadian clocks enable organisms to anticipate daily changes in the environment and coordinate temporal rhythms in physiology and behavior with the 24-h day-night cycle. The robust cycling of circadian gene expression is critical for proper timekeeping, and is regulated by transcription factor binding, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Recently, it has become clear that dynamic alterations in chromatin landscape at the level of histone posttranslational modification and nucleosome density facilitate rhythms in transcription factor recruitment and RNAPII activity, and are essential for progression through activating and repressive phases of circadian transcription. Here, we discuss the characterization of the BRAHMA (BRM) chromatin-remodeling protein in Drosophila in the context of circadian clock regulation. By dissecting its catalytic vs. non-catalytic activities, we propose a model in which the non-catalytic activity of BRM functions to recruit repressive factors to limit the transcriptional output of CLOCK (CLK) during the active phase of circadian transcription, while the primary function of the ATP-dependent catalytic activity is to tune and prevent over-recruitment of negative regulators by increasing nucleosome density. Finally, we divulge ongoing efforts and investigative directions toward a deeper mechanistic understanding of transcriptional regulation of circadian gene expression at the chromatin level. 
26925229	Enhanced colorectal sensitivity (i.e. visceral hypersensitivity) is thought to be a pathophysiological mechanism in irritable bowel syndrome (IBS). In healthy men a circadian variation in rectal perception to colonic distention was described. Disturbed day and night rhythms, which occur in shift work and trans meridian flights, are associated with the prevalence of IBS. This raises the question whether disruptions of circadian control are responsible for the observed pathology in IBS. Prior to investigating altered rhythmicity in relation to visceral hypersensitivity in a rat model for IBS, it is relevant to establish whether normal rats display circadian variation similar to healthy men. In rodents colorectal distension leads to reproducible contractions of abdominal musculature. We used quantification of this so called visceromotor response (VMR) by electromyography (EMG) to assess visceral sensitivity in rats. We assessed the VMR in normal male Long Evans rats at different time points of the light/dark cycle. Although a control experiment with male maternal separated rats confirmed that intentionally inflicted (i.e. stress induced) changes in VMR can be detected, normal male Long Evans rats showed no variation in VMR along the light/dark cycle in response to colorectal distension.	In the absence of a daily rhythm of colorectal sensitivity in normal control rats it is not possible to investigate possible aberrancies in our rat model for IBS.	
26923944	Circadian rhythm, which is controlled by circadian genes, regulates metabolic balance including the circulating levels of glucose, fatty acids, triglycerides, various hormones and so on. The study aimed to investigate the impact of potential polymorphisms in circadian genes on abdominal obesity among Chinese Han adults.A total of 260 cases with abdominal obesity and 260 controls were recruited by individual matching. Demographic characteristics and lifestyle information were collected by a validated questionnaire, and anthropometric parameters was measured by physical examination. Twenty-three single nucleotide polymorphisms (SNPs) in three circadian genes, CLOCK, CRY1 and CRY2, were genotyped by MassArray technique.	Five SNPs significantly deviated from Hardy-Weinberg equilibrium (HWE) among controls, so eighteen SNPs were taken into logistic regression analysis. Independently, CLOCK rs10002541 (CC genotype vs. TT genotype: OR: 0.45, 95% CI: 0.23-0.86), CLOCK rs6850524 (CC genotype vs. GG genotype: OR: 0.50, 95% CI: 0.25-0.99) and CRY1 rs10861688 (TT genotype vs. CC genotype: OR: 0.50, 95% CI: 0.25-0.97) were negatively associated with the risk of abdominal obesity. Haplotype analysis showed that the haplotypes of CG and TG for CLOCK rs10002541 and rs4864546 had significant associations with abdominal obesity. Compared with the carriers of TA, those of CG were observed to have a lower risk (OR: 0.74, 95% CI: 0.56-0.99) of abdominal obesity, and those of TG presented a higher risk (OR: 1.70, 95% CI: 1.03-2.81).	Our findings suggest that CLOCK and CRY1 polymorphisms might be involved in individual susceptibility to abdominal obesity in Chinese Han population.	
26923637	Disruption of circadian rhythm is associated with cancer development and progression. MicroRNAs (miRNAs) are a class of small non-coding RNAs that trigger mRNA translation inhibition. We aimed to evaluate the role of Per1 and related miRNAs in cholangiocarcinoma growth.The expression of clock genes was evaluated in human cholangiocarcinoma tissue arrays and cholangiocarcinoma lines. The rhythmic expression of clock genes was evaluated in cholangiocarcinoma cells and H69 (non-malignant cholangiocytes) by qPCR. We measured cell proliferation, cell cycle and apoptosis in Mz-ChA-1 cells after Per1 overexpression. We examined tumor growth in vivo after injection of Per1 overexpressing cells. We verified miRNAs that targets Per1. The circadian rhythm of miR-34a was evaluated in cholangiocarcinoma and H69 cells. We evaluated cell proliferation, apoptosis and invasion after inhibition of miR-34a in vitro, and the potential molecular mechanisms by mRNA profiling after overexpression of Per1.	Expression of Per1 was decreased in cholangiocarcinoma. The circadian rhythm of Per1 expression was lost in cholangiocarcinoma cells. Decreased cell proliferation, lower G2/M arrest, and enhanced apoptosis were shown in Per1 overexpressing cells. An in vivo study revealed decreased tumor growth, decreased proliferation, angiogenesis and metastasis after overexpressing Per1. Per1 was verified as a target of miR-34a. miR-34a was rhythmically expressed in cholangiocarcinoma cells and H69. The inhibition of miR-34a decreased proliferation, migration and invasion in cholangiocarcinoma cells. mRNA profiling has shown that overexpression of Per1 inhibits cell growth through regulation of multiple cancer-related pathways, such as cell cycle, cell growth and apoptosis pathways.	Disruption of circadian rhythms of clock genes contribute to the malignant phenotypes of human cholangiocarcinoma.	The current study is about how biological clock and its regulators affect the bile duct tumor growth. The disruption of biological clock has a negative impact in different cancers. Per1 is a gene that is involved in maintaining the biological clock and show 24h oscillation. Reduced levels of Per1 and disruption of 24h circadian rhythm was found in bile duct cancer cells. Therefore, a genetic modified bile duct cancer cells was created. It has a higher level of Per1 expression and partially recovered circadian rhythm. Those genetic modified cells also displayed slower cell growth or higher rate of cell death. We also used mice model that lack of immune system to show that our genetic modified bile duct cells form smaller tumor. In addition, we tried to see how Per1 is communicating with other genes in regarding of controlling the tumor growth. We found Per1 is regulated by microRNA-34a, a small non-coding RNA that directly binds to genes and inhibit gene expression. Decreased level of miR-34a has also significantly reduced tumor growth through controlling the cell growth and cell death balance. Therefore bile duct cancer patients may be treated with miR-34a inhibitor or Per1 stimulator in the future.	
26922944	Cluster headache (CH) is regarded as a chronobiological disorder. The hypothalamic biological clock may thus be involved in the pathophysiology, but few studies have actually investigated this in CH patients. A variable number tandem repeat (VNTR) polymorphism of the PER3 clock gene has been associated to preferred daily rhythm (chronotype) in several studies. We aimed to study the distribution of PER3 VNTR polymorphisms and chronotypes in a CH population.We used blood samples from a biobank of CH patients for genetic tests, and invited all tested patients to complete the Horne-Ostberg Morningness-eveningness Questionnaire (MEQ), the Pittsburgh sleep quality Index (PSQI) and the Shift Work Index. Genotypes were compared to a previously tested population of 432 healthy students.	One hundred forty nine patients were genotyped, and we found no difference in PER3 VNTR polymorphisms between patients and controls. Seventy-four patients completed the MEQ (54 men, 20 women, mean age 52.3 years ± 13.4), and chronotypes were as follows: 12 % morning-, 37 % intermediate-, and 51 % evening types. Compared with a previous Danish study of CH patients and controls, there were no difference in chronotype distribution. Sixty percent of patients were defined as bad sleepers (PSQI >5), and 51 % of patients currently employed were shift workers.	No association between CH, PER3 VNTR polymorphism and chronotype was found in this study.	
26922082	The hypothesis that circadian clocks confer adaptive advantage to organisms has been proposed based on its ubiquity across almost all levels of complexity and organization of life-forms. This thought has received considerable attention, and studies employing diverse strategies have attempted to investigate it. However, only a handful of them have examined how selection for circadian clock controlled rhythmic behaviors influences life-history traits which are known to influence Darwinian fitness. The 'early' and 'late' chronotypes are amongst the most widely studied circadian phenotypes; however, life-history traits associated with these chronotypes, and their consequences on Darwinian fitness remain largely unexplored, primarily due to the lack of a suitable model system. Here we studied several life-history traits of Drosophila melanogaster populations that were subjected to laboratory selection for morning (early) and evening (late) emergence.We report that the late eclosion chronotypes evolved longer pre-adult duration as compared to the early eclosion chronotypes both under light/dark (LD) and constant dark (DD) conditions, and these differences appear to be mediated by both clock dependent and independent mechanisms. Furthermore, longer pre-adult duration in the late chronotypes does not lead to higher body-mass at pupariation or eclosion, but the late females were significantly more fecund and lived significantly shorter as compared to the early females.	Coevolution of multiple life-history traits in response to selection on timing of eclosion highlights correlations of the genetic architecture governing timing of eclosion with that of fitness components which suggests that timing ecologically relevant behaviors at specific time of the day might confer adaptive advantage.	
26921714	Measures of brain morphometry derived from T1-weighted (T1W) magnetic resonance imaging (MRI) are widely used to elucidate the relation between brain structure and function. However, the computation of T1W morphometric measures can be confounded by subject-related factors such as head motion and level of hydration. A recent study reported subtle yet significant changes in brain volume from morning to evening in a large group of patient populations as well as in healthy elderly individuals. In addition, there is a growing recognition that factors such as circadian rhythm can impact MRI measures of brain function and structure. Here, we provide a comprehensive assessment of the impact of time-of-day (TOD) on widely used measures of brain morphometry in a group of 19 healthy young adults. Our results show that (a) even in a small group of healthy adult volunteers, a highly significant reduction in apparent brain volume, from morning to evening, could be detected; (b) the apparent volume of all three major tissue compartments - gray matter, white matter, and cerebrospinal fluid - were influenced by TOD, and the magnitude of the TOD effect varied across the tissue compartments; (c) measures of cortical thickness, cortical surface area, and gray matter density computed with widely used neuroimaging software suites (i.e., FreeSurfer, FSL-VBM) were all affected by TOD, while other measures, such as curvature indices and sulcal depth, were not; and (d) the effect of TOD appeared to have a greater impact on morphometric measures of the frontal and temporal lobe than on other major lobes of the brain. Our results suggest that the TOD effect is a physiological phenomenon and that controlling for the effect of TOD is crucial for proper interpretation of apparent structural differences measured with T1W morphometry. 
26920423	The deposition of β-amyloid protein (Aβ) is one of the pathological characteristics of Alzheimer's disease (AD) and can disrupt circadian rhythm and impair learning and memory. Exendin-4, a therapeutic drug for type II diabetes mellitus (T2DM), exerts neuroprotective effects from the toxicity of Aβ. However, it is not clear whether Exendin-4 protects against Aβ-induced disruption of circadian rhythm. The neuroprotective effects of Exendin-4 have been studied using injection of Exendin-4 into the lateral ventricle and abdomen. However, these procedures are not suitable for clinical application.First, male C57BL/6 mice received triple distilled water or Exendin-4 (0.1 nmol, 0.5 nmol) by intranasal administration. Exendin-4 levels were measured in the hippocampal samples using an ELISA Kit. Then, the study examined whether intranasal or hippocampal administration of Exendin-4 antagonized Aβ-induced disruption of circadian rhythm as well as impairment of learning and memory using the wheel-running activity assay and the Morris water maze test.	The study showed that intranasally administered Exendin-4 passed through the blood-brain barrier. Aβ31-35 given by intrahippocampal injection disrupted circadian rhythm and impaired learning and memory in C57BL/6 mice, and Exendin-4 given by nasal cavity or hippocampal administration ameliorated Aβ31-35-induced circadian rhythm disturbance of locomotor activity and impairment of learning and memory.	These findings provide pivotal experimental support for further study of the neuroprotective effects and clinical application of Exendin-4.	
26920328	One way of ensuring the continuity of health care is the shift work, which is burdensome and it can lead to sleep disturbances.The aim of the study was to measure the typical Hungarian nursing shift systems in hospitals, to analyse the causes of irregular work schedules, and to compare the sleep quality of nurses in different work schedules.	236 head nurses filled out the national online survey, and 217 nurses in clinics of the University of Pécs filled the Hungarian version of Bergen Shift Work Sleep Questionnaire.	The head nurses provided data of 8697 nurses's schedules. 51.89% of nurses work in flexible shift system. 1944 employees work in regular shift system, most of them in the following order: 12-hour day shift and 12-hour night shift, followed by a one- or two-day rest. Where there is no system of shifts, the most frequent causes are the needs of nurses and the nurse shortage. Nurses who are working in irregular shift system had worse sleep quality than nurses who are working in flexible and regular shift system (p = 0.044).	It would be helpful if the least burdensome shift system could be established.	
26920093	Microalgal triacylglycerol (TAG), a promising source of biofuel, is induced upon nitrogen starvation (-N), but the proteins and genes involved in this process are poorly known. We performed isobaric tagging for relative and absolute quantification (iTRAQ)-based quantitative proteomics to identify Chlorella proteins with modulated expression under short-term -N. Out of 1736 soluble proteins and 2187 membrane-associated proteins identified, 288 and 56, respectively, were differentially expressed under -N. Gene expression analysis on select genes confirmed the same direction of mRNA modulation for most proteins. The MYB-related transcription factor ROC40 was the most induced protein, with a 9.6-fold increase upon -N. In a previously generated Chlamydomonas mutant, gravimetric measurements of crude total lipids revealed that roc40 was impaired in its ability to increase the accumulation of TAG upon -N, and this phenotype was complemented when wild-type Roc40 was expressed. Results from radiotracer experiments were consistent with the roc40 mutant being comparable to the wild type in recycling membrane lipids to TAG but being impaired in additional de novo synthesis of TAG during -N stress. In this study we provide evidence to support the hypothesis that transcription factor ROC40 has a role in -N-induced lipid accumulation, and uncover multiple previously unknown proteins modulated by short-term -N in green algae. 
26919600	To evaluate circadian and postprandial variations in plasma citrulline concentration in healthy dogs.8 healthy Beagles.	Blood samples were collected from dogs after 12 hours of food withholding (0 hours; 8:00 am) and then every 2 hours for 12 hours (until 8:00 pm) and again at 24 hours (8:00 am the next day). The same protocol was repeated, with the only difference being that a meal was given immediately after the 0-hour sample collection point. Plasma citrulline concentration was measured by ion exchange chromatography.	No significant difference in plasma citrulline concentration was identified among measurement points when food was withheld. Mean ± SD plasma citrulline concentration at 4 hours (72.2 ± 12.7 μmol/L) and 24 hours (56.1 ± 12.5 μmol/L) after dogs were fed was significantly different from that at 0 hours (64.4 ± 12.7 μmol/L).	Plasma citrulline concentration had no circadian variation in unfed dogs but increased significantly in fed dogs 4 hours after a meal. Therefore, food should be withheld from dogs for 8 to 12 hours before blood sample collection for measurement of citrulline concentration.	
26919177	Prehypertension is related to a higher risk of cardiovascular events than normotension. Our previous study reported that cold exposure elevates the amplitude of the morning blood pressure surge (MBPS) and is associated with a sympathetic increase during the final sleep transition, which might be critical for sleep-related cardiovascular events in normotensives. However, few studies have explored the effects of cold exposure on autonomic function during sleep transitions and changes of autonomic function among prehypertensives. Therefore, we conducted an experiment for testing the effects of cold exposure on changes of autonomic function during sleep and the MBPS among young prehypertensives are more exaggerate than among young normotensives. The study groups consisted of 12 normotensive and 12 prehypertensive male adults with mean ages of 23.67 ± 0.70 and 25.25 ± 0.76 years, respectively. The subjects underwent cold (16°C) and warm (23°C) conditions randomly. The room temperature was maintained at either 23°C or 16°C by central air conditioning and recorded by a heat-sensitive sensor placed on the forehead and extended into the air. BP was measured every 30 minutes by using an autonomic BP monitor. Electroencephalograms, electrooculograms, electromyograms, electrocardiograms, and near body temperature were recorded by miniature polysomnography. Under cold exposure, a significantly higher amplitude of MBPS than under the warm condition among normotensives; however, this change was more exaggerated in prehypertensives. Furthermore, there was a significant decrease in parasympathetic-related RR and HF during the final sleep transition and a higher early-morning surge in BP and in LF% among prehypertensives, but no such change was found in normotensives. Our study supports that cold exposure might increase the risk of sleep-related cardiovascular events in prehypertensives. 
26918440	Antarctic residence holds many challenges to human physiology, like increased psycho-social tension and altered circadian rhythm, known to influence sleep. We assessed changes in sleep patterns during 13 months of overwintering at the German Stations Neumayer II and III from 2008 to 2014, with focus on gender, as many previous investigations were inconclusive regarding gender-based differences or had only included men.Time in bed, sleep time, sleep efficiency, number of arousals, sleep latency, sleep onset, sleep offset, and physical activity level were determined twice per month during seven overwintering campaigns of n = 54 participants (37 male, 17 female) using actimetry. Data were analyzed using polynomial regression and analysis of covariance for change over time with the covariates gender, inhabited station, overwintering season and influence of physical activity and local sunshine radiation.	We found overall longer times in bed (p = 0.004) and sleep time (p = 0.014) for women. The covariate gender had a significant influence on time in bed (p<0.001), sleep time (p<0.001), number of arousals (p = 0.04), sleep latency (p = 0.04), and sleep onset (p<0.001). Women separately (p = 0.02), but not men (p = 0.165), showed a linear increase in number of arousals. Physical activity decreased over overwintering time for men (p = 0.003), but not for women (p = 0.174). The decline in local sunshine radiation led to a 48 minutes longer time in bed (p<0.001), 3.8% lower sleep efficiency (p<0.001), a delay of 32 minutes in sleep onset (p<0.001), a delay of 54 minutes in sleep offset (p<0.001), and 11% less daily energy expenditure (p<0.001), for all participants in reaction to the Antarctic winter's darkness-phase.	Overwinterings at the Stations Neumayer II and III are associated with significant changes in sleep patterns, with dependences from overwintering time and local sunshine radiation. Gender appears to be an influence, as women showed a declining sleep quality, despite that their physical activity remained unchanged, suggesting other causes such as a higher susceptibility to psycho-social stress and changes in environmental circadian rhythm during long-term isolation in Antarctica.	
26917772	In Drosophila, molecular clocks control circadian rhythmic behavior through a network of ~150 pacemaker neurons. To explain how the network's neuronal properties encode time, we performed brainwide calcium imaging of groups of pacemaker neurons in vivo for 24 hours. Pacemakers exhibited daily rhythmic changes in intracellular Ca(2+) that were entrained by environmental cues and timed by molecular clocks. However, these rhythms were not synchronous, as each group exhibited its own phase of activation. Ca(2+) rhythms displayed by pacemaker groups that were associated with the morning or evening locomotor activities occurred ~4 hours before their respective behaviors. Loss of the receptor for the neuropeptide PDF promoted synchrony of Ca(2+) waves. Thus, neuropeptide modulation is required to sequentially time outputs from a network of synchronous molecular pacemakers. 
26917036	Ecto-5'-nucleotidase (eN) is the major extracellular adenosine-producing ecto-enzyme in mouse brain. Via the production of adenosine, eN participates in many physiological and pathological processes, such as wakefulness, inflammation, nociception and neuroprotection. The mechanisms regulating the expression of eN are therefore of considerable neurobiological and clinical interest. Having previously described a modulatory effect of melatonin in the regulation of eN mRNA levels, we decided to analyze the melatonin receptor subtype involved in the regulation of eN mRNA levels by comparing eN mRNA patterns in melatonin-proficient transgenic mice lacking either the melatonin receptor subtype 1 (MT1 KO) or both melatonin receptor subtypes (MT1 and MT2; MT1/2 KO) with the corresponding melatonin-proficient wild-type (WT) controls. By means of radioactive in situ hybridization, eN mRNA levels were found to be diminished in both MT1 and MT1/2 KO mice compared with WT controls suggesting stimulatory impacts of melatonin receptors on eN mRNA levels. Whereas eN mRNA levels increased during the day and peaked at night in WT and MT1 KO mice, eN mRNA levels at night were reduced and the peak was shifted toward day-time in double MT1/2 KO mice. These data suggest that the MT2 receptor subtype may play a role in the temporal regulation of eN mRNA availability. Notably, day-time locomotor activity was significantly higher in MT1/2 KO compared with WT mice. Our results suggest melatoninergic signaling as an interface between the purinergic system and the circadian system. 
26915801	The circadian clock has been demonstrated playing important roles in human tumorigenic process; however, the detailed clinical implications of circadian disruption on tumors have not been well understood. In this study, we investigated the expression pattern of Bmal1, the core component of the circadian system, in human pancreatic ductal adenocarcinoma (PDA). Our immunohistochemistry analysis showed that the protein level of Bmal1 was significantly decreased in tumor tissues from 87 patients with PDA compared with adjacent non-cancerous tissues. Low Bmal1 expression was associated with the TNM/clinical stage, histological differentiation, and vascular invasion of PDA; but no significant relevance to patient age, gender, the tumor location, or the size. Furthermore, Kaplan-Meier survival analysis revealed that PDA patients with low Bmal1 expression had shorter overall survival (OS) times as well as disease-free times (DFS) compared to the patients with high Bmal1 expression. Lastly, univariate and multivariate analyses identified low Bmal1 expression as an independent prognostic factor for poor survival outcome for patients with PDA. Collectively, our present study demonstrated that the decreased expression of Bmal1 is correlated with the tumor progression and poor prognosis in human PDA, which implicated its potential to be used as a biomarker for diagnosis and prognosis of PDA. 
26915576	To investigate if shift work or sleep disturbances are risk factors for central serous chorioretinopathy (CSCR).Prospective case-control study.	Forty patients with active CSCR and 40 controls (age- and sex-matched) were prospectively recruited from the Ophthalmology Department of Hôtel Dieu Hospital, Paris, between November 2013 and December 2014. All patients were asked to complete a questionnaire addressing previously described risk factors and working hours, as well as the Insomnia Severity Index (ISI), a validated instrument for assessing sleep disturbances.	The mean age of the CSCR group was 44 ± 9 years, whereas the mean age of the control group was 43 ± 10 years. By use of multivariate analysis, shift work (odds ratio [OR] [95% confidence interval]: 5 [1.2-20.4]; P = .02), steroid use (OR: 5.5 [1.1-26.2]; P = .03), and recent psychological stress (OR: 15.3 [4.1-54.5]; P < .001) were found to be independently associated with CSCR.	The outcomes of this study suggest that shift work is an independent risk factor of CSCR. Further studies are required to confirm these results and to examine if work reconversion would be beneficial in the treatment of patients with chronic/recurrent CSCR.	
26915143	A wearable thermometry for core body temperature (CBT) measurement has both healthcare and clinical applications. On the basis of the mechanism of bioheat transfer, we earlier designed and improved a wearable thermometry using the dual-heat-flux method for CBT measurement. In this study, this thermometry is examined experimentally. We studied a fast-changing CBT measurement (FCCM, 55 min, 12 subjects) inside a thermostatic chamber and performed long-term monitoring of CBT (LTM, 24 h, six subjects). When compared with a reference, the CoreTemp CM-210 by Terumo, FCCM shows 0.07 °C average difference and a 95% CI of [-0.27, 0.12] °C. LTM shows no significant difference in parameters for the inference of circadian rhythm. The FCCM and LTM both simulated scenarios in which this thermometry could be used for intensive monitoring and daily healthcare, respectively. The results suggest that because of its convenient design, this thermometry may be an ideal choice for conventional CBT measurements.
26915140	Core body temperature is a reliable marker for circadian rhythm. As characteristics of the circadian body temperature rhythm change during diverse health problems, such as sleep disorder and depression, body temperature monitoring is often used in clinical diagnosis and treatment. However, the use of current thermometers in circadian rhythm monitoring is impractical in daily life. As heart rate is a physiological signal relevant to thermoregulation, we investigated the feasibility of heart rate monitoring in estimating circadian body temperature rhythm. Various heart rate parameters and core body temperature were simultaneously acquired in 21 healthy, ambulatory subjects during their routine life. The performance of regression analysis and the extended Kalman filter on daily body temperature and circadian indicator (mesor, amplitude, and acrophase) estimation were evaluated. For daily body temperature estimation, mean R-R interval (RRI), mean heart rate (MHR), or normalized MHR provided a mean root mean square error of approximately 0.40 °C in both techniques. The mesor estimation regression analysis showed better performance than the extended Kalman filter. However, the extended Kalman filter, combined with RRI or MHR, provided better accuracy in terms of amplitude and acrophase estimation. We suggest that this noninvasive and convenient method for estimating the circadian body temperature rhythm could reduce discomfort during body temperature monitoring in daily life. This, in turn, could facilitate more clinical studies based on circadian body temperature rhythm.
26915078	Aging is associated with changes in sleep duration and quality, as well as increased rates of pathologic/disordered sleep. While several factors contribute to these changes, emerging research suggests that age-related changes in the mammalian central circadian clock within the suprachiasmatic nucleus (SCN) may be a key factor. Prior work from our group suggests that circadian output from the SCN declines because of aging. Furthermore, we have previously observed age-related infertility in female mice, caused by a mismatch between environmental light-dark cycles and the intrinsic, internal biological clocks. In this review, we address regulatory mechanisms underlying circadian rhythms in mammals and summarize recent literature describing the effects of aging on the circadian system. 
26913199	The type of medical review before an adverse event influences patient outcome. Delays in the up-transfer of patients requiring intensive care are associated with higher mortality rates. Timely detection and response to a deteriorating patient constitute an important function of the rapid response system (RRS). The activation of the RRS for at-risk patients constitutes the system's afferent limb. Afferent limb failure (ALF), an important performance measure of rapid response systems, constitutes a failure to activate a rapid response team (RRT) despite criteria for calling an RRT. There are diurnal variations in hospital staffing levels, the performance of rapid response systems and patient outcomes. Fewer ward-based nursing staff at night may contribute to ALF. The diurnal variability in RRS activity is greater in unmonitored units than it is in monitored units for events that should result in a call for an RRT. RRT events include a significant abnormality in either the pulse rate, blood pressure, conscious state or respiratory rate. There is also diurnal variation in RRT summoning rates, with most activations occurring during the day. The reasons for this variation are mostly speculative, but the failure of the afferent limb of RRT activation, particularly at night, may be a factor. The term "circadian variation/rhythm" applies to physiological variations over a 24-h cycle. In contrast, diurnal variation applies more accurately to extrinsic systems. Circadian rhythm has been demonstrated in a multitude of bodily functions and disease states. For example, there is an association between disrupted circadian rhythms and abnormal vital parameters such as anomalous blood pressure, irregular pulse rate, aberrant endothelial function, myocardial infarction, stroke, sleep-disordered breathing and its long-term consequences of hypertension, heart failure and cognitive impairment. Therefore, diurnal variation in patient outcomes may be extrinsic, and more easily modifiable, or related to the circadian variation inherent in human physiology. Importantly, diurnal variations in the implementation and performance of the RRS, as gauged by ALF, the RRT response to clinical deterioration and any variations in quality and quantity of patient monitoring have not been fully explored across a diverse group of hospitals. 
26913197	In the face of chronic stress, some individuals can maintain normal function while others go on to develop mental illness. Addiction, affecting one in every twelve people in America, is a substance use disorder long associated with stressful life events and disruptions in the sleep/wake cycle. The circadian and stress response systems have evolved to afford adaptability to environmental changes and allow for maintenance of functional stability, or homeostasis. This mini-review will discuss how circadian rhythms and stress individually affect drug response, affect each other, and how their interactions may regulate reward-related behavior. In particular, we will focus on the interactions between the circadian clock and the regulation of glucocorticoids by the hypothalamic-pituitary-adrenal (HPA) axis. Determining how these two systems act on dopaminergic reward circuitry may not only reveal the basis for vulnerability to addiction, but may also illuminate potential therapeutic targets for future investigation. 
26912639	We report on a quantitative analysis of electrocorticography data from a study that acquired continuous ambulatory recordings in humans over extended periods of time. The objectives were to examine patterns of seizures and spontaneous interictal spikes, their relationship to each other, and the nature of periodic variation. The recorded data were originally acquired for the purpose of seizure prediction, and were subsequently analysed in further detail. A detection algorithm identified potential seizure activity and a template matched filter was used to locate spikes. Seizure events were confirmed manually and classified as either clinically correlated, electroencephalographically identical but not clinically correlated, or subclinical. We found that spike rate was significantly altered prior to seizure in 9 out of 15 subjects. Increased pre-ictal spike rate was linked to improved predictability; however, spike rate was also shown to decrease before seizure (in 6 out of the 9 subjects). The probability distribution of spikes and seizures were notably similar, i.e. at times of high seizure likelihood the probability of epileptic spiking also increased. Both spikes and seizures showed clear evidence of circadian regulation and, for some subjects, there were also longer term patterns visible over weeks to months. Patterns of spike and seizure occurrence were highly subject-specific. The pre-ictal decrease in spike rate is not consistent with spikes promoting seizures. However, the fact that spikes and seizures demonstrate similar probability distributions suggests they are not wholly independent processes. It is possible spikes actively inhibit seizures, or that a decreased spike rate is a secondary symptom of the brain approaching seizure. If spike rate is modulated by common regulatory factors as seizures then spikes may be useful biomarkers of cortical excitability.
26911716	Our understanding of the molecular underpinnings of the mammalian circadian oscillator and its tight connection to physiology has progressed tremendously during the past decades. The liver is considered the prototypic experimental model tissue for circadian research in peripheral organs. Studies on liver clocks have been highly productive and yielded information about widely different aspects of circadian biology. The liver, as one of the largest organs in the body, has often been used for the identification of core clock and auxiliary clock components, for example, by biochemical purifications. Because the liver is also a major metabolic hub, studies addressing the interplay between circadian clocks and metabolism have been insightful. In addition, the use of liver-specific loss-of-function models for clock components highlighted not only specific physiological roles of the hepatic clock but also its interplay with systemic cues and oscillators in other organs. Recently, technological advances in omics approaches have been successfully applied on the liver, providing a comprehensive depiction of pervasive circadian control of gene expression and protein and metabolite accumulation. In this review, we chose to illuminate specific examples that demonstrate how different experimental approaches--namely, biochemical, metabolic, genetic, and omics methodologies--have advanced our knowledge regarding circadian liver biology and chronobiology in general.
26911229	Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood. 
26910317	The circadian clock system confers daily anticipatory physiological processes with the ability to be reset by environmental cues. This "circadian adaptation system" (CAS), driven by cell-autonomous molecular clocks, orchestrates various rhythmic physiological processes in the entire body. Hence, the dysfunction of these clocks exacerbates various diseases, which may partially be due to the impairment of protective pathways. If this is the case, how does the CAS respond to cell injury stresses that are critical in maintaining health and life by evoking protective pathways? To address this question, here we review and discuss recent evidence revealing life-protective (pro-survival) molecular networks between clock (e.g., BMAL1, CLOCK, and PER2) and adaptation (e.g., HSF1, Nrf2, NF-κB, and p53) pathways, which are evoked by various cell injury stresses (e.g., heat, reactive oxygen species, and UV). The CK2 protein kinase-integrated interplay of the BMAL1 (clock) and HSF1 (heat-shock response) pathways is one of the crucial events in CAS. 

26907879	The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies. 
26907843	The study investigated the effect of the time-of-day at which maximal isometric voluntary co-contraction (MIVCC) training is conducted on the adaptation and diurnal variation of maximal and explosive force production. Twenty active men underwent a 6-week (3 times per week) MIVCC training of the right elbow joint. The participants were randomly assigned to a morning training group (MTG, 07:00-08:00 hours) and evening training group (ETG, 17:00-18:00 hours). The maximal voluntary force (MVF) and maximal rate of force development (MRFD) during isometric elbow flexion (MVFF and MRFD(F)) and extension (MVF(E) and MRFD(E)) were recorded before (T0) and after (T1) training in the morning and evening. At T0, MVF and MRFD were higher in the evening compared with those in the morning for the MTG and ETG (p ≤ 0.05). At T1, MVFF and MVFE increased in the morning and evening for both groups (p < 0.001). The MRFD(F) and MRFD(E) increased only if training and test session were scheduled at the same time. The relative increase of MVF was greater at the specific time of training for the MTG (12 and 17.6% in MVF(F) and MVF(E), respectively) and ETG (9.8 and 13.4% in MVF(F) and MVF(E), respectively). The diurnal variations in MVF and MRF(D) during flexion and extension disappeared in the MTG and persisted in the ETG. Maximal isometric voluntary co-contraction training enhanced muscle strength whatever the time-of-day at which the training was scheduled without alteration of explosive force. In contrast, to optimize the muscle strength, our results suggested that morning training may be accompanied by the greatest muscle strength gain and blunted muscle strength variation observed between the morning and evening.
26907237	Citation indexes represent helpful tools for evaluating the impact of articles on research. The aim of this study was to obtain the top-100 ranking of the most cited papers on melatonin, a relevant neurohormone mainly involved in phase-adjusting the biological clock and with certain sleep-promoting capability. An article search was carried out on the Institute for Scientific Information (ISI) Web of Science platform. Numbers of citations, names of authors, journals and their 2014-impact factor, year of publication, and experimental designs of studies were recorded. The ranking of the 100-most cited articles on melatonin research (up to February 2016) revealed a citation range from 1623 to 310. Narrative reviews/expert opinions were the most frequently cited articles, while the main research topics were oxidative stress, sleep physiology, reproduction, circadian rhythms and melatonin receptors. This study represents the first detailed analysis of the 100 top-cited articles published in the field of melatonin research, showing its impact and relevance in the biomedical field. 
26906410	Prunella vulgaris L. is a medical plant cultivated in sloping, sun-shaded areas in China. Recently, owing to air-environmental stress, especially drought stress strongly inhibits plant growth and development, the appropriate fertilizer supply can alleviate these effects. However, these is little information about their effects on P. vulgaris growing in arid and semi-arid areas with limited water and fertilizer supply.In this study, water stress decreased the photosynthetic pigment contents, inhibited photosynthetic efficiency, induced photodamage in photosystem 2 (PS2), and decreased leaf instantaneous WUE (WUEi). The decreased net photosynthetic rate (Pn) under medium drought stress compared with the control might result from stomatal limitations. However, fertilizer supply improved photosynthetic capacity by increasing the photosynthetic pigment contents and enhancing photosynthetic efficiency under water deficit. Moreover, medium fertilization also increased WUEi under the two water conditions, but fertilizer supply did little to alleviate the PS2 photodamage caused by drought stress. Hence, drought stress was the primary limitation in the photosynthetic process of P. vulgaris seedlings, while the photosynthetic characteristics of the seedlings exhibited positive responses to fertilizer supply.	Appropriate fertilizer supply is recommended to improve photosynthetic efficiency, enhance WUEi and alleviate photodamage under drought stress.	
26905339	Evidence of the link between job strain and cortisol levels has been inconsistent. This could be due to failure to account for cortisol variability leading to underestimated standard errors. Our objective was to model the relationship between job strain and the whole cortisol curve, accounting for sources of cortisol variability. Our functional mixed-model approach incorporated all available data-18 samples over 3 days-and uncertainty in estimated relationships. We used employed participants from the Multi-Ethnic Study of Atherosclerosis Stress I Study and data collected between 2002 and 2006. We used propensity score matching on an extensive set of variables to control for sources of confounding. We found that job strain was associated with lower salivary cortisol levels and lower total area under the curve. We found no relationship between job strain and the cortisol awakening response. Our findings differed from those of several previous studies. It is plausible that our results were unique to middle- to older-aged racially, ethnically, and occupationally diverse adults and were therefore not inconsistent with previous research among younger, mostly white samples. However, it is also plausible that previous findings were influenced by residual confounding and failure to propagate uncertainty (i.e., account for the multiple sources of variability) in estimating cortisol features. 
26904978	The mammalian circadian system is a hierarchical network of oscillators organized to optimally coordinate behavior and physiology with daily environmental cycles. The suprachiasmatic nucleus (SCN) of the hypothalamus is at the top of this hierarchy, synchronizing to the environmental light-dark cycle, and coordinates the phases of peripheral clocks. The Period genes are critical components of the molecular timekeeping mechanism of these clocks. Circadian clocks are disabled in Period1/2/3 triple mutant mice, resulting in arrhythmic behavior in constant conditions. We uncovered rhythmic behavior in this mutant by simply exposing the mice to timed access to a palatable meal or running wheel. The emergent circadian behavior rhythms free-ran for many cycles under constant conditions without cyclic environmental cues. Together, these data demonstrate that the palatable meal-inducible circadian oscillator (PICO) and wheel-inducible circadian oscillator (WICO) are generated by non-canonical circadian clocks. Entrainment of these novel oscillators by palatable snacks and timed exercise could become novel therapeutics for human conditions caused by disruptions of the circadian clocks. 
26904049	The circadian clock is an endogenous timekeeper that allows organisms to anticipate and adapt to the daily variations of their environment. The plant clock is an intricate network of interlocked feedback loops, in which transcription factors regulate each other to generate oscillations with expression peaks at specific times of the day. Over the last decade, mathematical modeling approaches have been used to understand the inner workings of the clock in the model plant Arabidopsis thaliana. Those efforts have produced a number of models of ever increasing complexity. Here, we present an alternative model that combines a low number of equations and parameters, similar to the very earliest models, with the complex network structure found in more recent ones. This simple model describes the temporal evolution of the abundance of eight clock gene mRNA/protein and captures key features of the clock on a qualitative level, namely the entrained and free-running behaviors of the wild type clock, as well as the defects found in knockout mutants (such as altered free-running periods, lack of entrainment, or changes in the expression of other clock genes). Additionally, our model produces complex responses to various light cues, such as extreme photoperiods and non-24 h environmental cycles, and can describe the control of hypocotyl growth by the clock. Our model constitutes a useful tool to probe dynamical properties of the core clock as well as clock-dependent processes. 
26903947	Fibroblast growth factor (Fgf) 8 is essential for the development of multiple brain regions. Previous studies from our laboratory showed that reduced Fgf8 signaling led to the developmental alterations of neuroendocrine nuclei that originated within the diencephalon, including the paraventricular (PVN) and supraoptic (SON) nuclei. To further understand the role of Fgf8 in the development of other hypothalamic nuclei, we examined if Fgf8 and its cognate receptor, Fgfr1, also impact the integrity of the suprachiasmatic nuclei (SCN). The SCN control an organism's circadian rhythm and contain vasoactive intestinal peptide (VIP)-producing neurons as the main input neurons. Mice hypomorphic for Fgf8, Fgfr1, or both were examined for their SCN volume and the number of VIP neurons on postnatal day (PN) 0; adult hypomorphic mice were further examined for SCN function by quantifying SCN neuronal activation using cFos as a marker. On PN0, mice homozygous for Fgf8 hypomorphy displayed the most severe reduction of the SCN volume and VIP neurons. Those heterozygous for Fgf8 hypomorphy alone or Fgf8 combined with Fgfr1 hypomorphy, called double heterozygotes (DH), showed normal SCN volume but significantly reduced VIP neurons, albeit less severely than the homozygotes. Adult wild type, heterozygous Fgf8 hypomorphs (F8 Het), and DH mice were also examined for SCN cFos activation at three time points: 1 h (morning), 6 h (afternoon), and 11 h (evening) after light onset. In F8 Het mice, a significant change in the pattern of cFos immunostaining that may reflect delayed morning SCN activation was observed. Overall, our studies provide evidence supporting that deficiencies in Fgf8 not only impact the structural integrity of the SCN but also the pattern of SCN activation in response to light. 
26903630	In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. 
26903624	Circadian rhythms in mammals are coordinated by the suprachiasmatic nucleus (SCN). SCN neurons define circadian time using transcriptional/posttranslational feedback loops (TTFL) in which expression of Cryptochrome (Cry) and Period (Per) genes is inhibited by their protein products. Loss of Cry1 and Cry2 stops the SCN clock, whereas individual deletions accelerate and decelerate it, respectively. At the circuit level, neuronal interactions synchronize cellular TTFLs, creating a spatiotemporal wave of gene expression across the SCN that is lost in Cry1/2-deficient SCN. To interrogate the properties of CRY proteins required for circadian function, we expressed CRY in SCN of Cry-deficient mice using adeno-associated virus (AAV). Expression of CRY1::EGFP or CRY2::EGFP under a minimal Cry1 promoter was circadian and rapidly induced PER2-dependent bioluminescence rhythms in previously arrhythmic Cry1/2-deficient SCN, with periods appropriate to each isoform. CRY1::EGFP appropriately lengthened the behavioral period in Cry1-deficient mice. Thus, determination of specific circadian periods reflects properties of the respective proteins, independently of their phase of expression. Phase of CRY1::EGFP expression was critical, however, because constitutive or phase-delayed promoters failed to sustain coherent rhythms. At the circuit level, CRY1::EGFP induced the spatiotemporal wave of PER2 expression in Cry1/2-deficient SCN. This was dependent on the neuropeptide arginine vasopressin (AVP) because it was prevented by pharmacological blockade of AVP receptors. Thus, our genetic complementation assay reveals acute, protein-specific induction of cell-autonomous and network-level circadian rhythmicity in SCN never previously exposed to CRY. Specifically, Cry expression must be circadian and appropriately phased to support rhythms, and AVP receptor signaling is required to impose circuit-level circadian function. 
26903623	The suprachiasmatic nucleus (SCN) defines 24 h of time via a transcriptional/posttranslational feedback loop in which transactivation of Per (period) and Cry (cryptochrome) genes by BMAL1-CLOCK complexes is suppressed by PER-CRY complexes. The molecular/structural basis of how circadian protein complexes function is poorly understood. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT-SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of Per2(Edo/Edo) mice by 1.5 h. Structural and biophysical analyses revealed that Edo alters the packing of the highly conserved interdomain linker of the PER2 PAS core such that, although PER2(Edo) complexes with clock proteins, its vulnerability to degradation mediated by casein kinase 1ε (CSNK1E) is increased. The functional relevance of this mutation is revealed by the ultrashort (<19 h) but robust circadian rhythms in Per2(Edo/Edo); Csnk1e(Tau/Tau) mice and the SCN. These periods are unprecedented in mice. Thus, Per2(Edo) reveals a direct causal link between the molecular structure of the PER2 PAS core and the pace of SCN circadian timekeeping. 
26902495	The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels. 
26901093	Mood disorders are associated with dysregulation of prefrontal cortex (PFC) function, circadian rhythms, and diurnal glucocorticoid (corticosterone [CORT]) circulation. Entrainment of clock gene expression in some peripheral tissues depends on CORT. In this study, we characterized over the course of the day the mRNA expression pattern of the core clock genes Per1, Per2, and Bmal1 in the male rat PFC and suprachiasmatic nucleus (SCN) under different diurnal CORT conditions. In experiment 1, rats were left adrenal-intact (sham) or were adrenalectomized (ADX) followed by 10 daily antiphasic (opposite time of day of the endogenous CORT peak) ip injections of either vehicle or 2.5 mg/kg CORT. In experiment 2, all rats received ADX surgery followed by 13 daily injections of vehicle or CORT either antiphasic or in-phase with the endogenous CORT peak. In sham rats clock gene mRNA levels displayed a diurnal pattern of expression in the PFC and the SCN, but the phase differed between the 2 structures. ADX substantially altered clock gene expression patterns in the PFC. This alteration was normalized by in-phase CORT treatment, whereas antiphasic CORT treatment appears to have eliminated a diurnal pattern (Per1 and Bmal1) or dampened/inverted its phase (Per2). There was very little effect of CORT condition on clock gene expression in the SCN. These experiments suggest that an important component of glucocorticoid circadian physiology entails CORT regulation of the molecular clock in the PFC. Consequently, they also point to a possible mechanism that contributes to PFC disrupted function in disorders associated with abnormal CORT circulation. 
26900325	Light-emitting diodes (LEDs) have been used to provide illumination in industrial and commercial environments. LEDs are also used in TVs, computers, smart phones, and tablets. Although the light emitted by most LEDs appears white, LEDs have peak emission in the blue light range (400-490 nm). The accumulating experimental evidence has indicated that exposure to blue light can affect many physiologic functions, and it can be used to treat circadian and sleep dysfunctions. However, blue light can also induce photoreceptor damage. Thus, it is important to consider the spectral output of LED-based light sources to minimize the danger that may be associated with blue light exposure. In this review, we summarize the current knowledge of the effects of blue light on the regulation of physiologic functions and the possible effects of blue light exposure on ocular health. 
26899944	Environmental progestins are implicated in endocrine disruption in vertebrates. Additional targets that may be affected in organisms are poorly known. Here we report that progesterone (P4) and drospirenone (DRS) interfere with the photo-transduction cascade and circadian rhythm network in the eyes of zebrafish. Breeding pairs of adult zebrafish were exposed to P4 and DRS for 21 days with different measured concentrations of 7-742 ng/L and 99-13´650 ng/L, respectively. Of totally 10 key photo-transduction cascade genes analyzed, transcriptional levels of most were significantly up-regulated, or normal down-regulation was attenuated. Similarly, for some circadian rhythm genes, dose-dependent transcriptional alterations were also observed in the totally 33 genes analyzed. Significant alterations occurred even at environmental relevant levels of 7 ng/L P4. Different patterns were observed for these transcriptional alterations, of which, the nfil3 family displayed most significant changes. Furthermore, we demonstrate the importance of sampling time for the determination and interpretation of gene expression data, and put forward recommendations for sampling strategies to avoid false interpretations. Our results suggest that photo-transduction signals and circadian rhythm are potential targets for progestins. Further studies are required to assess alterations on the protein level, on physiology and behavior, as well as on implications in mammals.
26899660	2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure in humans is associated with marked immune suppressions and increased incidence of lymphoblastic diseases. To elucidate mechanisms of impairments in humoral immune responses, we used a murine model. Following a 20-week administration of low doses of TCDD, we observed severely reduced antibody titers, dramatically decreased number of splenic Th1 and Th2 cells and an increase in CD19(+) B cells. Transcriptional profiling of CD19(+) B cells showed that markers of pre-B cells were significantly elevated, indicating delayed B cell maturation. These changes in B cells were accompanied by decreases of T helper cell numbers and reduced IgM and IgG titers. A transcriptome analysis of splenic B cells followed by Ingenuity Pathway Analysis (IPA) revealed a set of differentially expressed genes known to play roles in tumorigenesis, cell-proliferation and cell-migration. The most up-regulated transcript gene was Eph receptor A2 (EphA2), a known oncogene, and the most down-regulated transcript was ZBTB16 that codes for a negative transcriptional regulator important in epigenetic chromatin remodeling. IPA identified cAMP-responsive element modulator (CREM) and cAMP-responsive element binding protein 1 (CREB1) as top upstream regulators. Consistently, a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREB1 binding sites in their promoter regions. In summary, our data showed that chronic TCDD exposure in mice caused suppressed humoral immunity accompanied with profound dysregulation of gene expression in splenic B-lymphocytes, likely through cAMP-dependent pathways. This dysregulation resulted in impairments in T-cell and B-cell differentiation and activation of the tumorigenic transcription program. 
26898952	The roles of miRNAs as important post-transcriptional regulators in the circadian clock have been suggested in several studies. But the search for circadian miRNAs has led to disparate results. Here we demonstrated that at least 57 miRNA primary transcripts are rhythmically transcribed in mouse liver. Most of these transcripts are under the regulation of circadian transcription factors such as BMAL1/CLOCK and REV-ERBα/β. However, the mature miRNAs derived from these transcripts are either not oscillating or oscillating at low amplitudes, which could explain the inconsistency of different circadian miRNA studies. In order to show that these circadian primary transcripts can give rise to miRNAs with circadian functions, we over-expressed one of them, miR-378, in mouse by adenovirus injection. We found a significant over-representation of circadian oscillating genes under-expressed by miR-378 over-expression in liver. In particular, we observed that miR-378 modulates the oscillation amplitudes of Cdkn1a in the control of cell cycle and Por in the regulation of oxidation reduction by forming partnership with different circadian transcription factors. Our study suggests that circadian transcription of miRNA at primary transcript level can be a good indicator for circadian miRNA functions. 
26898837	Cryptochromes are a ubiquitous group of blue-light absorbing flavoproteins that in the mammalian retina have an important role in the circadian clock. In birds, cryptochrome 1a (Cry1a), localized in the UV/violet-sensitive S1 cone photoreceptors, is proposed to be the retinal receptor molecule of the light-dependent magnetic compass. The retinal localization of mammalian Cry1, homologue to avian Cry1a, is unknown, and it is open whether mammalian Cry1 is also involved in magnetic field sensing. To constrain the possible role of retinal Cry1, we immunohistochemically analysed 90 mammalian species across 48 families in 16 orders, using an antiserum against the Cry1 C-terminus that in birds labels only the photo-activated conformation. In the Carnivora families Canidae, Mustelidae and Ursidae, and in some Primates, Cry1 was consistently labeled in the outer segment of the shortwave-sensitive S1 cones. This finding would be compatible with a magnetoreceptive function of Cry1 in these taxa. In all other taxa, Cry1 was not detected by the antiserum that likely also in mammals labels the photo-activated conformation, although Western blots showed Cry1 in mouse retinal cell nuclei. We speculate that in the mouse and the other negative-tested mammals Cry1 is involved in circadian functions as a non-light-responsive protein. 
26898709	Losing the E-cadherin plays an important role in the metastasis of cancer. The regulation of the expression of E-cadherin is unclear. Circadian rhythm alteration is associated with the pathogenesis of a number of cancers. This study aims to investigate the role of one of the circadian proteins, period-2 (Per2) in repressing the expression of E-cadherin in esophageal cancer (esophageal cancer). We observed that the levels of circadian protein Per2 were significantly increased and E-cadherin was significantly decreased in the tissue of human esophageal cancer with metastasis as compared with non-metastatic esophageal cancer. Overexpression of Per2 in the esophageal cancer cells markedly repressed the expression of E-cadherin. The pHDAC1 was detected in human esophageal cancer with metastasis, which was much less in the esophageal cancer tissue without metastasis. Overexpression of Per2 increased the levels of pHDAC1 as well as the E-cadherin repressors at the E-cadherin promoter locus. Overexpression of Per2 markedly increased the migratory capacity of esophageal cancer cells, which was abolished by the inhibition of HDAC1. We conclude that Per-2 plays an important role in the esophageal cancer cell metastasis, which may be a novel therapeutic target for the treatment of esophageal cancer. 
26898574	The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. 
26897608	Glowworms are larval fungus gnats that emit light from a specialised abdominal light organ. The light attracts small arthropod prey to their web-like silk snares. Larvae glow throughout the night and can modulate their bioluminescence in response to sensory input. To better understand light output regulation and its ecological significance, we examined the larvae's reaction to light exposure, vibration and sound. Exposure to a 5-min light pulse in the laboratory causes larvae to exponentially decrease their light output over 5-10 min until they completely switch off. They gradually return to pre-exposure levels but do not show a rebound. Larvae are most sensitive to ultraviolet light, then blue, green and red. Vibration of the larval snares results in a several-fold increase in bioluminescence over 20-30 s, followed by an exponential return to pre-exposure levels over 15-30 min. Under some conditions, larvae can respond to vibration by initiating bioluminescence when they are not glowing; however, the response is reduced compared to when they are glowing. We propose that inhibitory and excitatory mechanisms combine to modulate bioluminescence intensity by regulating biochemical reactions or gating the access of air to the light organ.
26897456	The study aimed to elucidate previously observed associations between morningness-eveningness and depressive symptomatology in university students. Relations between components of depressive symptomatology and morningness-eveningness were analysed.Nine hundred and seventy-four university students completed Polish versions of the Centre for Epidemiological Studies - Depression scale (CES-D; Polish translation appended to this paper) and the Composite Scale of Morningness. Principal component analysis (PCA) was used to test the structure of depressive symptoms. Pearson and partial correlations (with age and sex controlled), along with regression analyses with morning affect (MA) and circadian preference as predictors, were used.	PCA revealed three components of depressive symptoms: depressed/somatic affect, positive affect, interpersonal relations. Greater MA was related to less depressive symptoms in three components. Morning circadian preference was related to less depressive symptoms in depressed/somatic and positive affects and unrelated to interpersonal relations. Both morningness-eveningness components exhibited stronger links with depressed/somatic and positive affects than with interpersonal relations. Three CES-D components exhibited stronger links with MA than with circadian preference. In regression analyses only MA was statistically significant for positive affect and better interpersonal relations, whereas more depressed/somatic affect was predicted by lower MA and morning circadian preference (relationship reversed compared to correlations).	Self-report assessment.	There are three groups of depressive symptoms in Polish university students. Associations of MA with depressed/somatic and positive affects are primarily responsible for the observed links between morningness-eveningness and depressive symptoms in university students. People with evening circadian preference whose MA is not lowered have less depressed/somatic affect.	
26896868	An outdoor MRI system for noninvasive, long-term measurements of sap flow in a living tree in its natural environment has been developed. An open-access, 0.2 T permanent magnet with a 160 mm gap was combined with a radiofrequency probe, planar gradient coils, electromagnetic shielding, several electrical units, and a waterproofing box. Two-dimensional cross-sectional images were acquired for a ring-porous tree, and the anatomical structures, including xylem and phloem, were identified. The MRI flow measurements demonstrated the diurnal changes in flow velocity in the stem on a per-pixel basis. These results demonstrate that our outdoor MRI system is a powerful tool for studies of water transport in outdoor trees.
26896396	Eukaryotic cells compartmentalize neutral lipids into organelles called lipid droplets (LDs), and while much is known about the role of LDs in storing triacylglycerols in seeds, their biogenesis and function in nonseed tissues are poorly understood. Recently, we identified a class of plant-specific, lipid droplet-associated proteins (LDAPs) that are abundant components of LDs in nonseed cell types. Here, we characterized the three LDAPs in Arabidopsis (Arabidopsis thaliana) to gain insight to their targeting, assembly, and influence on LD function and dynamics. While all three LDAPs targeted specifically to the LD surface, truncation analysis of LDAP3 revealed that essentially the entire protein was required for LD localization. The association of LDAP3 with LDs was detergent sensitive, but the protein bound with similar affinity to synthetic liposomes of various phospholipid compositions, suggesting that other factors contributed to targeting specificity. Investigation of LD dynamics in leaves revealed that LD abundance was modulated during the diurnal cycle, and characterization of LDAP misexpression mutants indicated that all three LDAPs were important for this process. LD abundance was increased significantly during abiotic stress, and characterization of mutant lines revealed that LDAP1 and LDAP3 were required for the proper induction of LDs during heat and cold temperature stress, respectively. Furthermore, LDAP1 was required for proper neutral lipid compartmentalization and triacylglycerol degradation during postgerminative growth. Taken together, these studies reveal that LDAPs are required for the maintenance and regulation of LDs in plant cells and perform nonredundant functions in various physiological contexts, including stress response and postgerminative growth.
26896395	The requirements of the water transport system of small herbaceous species differ considerably from those of woody species. Despite their ecological importance for many biomes, knowledge regarding herb hydraulics remains very limited. We compared key hydraulic features (vulnerability to drought-induced hydraulic decline, pressure-volume relations, onset of cellular damage, in situ variation of water potential, and stomatal conductance) of three Ranunculus species differing in their soil humidity preferences and ecological amplitude. All species were very vulnerable to water stress (50% reduction in whole-leaf hydraulic conductance [kleaf] at -0.2 to -0.8 MPa). In species with narrow ecological amplitude, the drought-exposed Ranunculus bulbosus was less vulnerable to desiccation (analyzed via loss of kleaf and turgor loss point) than the humid-habitat Ranunculus lanuginosus Accordingly, water stress-exposed plants from the broad-amplitude Ranunculus acris revealed tendencies toward lower vulnerability to water stress (e.g. osmotic potential at full turgor, cell damage, and stomatal closure) than conspecific plants from the humid site. We show that small herbs can adjust to their habitat conditions on interspecific and intraspecific levels in various hydraulic parameters. The coordination of hydraulic thresholds (50% and 88% loss of kleaf, turgor loss point, and minimum in situ water potential) enabled the study species to avoid hydraulic failure and damage to living cells. Reversible recovery of hydraulic conductance, desiccation-tolerant seeds, or rhizomes may allow them to prioritize toward a more efficient but vulnerable water transport system while avoiding the severe effects that water stress poses on woody species.
26896306	Nocturnal dominance of the incidence of spontaneous ventricular tachyarrhythmias has been reported in patients with Brugada syndrome (BrS). The purpose of the present study is to analyze the QT dynamics and autonomic balance as well as their diurnal variations in BrS patients.Of the 33 consecutive patients with BrS included in the study, 14 had a history of cardiopulmonary arrest due to spontaneous ventricular fibrillation (VF) episodes (VF-BrS) and 19 had asymptomatic BrS (A-BrS). QT dynamics and heart rate variability were analyzed using 24-h Holter electrocardiogram recordings.	Of the total 14 first cardiopulmonary arrest episodes due to spontaneous VF, 11 (79%) occurred in VF-BrS patients during the nighttime or at rest. The QT/RR slope during daytime was significantly steeper than that during nighttime in the A-BrS patients (p=0.031), but not in the VF-BrS patients (p=1.0). There were significant diurnal differences pertaining to the high-frequency (HF) and low-frequency (LF)/HF ratios in the A-BrS patients (p=0.019 and p=0.019, respectively), but not in the VF-BrS patients (p=1.0 and p=1.0, respectively). The VF-BrS patients were characterized by relatively high LF/HF ratios, whereas the A-BrS patients were characterized by relatively low LF/HF ratios throughout the daytime and nighttime. Furthermore, the LF/HF ratios during the nighttime in the VF-BrS patients were significantly higher than those in the A-BrS patients (p=0.021).	Most first episodes of spontaneous VF in the VF-BrS patients occurred during the nighttime or at rest. The autonomic imbalance of paradoxical nocturnal elevation of the sympathetic tone along with an underlying persistent sympathetic tone throughout the day may play a key role for spontaneous VF initiation in BrS patients.	
26896174	The subtidal crab Dyspanopeus sayi has a circadian rhythm in larval release with a free-running period of 24.1 h. Under constant conditions, eggs hatch primarily in the 4-h interval after the time of sunset. The study tested the new model for entrainment in subtidal crabs, which proposes that the female perceives the environmental cycles and entrains the endogenous rhythm in the embryos. Results verified the model for D. sayi. Hatching by embryos collected from the field when they had not yet developed eye pigments, and were kept in constant conditions attached to their mother, exhibited the circadian hatching rhythm. Attached embryos could also be entrained to a new photoperiod in the laboratory before they developed eye pigments. Further, mature embryos removed from the female hatched rhythmically, indicating that a circadian rhythm resides in the embryos. However, if mature embryos with eye pigments were removed from the female and exposed to a new light-dark cycle, they could not be entrained to the new cycle; rather, they hatched according to the timing of the original light-dark cycle. Nevertheless, detached, mature embryos would entrain to a new light-dark cycle if they were in chemical, but not physical, contact with the female. Thus, the female perceives the light-dark cycle, and uses chemical cues to entrain the circadian rhythm of hatching by the embryos. 
26895652	Disturbed circadian rhythm is a potentially modifiable cause of delirium among patients in intensive-care units (ICUs). Bright-light therapy in the daytime can realign circadian rhythm and reduce the incidence of delirium. We investigated whether a high-intensity dynamic light application (DLA) would reduce ICU-acquired delirium.Between July 1, 2011, and Sept 9, 2013, 734 patients were enrolled, 361 in the DLA group and 373 in the control group. Delirium occurred in 137 (38%) of 361 DLA patients and 123 (33%) of 373 control patients (odds ratio 1·24, 95% CI 0·92-1·68, p=0·16). No adverse events were noted in patients or staff.	DLA as a single intervention does not reduce the cumulative incidence of delirium. Bright-light therapy should be assessed as part of a multicomponent strategy.	None.	
26895328	Heterodimers of CLOCK and BMAL1 are the major transcriptional activators of the mammalian circadian clock. Because the paralog NPAS2 can substitute for CLOCK in the suprachiasmatic nucleus (SCN), the master circadian pacemaker, CLOCK-deficient mice maintain circadian rhythms in behavior and in tissues in vivo. However, when isolated from the SCN, CLOCK-deficient peripheral tissues are reportedly arrhythmic, suggesting a fundamental difference in circadian clock function between SCN and peripheral tissues. Surprisingly, however, using luminometry and single-cell bioluminescence imaging of PER2 expression, we now find that CLOCK-deficient dispersed SCN neurons and peripheral cells exhibit similarly stable, autonomous circadian rhythms in vitro. In CLOCK-deficient fibroblasts, knockdown of Npas2 leads to arrhythmicity, suggesting that NPAS2 can compensate for loss of CLOCK in peripheral cells as well as in SCN. Our data overturn the notion of an SCN-specific role for NPAS2 in the molecular circadian clock, and instead indicate that, at the cellular level, the core loops of SCN neuron and peripheral cell circadian clocks are fundamentally similar. 
26892296	It is claimed that a correlation exists between disturbance of circadian rhythms by factors such as alteration of normal light-dark cycle and the development of addiction. However, the exact mechanisms involved in this relationship are not much understood. Here we have studied the effect of constant light on morphine voluntary consumption and withdrawal symptoms and also investigated the involvement of Per1, Per2 and dopamine D1 receptor in these processes. Male wistar rats were kept under standard (LD) or constant light (LL) conditions for one month. The plasma concentration of melatonin was evaluated by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to determine the mRNA expression of Per1, Per2 and dopamine D1 receptor in the striatum and prefrontal cortex. Morphine preference (50mg/L) was evaluated in a two-bottle-choice paradigm for 10 weeks and withdrawal symptoms were recorded after administration of naloxone (3mg/kg). One month exposure to constant light resulted in a significant decrease of melatonin concentration in the LL group. In addition, mRNA levels of Per2 and dopamine D1 receptor were up-regulated in both the striatum and prefrontal cortex of the LL group. However, expression of Per1 gene was only up-regulated in the striatum of LL rats in comparison to LD animals. Furthermore, after one month exposure to constant light, morphine consumption and preference ratio and also severity of naloxone-induced withdrawal syndrome were significantly greater in LL animals. It is concluded that exposure to constant light by up-regulation of Per2 and dopamine D1 receptor in the striatum and prefrontal cortex and up-regulation of Per1 in the striatum and the possible involvement of melatonin makes animals vulnerable to morphine preference and addiction.
26892295	Developmental ethanol (EtOH) exposure can lead to long-lasting cognitive impairment, hyperactivity, and emotional dysregulation among other problems. In healthy adults, sleep plays an important role in each of these behavioral manifestations. Here we explored circadian rhythms (activity, temperature) and slow-wave sleep (SWS) in adult mice that had received a single day of EtOH exposure on postnatal day 7 and saline littermate controls. We tested for correlations between slow-wave activity and both contextual fear conditioning and hyperactivity. Developmental EtOH resulted in adult hyperactivity within the home cage compared to controls but did not significantly modify circadian cycles in activity or temperature. It also resulted in reduced and fragmented SWS, including reduced slow-wave bout duration and increased slow-wave/fast-wave transitions over 24-h periods. In the same animals, developmental EtOH exposure also resulted in impaired contextual fear conditioning memory. The impairment in memory was significantly correlated with SWS fragmentation. Furthermore, EtOH-treated animals did not display a post-training modification in SWS which occurred in controls. In contrast to the memory impairment, sleep fragmentation was not correlated with the developmental EtOH-induced hyperactivity. Together these results suggest that disruption of SWS and its plasticity are a secondary contributor to a subset of developmental EtOH exposure's long-lasting consequences. 
26891917	The suprachiasmatic nucleus (SCN) is a group of cells that functions as a biological master clock. In different SCN cells, oscillations of biochemical markers such as the expression-level of clock genes, are not synchronized but instead form slow circadian phase waves propagating over the whole cell population spatio-temporal structure is a fixed property set by the anatomy of a given SCN. Here, we show that this is not the case in early postnatal SCN. Earlier studies presumed that their Based on bioluminescence imaging experiments with Per2-Luciferase mice SCN cultures which guided computer simulations of a realistic model of the SCN, we demonstrate that the wave is not unique but can be in various modes including phase- coherent oscillation, crescent-shaped wave, and most notably, a rotating pinwheel wave that conceptually resembles a wall clock with a rotating hand. Furthermore, mode transitions can be induced by a pulse of 38.5 °C temperature perturbation. Importantly, the waves support a significantly different period, suggesting that neither a spatially-fixed phase ordering nor a specialized pacemaker having a fixed period exist in these studied SCNs. These results lead to new important questions of what the observed multi-stability means for the proper function of an SCN and its arrhythmia.
26890590	Shift workers have worse health outcomes than employees who work standard business hours. However, it is unclear how this poorer health shift may be related to employee work productivity.The purpose of this systematic review is to assess the relationship between shift work and errors and performance.	Searches of MEDLINE/PubMed, EBSCOhost, and CINAHL were conducted to identify articles that examined the relationship between shift work, errors, quality, productivity, and performance. All articles were assessed for study quality.	A total of 435 abstracts were screened with 13 meeting inclusion criteria. Eight studies were rated to be of strong, methodological quality. Nine studies demonstrated a positive relationship that night shift workers committed more errors and had decreased performance.	Night shift workers have worse health that may contribute to errors and decreased performance in the workplace.	
26890490	A differential demand for copper (Cu) of essential cupro-proteins that act within the mitochondrial and chloroplastal electronic transport chains occurs along the daily light/dark cycles. This requires a fine-tuned spatiotemporal regulation of Cu delivery, becoming especially relevant under non-optimal growth conditions. When scarce, Cu is imported through plasma membrane-bound high affinity Cu transporters (COPTs) whose coding genes are transcriptionally induced by the SPL7 transcription factor. Temporal homeostatic mechanisms are evidenced by the presence of multiple light- and clock-responsive regulatory cis elements in the promoters of both SPL7 and its COPT targets. A model is presented here for such temporal regulation that is based on the synchrony between the basal oscillatory pattern of SPL7 and its targets, such as COPT2. Conversely, Cu feeds back to coordinate intracellular Cu availability on the SPL7-dependent regulation of further Cu acquisition. This occurs via regulation at COPT transporters. Moreover, exogenous Cu affects several circadian-clock components, such as the timing of GIGANTEA transcript abundance. Together we propose that there is a dynamic response to Cu that is integrated over diurnal time to maximize metabolic efficiency under challenging conditions.
26889020	Night shift work has been associated with poor sleep, weight gain, metabolic syndrome, which are recognised risk factor for diabetes. However, only a few studies have examined the effect of shift work on diabetes risk. Here, we study the association between shift work and incidence of diabetes in Danish nurses.We used the Danish Nurse Cohort with 28,731 participating female nurses recruited in 1993 (19,898) or 1999 (8833), when self-reported baseline information on diabetes prevalence, lifestyle and working time were collected, and followed them in the Danish Diabetes Register for incidence of diabetes until 2013. Nurses reported whether they worked night, evening, rotating or day shifts. We analysed the association between working time and diabetes incidence using a Cox proportional hazards model adjusted for diabetes risk factors, separately with and without adjustment for body mass index (BMI) which might be an intermediate variable.	Of 19,873 nurses who worked and were diabetes-free at recruitment, 837 (4.4%) developed diabetes during 15 years of follow-up. The majority of nurses (62.4%) worked day shifts, 21.8% rotating shift, 10.1% evening and 5.5% night shifts. Compared with nurses who worked day shifts, we found statistically significantly increased risk of diabetes in nurses who worked night (1.58; 1.25 to 1.99) or evening shifts (1.29; 1.04 to 1.59) in the fully adjusted models including BMI.	Danish nurses working night and evening shifts have increased risk for diabetes, with the highest risk associated with current night shift work.	
26888917	The increasing use of electric lights has modified the natural light environment dramatically, posing novel challenges to both humans and wildlife. Indeed, several biomedical studies have linked artificial light at night to the disruption of circadian rhythms, with important consequences for human health, such as the increasing occurrence of metabolic syndromes, cancer and reduced immunity. In wild animals, light pollution is associated with changes in circadian behaviour, reproduction and predator-prey interactions, but we know little about the underlying physiological mechanisms and whether wild species suffer the same health problems as humans. In order to fill this gap, we advocate the need for integrating ecological studies in the field, with chronobiological approaches to identify and characterize pathways that may link temporal disruption caused by light at night and potential health and fitness consequences.

26888119	The onset of cardiovascular diseases often shows time-of-day variation. Acute myocardial infarction or ventricular arrhythmia such as ventricular tachycardia occurs mainly in the early morning. Multiple biochemical and physiological parameters show circadian rhythm, which may account for the diurnal variation of cardiovascular events. These include the variations in blood pressure, activity of the autonomic nervous system and renin-angiotensin axis, coagulation cascade, vascular tone and the intracellular metabolism of cardiomyocytes. Importantly, the molecular clock system seems to underlie the circadian variation of these parameters. The center of the biological clock, also known as the central clock, exists in the suprachiasmatic nucleus. In contrast, the molecular clock system is also activated in each cell of the peripheral organs and constitute the peripheral clock. The biological clock system is currently considered to have a beneficial role in maintaining the homeostasis of each organ. Discoordination, however, between the peripheral clock and external environment could potentially underlie the development of cardiovascular events. Therefore, understanding the molecular and cellular pathways by which cardiovascular events occur in a diurnal oscillatory pattern will help the establishment of a novel therapeutic approach to the management of cardiovascular disorders. 
26888117	Many human behaviors and physiological activities show circadian rhythms. Circadian rhythms generated by central and peripheral clocks maintain homeostasis, including the regulation of metabolic processes. Biological rhythmicity is important for metabolic health, but circadian rhythms are affected and impaired by nocturnal activities and irregular food intake in modern society. Disruption of sleep is an established risk factor for diabetes and is known to promote systemic metabolic dysfunction in both humans and rodents. Metabolic stress promotes circadian clock disorders and modulation of clock gene expression has a causal role in the development of metabolic dysfunction. Maintenance of a physiological circadian rhythm is crucial for metabolic health and is an important strategy for combating obesity. 
26886755	Circadian rhythms modulate many physiologic processes and behaviors. Therefore, their disruption causes a variety of potential adverse effects in humans and animals. Circadian disruption induced by constant light exposure has been discovered to produce pathophysiologic consequences after brain injury. However, the underlying mechanisms that lead to more severe impairment and disruption of neurophysiologic processes are not well understood. Here, we evaluated the effect of constant light exposure on the neurobehavioral impairment and survival of neurons in rats after traumatic brain injury (TBI). Sixty adult male Sprague-Dawley rats were subjected to a weight-drop model of TBI and then exposed to either a standard 12-/12-h light/dark cycle or a constant 24-h light/light cycle for 14 days. Our results showed that 14 days of constant light exposure after TBI significantly worsened the sensorimotor and cognitive deficits, which were associated with decreased body weight, impaired water and food intake, increased cortical lesion volume, and decreased neuronal survival. Furthermore, environmental circadian disruption inhibited cell proliferation and newborn cell survival and decreased immature cell production in rats subjected to the TBI model. We conclude that circadian disruption induced by constant light exposure worsens histologic and neurobehavioral impairment and inhibits neurogenesis in adult TBI rats. Our novel findings suggest that light exposure should be decreased and circadian rhythm reestablished in hospitalized TBI patients and that drugs and strategies that maintain circadian rhythm would offer a novel therapeutic option. 
26886115	Determining target intraocular pressure (IOP) in glaucoma patients is multifaceted, requiring attention to many different factors such as glaucoma type, severity of disease, age, race, family history, corneal thickness and hysteresis, and initial IOP. Even with all these variables accounted for, there are still patients who have progression of the disease despite achieving target IOP. Intraocular pressure variability has been identified as a potential independent risk factor for glaucoma progression but is currently difficult to quantify in individual patients. New technologies enabling measurement of both diurnal and nocturnal IOP may necessitate modifying our concept of target pressure. 
26886086	To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy.We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800.	Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07).	Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.	
26885402	The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic "inverted U shape" response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning, and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration, and context at exposure. These criteria are met by neuronal activity and the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity, and adaptive trajectories. 
26885400	Functional and effective connectivity of cortical areas are essential for normal brain function under different behavioral states. Appropriate cortical activity during sleep and wakefulness is ensured by the balanced activity of excitatory and inhibitory circuits. Ultimately, fast, millisecond cortical rhythmic oscillations shape cortical function in time and space. On a much longer time scale, brain function also depends on prior sleep-wake history and circadian processes. However, much remains to be established on how the brain operates at the neuronal level in humans during sleep and wakefulness. A key limitation of human neuroscience is the difficulty in isolating neuronal excitation/inhibition drive in vivo. Therefore, computational models are noninvasive approaches of choice to indirectly access hidden neuronal states. In this review, we present a physiologically driven in silico approach, Dynamic Causal Modelling (DCM), as a means to comprehend brain function under different experimental paradigms. Importantly, DCM has allowed for the understanding of how brain dynamics underscore brain plasticity, cognition, and different states of consciousness. In a broader perspective, noninvasive computational approaches, such as DCM, may help to puzzle out the spatial and temporal dynamics of human brain function at different behavioural states. 
26885250	This work reviews concepts regarding oxidative stress and the mechanisms by which endogenous and exogenous factors produce reactive oxygen species (ROS). It also surveys the relationships between oxidative stress, circadian rhythms, and retinal damage in humans, particularly those related to light and photodamage. In the first section, the production of ROS by different cell organelles and biomolecules and the antioxidant mechanisms that antagonize this damage are reviewed. The second section includes a brief review of circadian clocks and their relationship with the cellular redox state. In the third part of this work, the relationship between retinal damage and ROS is described. The last part of this work focuses on retinal degenerative pathology, age-related macular degeneration, and the relationships between this pathology, ROS, and light. Finally, the possible interactions between the retinal pigment epithelium (RPE), circadian rhythms, and this pathology are discussed. 
26884301	The normal circadian rhythm of hormones in critical patients becomes chaotic causing some hormones to increase and others to decrease abnormally. The goal of this study is to evaluate hormonal changes in severely ill patients and to investigate the relationship between hormonal changes and mortality and morbidity.We enrolled 20 patients (10 F/10 M). Blood samples were collected on day 0, day 5, and day 10. If a patient was discharged before these defined days, a sample was drawn on that day. Twenty healthy controls were included.	Female patients had lower LH, FSH, and fT₃ and higher PRL and cortisol levels than controls on admission to the intensive care unit (ICU) (pLH = 0.021, pFSH:0.001, pfT3 = 0.021, pPRL = 0.042, pCortisol <0.001, respectively). Men had significantly low testosterone and fT3, and high PRL and cortisol levels on ICU admission (pT = 0.01, pfT3 = 0.043, pPRL = 0.005, pCortisol < 0.001, respectively). The lowest levels of gonadotropins in both genders and testosterone in men were measured on day 5. Cortisol levels decreased in the patients discharged from the ICU (p = 0.01). FSH levels increased in recovered women (pFSH = 0.043). The mortality rate was 30%. There were correlations between admission TSH and NIMV duration (p = 0.006), fT3 and APACHE II (p = 0.001), and PRL and mortality (p = 0.044). Positive correlations between E2 and APACHE II (p = 0.003) in females, and PRL and APACHE II (p = 0.022) in males were also displayed.	Critically ill patients develop significant changes in neuroendocrine axes. Alterations in hormones correlate with the disease severity and mortality. (Endokrynol Pol 2016; 67 (3): 305-312).	
26883841	Cardiovascular disease occurs as frequently in older people with intellectual disabilities as in the same aged general population. However, there are indications for underdiagnosis of myocardial infarction due to atypical or absent complaints. Obesity, diabetes and peripheral arterial disease are more common in this group than in the general population. Hypertension, metabolic syndrome and kidney disease occur as frequently as in the general population while hypercholesterolemia occurs less often. Cardiovascular disease risk factors are underdiagnosed in people with intellectual disabilities. This could be reduced by educating supporting staff and caregivers and systematic screening for cardiovascular risk factors by the general practitioner. The customary guidelines should be followed in the treatment of cardiovascular risk factors and cardiovascular disease. Lifestyle interventions and treatment of specific causal factors, such as the use of psychotropic drugs and chronic circadian rhythm disorders, require a specialised approach.
26883207	Maternal physiological adaptations, such as changes to the hypothalamic-pituitary-adrenal (HPA) axis, are central to pregnancy success. Circadian variation of the HPA axis is dependent on clock gene rhythms in the hypothalamus, but it is not known whether pregnancy-induced changes in maternal glucocorticoid levels are mediated via this central clock. We hypothesized that hypothalamic expression of clock genes changes across mouse pregnancy and this is linked to altered HPA activity. The anterior hypothalamus and maternal plasma were collected from C57Bl/6J mice prior to pregnancy and on days 6, 10, 14 and 18 of gestation (term=d19), across a 24-h period (0800, 1200, 1600, 2000, 0000, 0400 h). Hypothalamic expression of clock genes and Crh was determined by qPCR, plasma ACTH concentration measured by Milliplex assay and plasma corticosterone concentration by LC-MS/MS. Expression of all clock genes varied markedly across gestation, most notably at mid-gestation when levels of each gene were elevated. The pregnancy-induced increase in maternal corticosterone levels (by up to 14-fold on day 14) was not accompanied by a parallel shift in plasma ACTH (28% lower on day 14 compared with non-pregnant levels). Moreover, while circadian rhythmicity in corticosterone was maintained up to day 14 of gestation, this was effectively lost by day 18. Overall, our data show that the central circadian clock undergoes marked adaptations throughout mouse pregnancy, changes that are likely to contribute to maternal physiological adaptations. Importantly, however, neither hypothalamic clock genes nor plasma ACTH levels appear to drive the marked increase in maternal corticosterone after mid-gestation. 
26882873	G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz. 

26882469	Abnormal diurnal blood pressure (BP) rhythms may contribute to the high cardiovascular disease risk in HIV-positive (HIV+) individuals. To synthesize the current literature on ambulatory BP monitoring (ABPM) in HIV+ individuals, a systematic literature review and meta-analysis were performed.Medical databases were searched through November 11, 2015 for studies that reported ABPM results in HIV+ individuals. Data were extracted by 2 reviewers and pooled differences between HIV+ and HIV-negative (HIV-) individuals in clinic BP and ABPM measures were calculated using random-effects inverse variance weighted models.	Of 597 abstracts reviewed, 8 studies with HIV+ cohorts met the inclusion criteria. The 420 HIV+ and 714 HIV- individuals in 7 studies with HIV- comparison groups were pooled for analyses. The pooled absolute nocturnal systolic and diastolic BP declines were 3.16% (95% confidence interval [CI]: 1.13%, 5.20%) and 2.92% (95% CI: 1.64%, 4.19%) less, respectively, in HIV+ versus HIV- individuals. The pooled odds ratio for non-dipping systolic BP (nocturnal systolic BP decline <10%) in HIV+ versus HIV- individuals was 2.72 (95% CI: 1.92, 3.85). Differences in mean clinic, 24-hour, daytime, or nighttime BP were not statistically significant. I2 and heterogeneity chi-squared statistics indicated the presence of high heterogeneity for all outcomes except percent DBP dipping and non-dipping SBP pattern.	An abnormal diurnal BP pattern may be more common among HIV+ versus HIV- individuals. However, results were heterogeneous for most BP measures, suggesting more research in this area is needed.	

26879834	There are some studies in attention deficit hyperactivity disorder (ADHD) which note altered circadian rhythms, suggesting abnormalities in melatonin physiology. In order to better characterize the possible melatonin alteration in ADHD, in this study we aimed to detect daytime, nighttime and 24 h levels of 6-hydroxymelatoninsulfate (6-OH MS) in the patients diagnosed with ADHD. Twenty-seven patients between 6 and 16 years-old, who had been diagnosed initially with ADHD, but without other physical and psychiatric disease history and who had not taken psychotropic pharmacotherapy for six months, plus 28 healthy volunteer controls, were included in the study. Urine samples were collected during the whole 24 h cycle, daytime and nighttime separately to assess the time-dependent excretion of the 6-OH MS, which is the main urine metabolite of melatonin. The Enzyme-Linked Immunosorbent Assay (ELISA) method was used for measuring the urine 6-OH MS level. Daytime (15.4 (8.9-24.8) ng/ml vs 6.9 (2.5-15.9) ng/ml, p=0.002), nighttime (102.9 (65.3-197.7) ng/ml vs 61.5 (37.2-114.4) ng/ml, p=0.012) and 24 h (54.1 (34.6-83.9) ng/ml vs 27.3 (14.3-48.9) ng/ml, p=0.000) 6-OH MS levels median (25p-75p) were found to be significantly higher in the ADHD group. After adjustment for age and sex, there was a statistically significant difference between the ADHD group (59.8 ± 4.9) and control group (33.8 ± 4.8) in 24-h 6-OH MS levels (F(1, 51)=13.673, p=.001, partial η2=.211). There was no relationship between 6-OH MS levels and Conners Parent Rating Scale short form subscale scores for the ADHD group. These findings indicate that melatonin production is increased in ADHD cases. Further research is needed to determine and thereby understand the mechanisms underlying the higher melatonin production, to assess the impact of altered melatonin on the pathophysiology of ADHD.
26878025	In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated.
26877166	Previous studies have demonstrated that a light-dark cycle has promoted better sleep development and weight gain in preterm infants than constant light or constant darkness. However, it was unknown whether brief light exposure at night for medical treatment and nursing care would compromise the benefits brought about by such a light-dark cycle. To examine such possibility, we developed a special red LED light with a wavelength of >675 nm which preterm infants cannot perceive. Preterm infants born at <36 weeks' gestational age were randomly assigned for periodic exposure to either white or red LED light at night in a light-dark cycle after transfer from the Neonatal Intensive Care Unit to the Growing Care Unit, used for supporting infants as they mature. Activity, nighttime crying and body weight were continuously monitored from enrolment until discharge. No significant difference in rest-activity patterns, nighttime crying, or weight gain was observed between control and experimental groups. The data indicate that nursing care conducted at 3 to 4-hour intervals exposing infants to light for <15 minutes does not prevent the infants from developing circadian rest-activity patterns, or proper body growth as long as the infants are exposed to regular light-dark cycles. 
26875906	Obstructive sleep apnoea (OSA) is considered a cause of secondary hypertension. About 50% of patients with OSA show elevated blood pressure levels. Non-dipper pattern (blunted or absent nocturnal decrease of blood pressure) is frequently observed in patients with OSA and is associated with increased cerebral, cardiovascular and renal events. The aim of this study was to observe the effect of barnidipine calcium channel blocker on these patients.Forty-one patients (mean age 69 ± 17 years, 18 females) with previously diagnosed OSA (by reduced channel home-based polysomnography) who were not being treated with continuous positive airway pressure (CPAP) because of contraindications or because of patient intolerance or rejection were evaluated. Non-dipper status was defined as the presence of a nighttime fall in systolic blood pressure (BP) which was < 10% that of daytime systolic BP as observed in a previous ambulatory blood pressure (ABP) monitoring. OSA was defined according to the presence of 5 or more episodes per hour of apnoea, hypopnoea or arousal due to respiratory effort. The reproducibility of non-dipping status was confirmed through a second 24-h ABP monitoring performed at baseline. On top of the previous stable treatment regimen (which excluded calcium-channel blockers), a 10 mg dosing of barnidipine hydrochloride at bedtime was added to all subjects during a 12-week period.	Among the 41 non-dipper patients, 32 (78%) showed complete normalization of circadian rhythm. Add-on treatment with barnidipine was generally well tolerated.	Bedtime dosing of the calcium-channel blocker (CCB) barnidipine significantly reduced mean nighttime systolic and diastolic ABP in hypertensive patients presenting with non-dipper pattern and OSA--not on CPAP treatment. Moreover, it restored the previously altered circadian rhythm in the majority of them.	
26875002	To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% every evening (qpm) with timolol maleate 0.5% twice daily (BID) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT).Phase 3, randomized, controlled, multicenter, double-masked, parallel-group clinical study.	Subjects aged ≥18 years with a diagnosis of OAG or OHT in 1 or both eyes.	Subjects were randomized (2:1) to a 3-month regimen of LBN 0.024% qpm or timolol 0.5% 1 drop BID. Intraocular pressure was measured at 8 am, 12 pm, and 4 pm of each postrandomization visit (week 2, week 6, and month 3). Adverse events were recorded throughout the study.	The primary efficacy end point was IOP in the study eye measured at each of the 9 assessment time points. Secondary efficacy end points included the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points.	Of 420 subjects randomized, 387 completed the study (LBN 0.024%, n = 264; timolol 0.5%, n = 123). At all 9 time points, the mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group (P ≤ 0.002). At all 9 time points, the percentage of subjects with mean IOP ≤18 mmHg and the percentage with IOP reduction ≥25% were significantly higher in the LBN 0.024% group versus the timolol 0.5% group (mean IOP ≤18 mmHg: 22.9% vs. 11.3%, P = 0.005; IOP reduction ≥25%: 34.9% vs. 19.5%, P = 0.001). Adverse events were similar in both treatment groups.	In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.	
26874590	Technology-related behaviors (e.g., computer use) before bedtime (BT) have been associated with poorer and shorter sleep in adolescents; however, less is known about other behaviors in relation to sleep. This study characterized a range of behaviors in the hour before bed (i.e., pre-BT behaviors [PBBs]) and examined their relationship with sleep parameters during school and vacation periods (i.e., restricted and extended sleep opportunities, respectively). Mechanistic roles of chronotype and cognitive presleep arousal (PSAcog) were also examined.During the last week of a school term and throughout a 2-week vacation, 146 adolescents (47.26% male, age M ± standard deviation = 16.2 ± 1.0 years) from the general community completed daily sleep measure using actigraphy, self-report measures on PBBs and PSAcog (Presleep Arousal Scale) for both school and vacation periods, and chronotype (Morningness-Eveningness Questionnaire).	Adolescents engaged in a variety of behaviors before bed. Notably, playing video games was associated with significantly later school and vacation BT and shorter school sleep duration (controlling for chronotype). During vacation, online social media was associated with significantly longer sleep onset latency, and this relationship was mediated by higher PSAcog. In contrast, on school nights, spending time with family was associated with significantly earlier BT and longer sleep duration.	Technology-related PBBs video games and online social media were risk factors for shorter and poorer sleep, whereas time with family was protective of sleep duration. In addressing sleep problems in adolescents, therapeutic procedures that target the potentially addictive nature of technology use and reduce PSAcog were implicated.	
26874562	Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response; CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC; however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders. 
26873990	Recent research unveiled a circadian regulation of the immune system in rodents, yet little is known about rhythms of immune functions in humans and how they are affected by circadian disruption. In this study, we assessed rhythms of cytokine secretion by immune cells and tested their response to simulated night shifts. PBMCs were collected from nine participants kept in constant posture over 24 h under a day-oriented schedule (baseline) and after 3 d under a night-oriented schedule. Monocytes and T lymphocytes were stimulated with LPS and PHA, respectively. At baseline, a bimodal rhythmic secretion was detected for IL-1β, IL-6, and TNF-α: a night peak was primarily due to a higher responsiveness of monocytes, and a day peak was partly due to a higher proportion of monocytes. A rhythmic release was also observed for IL-2 and IFN-γ, with a nighttime peak due to a higher cell count and responsiveness of T lymphocytes. Following night shifts, with the exception of IL-2, cytokine secretion was still rhythmic but with peak levels phase advanced by 4.5-6 h, whereas the rhythm in monocyte and T lymphocyte numbers was not shifted. This suggests distinct mechanisms of regulation between responsiveness to stimuli and cell numbers of the human immune system. Under a night-oriented schedule, only cytokine release was partly shifted in response to the change in the sleep-wake cycle. This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers. 
26873744	The circadian clock system has been linked to the onset and development of obesity and some accompanying comorbidities. Epigenetic mechanisms, such as DNA methylation, are putatively involved in the regulation of the circadian clock system. The aim of this study was to investigate the influence of a weight loss intervention based on an energy-controlled Mediterranean dietary pattern in the methylation levels of 3 clock genes, BMAL1, CLOCK, and NR1D1, and the association between the methylation levels and changes induced in the serum lipid profile with the weight loss treatment. The study sample enrolled 61 women (body mass index = 28.6 ± 3.4 kg/m(2); age: 42.2 ± 11.4 years), who followed a nutritional program based on a Mediterranean dietary pattern. DNA was isolated from whole blood obtained at the beginning and end point. Methylation levels at different CpG sites of BMAL1, CLOCK, and NR1D1 were analyzed by Sequenom's MassArray. The energy-restricted intervention modified the methylation levels of different CpG sites in BMAL1 (CpGs 5, 6, 7, 9, 11, and 18) and NR1D1 (CpGs 1, 10, 17, 18, 19, and 22). Changes in cytosine methylation in the CpG 5 to 9 region of BMAL1 with the intervention positively correlated with the eveningness profile (p = 0.019). The baseline methylation of the CpG 5 to 9 region in BMAL1 positively correlated with energy (p = 0.047) and carbohydrate (p = 0.017) intake and negatively correlated with the effect of the weight loss intervention on total cholesterol (p = 0.032) and low-density lipoprotein cholesterol (p = 0.005). Similar significant and positive correlations were found between changes in methylation levels in the CpG 5 to 9 region of BMAL1 due to the intervention and changes in serum lipids (p < 0.05). This research describes apparently for the first time an association between changes in the methylation of the BMAL1 gene with the intervention and the effects of a weight loss intervention on blood lipids levels. 
26873742	Melatonin is synthesized in peripheral locations of vertebrates, including the gastrointestinal tract (GIT). In teleost, information regarding this topic is scarce. Here we studied the presence and synthesis of melatonin at the rainbow trout GIT. Different sections of trout GIT (from esophagus to hindgut) were dissected out and assayed for contents of melatonin, serotonin (5-HT) and its metabolite, 5-hydroxyindole acetic acid, as well as for aanat1, aanat2 and hiomt mRNA abundance. A trout group was pinealectomized to evaluate changes in plasma and gut melatonin content. Finally, the daily profile of melatonin and 5-HT content, and aanat1, aanat2 and hiomt mRNA abundance were analyzed in gut of trout kept under normal lighting, and then under constant darkness. Melatonin was detected in all GIT regions with higher concentrations in the muscular wall than in the mucosa, a similar trend to that of 5-HT. In contrast, transcripts of melatonin synthesis enzymes were more abundant in the mucosa. Pinealectomy did not affect melatonin levels in midgut and hindgut either at day or at night. Additionally, no daily rhythms could be defined for melatonin content in gut tissues but increases during late light phase and at midnight occurred. However, aanat1, aanat2 and hiomt mRNA abundance showed clear daily rhythms with peaks at night. These rhythms remained with a 3-h phase advanced peak in fish exposed to constant darkness. Our results provide clear evidence for a local synthesis of melatonin in trout GIT that might be influenced by the content of 5-HT in the tissue. The process is affected by environmental light cycle and is likely to be under circadian regulation. 
26873024	A recent publication shows that, during their domestication and spread from Equatorial South America, circadian rhythms of tomatoes have been modified. The modifications have resulted in tomato plants that are adapted to growing under the long day conditions characteristic of summers at higher latitudes. 
26872568	To investigate the link between lower urinary tract symptoms (LUTS) and metabolic disorders.This report results from presentations and subsequent discussions about LUTS and metabolic disorders at the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, 2014.	There are common pathophysiological determinants for the onset of LUTS and the metabolic syndrome (MetS). Both conditions are multifactorial, related to disorders in circadian rhythms and share common risk factors. As in men with erectile dysfunction, these potentially modifiable lifestyle factors may be novel targets to prevent and treat LUTS. The link between LUTS and metabolic disorders is discussed by using sleep, urine production and bladder function as underlying mechanisms that need to be further explored during future research.	Recent findings indicate a bidirectional relationship between LUTS and the MetS. Future research has to explore underlying mechanisms to explain this relationship, in order to develop new preventive and therapeutic recommendations, such as weight loss and increasing physical activity. The second stage is to determine the effect of these new treatment approaches on the severity of LUTS and each of the components of the MetS.	
26872557	The aim of this study was to investigate the effect of season of diagnosis on the outcome of patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). In this study, we included curatively treated DLBCL (n = 5875) and HL (n = 1693) patients, diagnosed between 2000 and 2011, based on data from the Swedish Lymphoma Register.Overall survival was significantly better for patients diagnosed with DLBCL during the summer months, but not for patients diagnosed with HL. The difference remained in a multivariable analysis adjusted for age, stage, performance status, number of extra nodal sites and year of diagnosis (HR 1.08; 95% CI 1.02-1.14, P = 0.0069). When analyzing the DLBCL patients according to gender in the multivariable model, the effect of season was shown to be restricted to male patients (HR = 1.09, 95% CI 1.01-1.17, P = 0.0269.	In summary, season of diagnosis was shown to have impact on overall survival in male patients with DLBCL. Possible explanations of our results are the higher vitamin D level during the summer months, the effects of sunlight on the circadian rhythm and the immune system, or the lower risk of infectious disease during the summer. Further investigations are needed to explore these hypotheses.	
26872485	Nocturnal enuresis is caused by a mismatch between the nocturnal bladder capacity and the nocturnal diuresis rate, in the presence of a deficient arousability in the majority of patients, according to the pediatric and urologic literature. Psychiatric and psychologic literature are still concentrating on the potential role of psychological factors and central nervous mechanisms in the pathogenesis, as is reflected in the DMS-5 criteria. However, research has clearly shown several important comorbidities between neuropsychological dysfunctions and nocturnal enuresis. Due to the increased comorbidity of (neuro)psychological problems, sleep problems, circadian rhythms, and enuresis, the question arises as to whether there is a possible common central pathway in the pathogenesis. It is likely that the coexistence of these problems can be attributed to a common central nervous system involvement. The specific role of the central nervous system remains unclear, but several pathways are possible. The high comorbidity between enuresis, sleep, and (neuro)psychological functioning is probably attributable to a common pathogenetic pathway, emphasizing the importance of a multidisciplinary focus in screening and treatment in children with nocturnal enuresis. 
26871695	Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s) and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHD males, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differences are associated with a smaller suprachiasmatic nucleus (SCN) in BACHD male mice at age of symptom onset (3 months), but are not associated with sex-specific differences in SCN daytime electrical activity deficits, or peptide expression (arginine vasopressin, vasoactive intestinal peptide) within the SCN. Notably, BACHD females exhibited delayed motor coordination deficits, as measured using rotarod and challenge beam. These findings suggest a sex specific factor plays a role both in non-motor and motor symptom progression for the BACHD mouse. 
26869012	Quetiapine is an atypical antipsychotic that can stabilise mood from any index episode of bipolar disorder. This study investigated the effects of seven-day quetiapine administration on sleep, circadian rhythms and emotional processing in healthy volunteers.Twenty healthy volunteers received 150 mg quetiapine XL for seven nights and 20 matched controls received placebo. Sleep-wake actigraphy was completed for one week both pre-dose and during drug treatment. On Day 8, participants completed emotional processing tasks.	Actigraphy revealed that quetiapine treatment increased sleep duration and efficiency, delayed final wake time and had a tendency to reduce within-day variability. There were no effects of quetiapine on subjective ratings of mood or energy. Quetiapine-treated participants showed diminished bias towards positive words and away from negative words during recognition memory. Quetiapine did not significantly affect facial expression recognition, emotional word categorisation, emotion-potentiated startle or emotional word/faces dot-probe vigilance reaction times.	These changes in sleep timing and circadian rhythmicity in healthy volunteers may be relevant to quetiapine's therapeutic actions. Effects on emotional processing did not emulate the effects of antidepressants. The effects of quetiapine on sleep and circadian rhythms in patients with bipolar disorder merit further investigation to elucidate its mechanisms of action.	
26868293	The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele. 
26868037	In fruit flies Drosophila melanogaster, environmental cycles of light and temperature are known to influence behavioral rhythms through dedicated sensory receptors. But the thermosensory pathways and molecular receptors by which thermal cycles modulate locomotor activity rhythms remain unclear. Here, we report that neurons expressing warmth-activated ion channel Drosophila Transient Receptor Potential-A1 (dTRPA1) modulate distinct aspects of the rhythmic activity/rest rhythm in a light-dependent manner. Under light/dark (LD) cycles paired with constantly warm ambient conditions, flies deficient in dTRPA1 expression are unable to phase morning and evening activity bouts appropriately. Correspondingly, we show that electrical activity of a few neurons targeted by the dTRPA1(SH)-GAL4 driver modulates temperature-dependent phasing of activity/rest rhythm under LD cycles. The expression of dTRPA1 also affects behavior responses to temperature cycles combined with constant dark (DD) or light (LL) conditions. We demonstrate that the mid-day "siesta" exhibited by flies under temperature cycles in DD is dependent on dTRPA1 expression in a small number of neurons that include thermosensory anterior cell neurons. Although a small subset of circadian pacemaker neurons may express dTRPA1, we show that CRY-negative dTRPA1(SH)-GAL4 driven neurons are critical for the suppression of mid-thermophase activity, thus enabling flies to exhibit siesta. In contrast to temperature cycles in DD, under LL, dTRPA1 is not required for exhibiting siesta but is important for phasing of evening peak. Our studies show that activity/rest rhythms are modulated in a temperature-dependent manner via signals from dTRPA1(SH)-GAL4 driven neurons. Taken together, these results emphasize the differential influence of thermoreceptors on rhythmic behavior in fruit flies in coordination with light inputs. 
26867698	Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets. 
26867621	Circadian clocks drive 24 h biological rhythms to optimize physiology and development in response to the rotation of the planet. In plants, photosynthesis is modulated by the circadian clock and contributes to daily rhythms in cellular metabolism. In addition to light and temperature, sugar produced from photosynthesis acts as a zeitgeber to contribute to setting of the plant circadian clock. Here, we describe methods to manipulate photosynthetic output and sugar availability in Arabidopsis seedlings. These protocols have been applied to investigate the effects on the Arabidopsis circadian network, but are easily adaptable to other processes in plants. 
26867620	Posttranscriptional control makes an important contribution to circadian regulation of gene expression. In higher plants, alternative splicing is particularly prevalent upon abiotic and biotic stress and in the circadian system. Here we describe in detail a high-resolution reverse transcription-PCR based panel (HR RT-PCR) to monitor alternative splicing events. The use of the panel allows the quantification of changes in the proportion of splice isoforms between different samples, e.g., different time points, different tissues, genotypes, ecotypes, or treatments. 
26867619	Genetic and molecular approaches revealed that the circadian clock network structure is comprised of several interlocked positive and negative transcriptional feedback loops. The network evolved to sense and integrate inputs from environmental cues to adjust daily rhythms in physiological processes. Compiling evidence indicates that part of this regulation happens at the transcriptional level through subtle adjustments in the expression of core clock genes. Thus, to better understand the network and identify the molecular mechanisms of clock input pathways, it is imperative to determine how core clock genes are regulated. For this purpose we developed reagents for an unbiased approach to identify transcription factors (TFs) interacting with the promoters of core clock genes. At the center of this approach lies the yeast one-hybrid (Y1H) assay in which a pool of proteins fused to the GAL4 transcriptional activation domain are tested for their ability to interact with a selected promoter fragment in yeast cells. Taking advantage of the fact that Arabidopsis TF genes are well annotated, we generated a comprehensive TF clone collection (TF ORFeome) and used it to replace the standard cDNA pool strategy traditionally used in Y1H screens. The use of this TF clone collection substantially accelerates the comprehensive discovery of promoter-specific DNA binding activities among all Arabidopsis TFs. Considering that this strategy can be extended to the study of the promoter interactome of any Arabidopsis gene, we developed a low throughput protocol that can be universally implemented to screen the ~2000 TF clone library. 
26867618	Gating is the mechanism by which the influence of an environmental signal on a particular output is temporally restricted by the circadian clock, so that the maximum response of the output to the signal occurs at a specific time. Gated regulation mechanisms have been described for several genes whose expression is strongly induced by light or temperature at certain times but repressed by the circadian clock at others. To reveal a gated pattern of expression in response to light, light pulses are applied in the dark at different times of the 24 h cycle and the transcriptional response of the gene of interest is then monitored with an appropriate technique. Luciferase (LUC) reporters have been the method of choice to study circadian rhythms in the past decades, but this methodology also provides an ideal platform for performing a gating assay. In this chapter, we describe a LUC imaging based protocol designed to test whether the influence of light on the expression of a gene of interest is gated by the circadian clock. 
26867616	The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato. 
26867054	To determine whether defining diurnal periods by self-report, fixed-time, or actigraphy produce different estimates of night-time and daytime ambulatory blood pressure (ABP).Over a median of 28 days, 330 participants completed two 24-h ABP and actigraphy monitoring periods with sleep diaries. Fixed night-time and daytime periods were defined as 0000-0600 h and 1000-2000 h, respectively. Using the first ABP period, within-individual differences for mean night-time and daytime ABP and kappa statistics for night-time and daytime hypertension (systolic/diastolic ABP≥120/70 mmHg and ≥135/85 mmHg, respectively) were estimated comparing self-report, fixed-time, or actigraphy for defining diurnal periods. Reproducibility of ABP was also estimated.	Within-individual mean differences in night-time systolic ABP were small, suggesting little bias, when comparing the three approaches used to define diurnal periods. The distribution of differences, represented by 95% confidence intervals (CI), in night-time systolic and diastolic ABP and daytime systolic and diastolic ABP was narrowest for self-report versus actigraphy. For example, mean differences (95% CI) in night-time systolic ABP for self-report versus fixed-time was -0.53 (-6.61, +5.56) mmHg, self-report versus actigraphy was 0.91 (-3.61, +5.43) mmHg, and fixed-time versus actigraphy was 1.43 (-5.59, +8.46) mmHg. Agreement for night-time and daytime hypertension was highest for self-report versus actigraphy: kappa statistic (95% CI) = 0.91 (0.86,0.96) and 1.00 (0.98,1.00), respectively. The reproducibility of mean ABP and hypertension categories was similar using each approach.	Given the high agreement with actigraphy, these data support using self-report to define diurnal periods on ABP monitoring. Further, the use of fixed-time periods may be a reasonable alternative approach.	
26866932	Integration of knowledge concerning circadian rhythms, metabolic networks, and sleep-wake cycles is imperative for unraveling the mysteries of biological cycles and their underlying mechanisms. During the last decade, enormous progress in circadian biology research has provided a plethora of new insights into the molecular architecture of circadian clocks. However, the recent identification of autonomous redox oscillations in cells has expanded our view of the clockwork beyond conventional transcription/translation feedback loop models, which have been dominant since the first circadian period mutants were identified in fruit fly. Consequently, non-transcriptional timekeeping mechanisms have been proposed, and the antioxidant peroxiredoxin proteins have been identified as conserved markers for 24-hour rhythms. Here, we review recent advances in our understanding of interdependencies amongst circadian rhythms, sleep homeostasis, redox cycles, and other cellular metabolic networks. We speculate that systems-level investigations implementing integrated multi-omics approaches could provide novel mechanistic insights into the connectivity between daily cycles and metabolic systems. 
26865997	Bipolar disorder is a heterogeneous condition with myriad clinical manifestations and many comorbidities leading to severe disabilities in the biopsychosocial realm. The objective of this review article was to underline recent advances in knowledge regarding the neurobiology of bipolar disorder. A further aim was to draw attention to new therapeutic targets in the treatment of bipolar disorder. To accomplish these goals, an electronic search was undertaken of the PubMed database in August 2015 of literature published during the last 10 years on the pathophysiology of bipolar disorder. A wide-ranging evaluation of the existing work was done with search terms such as "mood disorders and biology," "bipolar disorder and HPA axis," "bipolar disorder and cytokines," "mood disorders and circadian rhythm," "bipolar disorder and oxidative stress," etc. This endeavor showed that bipolar disorder is a diverse condition sharing neurobiological mechanisms with major depressive disorder and psychotic spectrum disorders. There is convincing evidence of crosstalk between different biological systems that act in a deleterious manner causing expression of the disease in genetically predisposed individuals. Inflammatory mediators act in concert with oxidative stress to dysregulate hormonal, metabolic, and circadian homeostasis in precipitating and perpetuating the illness. Stress, whether biologically or psychologically mediated, is responsible for the initiation and progression of the diathesis. Bipolar spectrum disorders have a strong genetic component; severe life stresses acting through various paths cause the illness phenotype. 
26865623	Animals use circadian rhythms to anticipate daily environmental changes. Circadian clocks have a profound effect on behavior. In Drosophila, for example, brain pacemaker neurons dictate that flies are mostly active at dawn and dusk. miRNAs are small, regulatory RNAs (≈22 nt) that play important roles in posttranscriptional regulation. Here, we identify miR-124 as an important regulator of Drosophila circadian locomotor rhythms. Under constant darkness, flies lacking miR-124 (miR-124(KO)) have a dramatically advanced circadian behavior phase. However, whereas a phase defect is usually caused by a change in the period of the circadian pacemaker, this is not the case in miR-124(KO) flies. Moreover, the phase of the circadian pacemaker in the clock neurons that control rhythmic locomotion is not altered either. Therefore, miR-124 modulates the output of circadian clock neurons rather than controlling their molecular pacemaker. Circadian phase is also advanced under temperature cycles, but a light/dark cycle partially corrects the defects in miR-124(KO) flies. Indeed, miR-124(KO) shows a normal evening phase under the latter conditions, but morning behavioral activity is suppressed. In summary, miR-124 controls diurnal activity and determines the phase of circadian locomotor behavior without affecting circadian pacemaker function. It thus provides a potent entry point to elucidate the mechanisms by which the phase of circadian behavior is determined.In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian locomotor behavior. Surprisingly, the period and phase of the neural circadian pacemakers driving locomotor rhythms are unaffected. Therefore, miR-124 is a critical modulator of the circadian output pathways that control circadian behavioral rhythms.	
26865608	The hypothalamus plays an important role in regulating sleep, but few hypothalamic sleep-promoting signaling pathways have been identified. Here we demonstrate a role for the neuropeptide QRFP (also known as P518 and 26RFa) and its receptors in regulating sleep in zebrafish, a diurnal vertebrate. We show that QRFP is expressed in ∼10 hypothalamic neurons in zebrafish larvae, which project to the hypothalamus, hindbrain, and spinal cord, including regions that express the two zebrafish QRFP receptor paralogs. We find that the overexpression of QRFP inhibits locomotor activity during the day, whereas mutation of qrfp or its receptors results in increased locomotor activity and decreased sleep during the day. Despite the restriction of these phenotypes to the day, the circadian clock does not regulate qrfp expression, and entrained circadian rhythms are not required for QRFP-induced rest. Instead, we find that QRFP overexpression decreases locomotor activity largely in a light-specific manner. Our results suggest that QRFP signaling plays an important role in promoting sleep and may underlie some aspects of hypothalamic sleep control.The hypothalamus is thought to play a key role in regulating sleep in vertebrate animals, but few sleep-promoting signaling pathways that function in the hypothalamus have been identified. Here we use the zebrafish, a diurnal vertebrate, to functionally and anatomically characterize the neuropeptide QRFP. We show that QRFP is exclusively expressed in a small number of neurons in the larval zebrafish hypothalamus that project widely in the brain. We also show that QRFP overexpression reduces locomotor activity, whereas animals that lack QRFP signaling are more active and sleep less. These results suggest that QRFP signaling participates in the hypothalamic regulation of sleep.	
26864762	Voltage-activated potassium channels (Kv channels) in the microvillar photoreceptors of arthropods are responsible for repolarization and regulation of photoreceptor signaling bandwidth. On the basis of analyzing Kv channels in dipteran flies, it was suggested that diurnal, rapidly flying insects predominantly express sustained K(+) conductances, whereas crepuscular and nocturnally active animals exhibit strongly inactivating Kv conductances. The latter was suggested to function for minimizing cellular energy consumption. In this study we further explore the evolutionary adaptations of the photoreceptor channelome to visual ecology and behavior by comparing K(+) conductances in 15 phylogenetically diverse insects, using patch-clamp recordings from dissociated ommatidia. We show that rapid diurnal flyers such as the blowfly (Calliphora vicina) and the honeybee (Apis mellifera) express relatively large noninactivating Kv conductances, conforming to the earlier hypothesis in Diptera. Nocturnal and/or slow-moving species do not in general exhibit stronger Kv conductance inactivation in the physiological membrane voltage range, but the photoreceptors in species that are known to rely more on vision behaviorally had higher densities of sustained Kv conductances than photoreceptors of less visually guided species. No statistically significant trends related to visual performance could be identified for the rapidly inactivating Kv conductances. Counterintuitively, strong negative correlations were observed between photoreceptor capacitance and specific membrane conductance for both sustained and inactivating fractions of Kv conductance, suggesting insignificant evolutionary pressure to offset negative effects of high capacitance on membrane filtering with increased conductance. 
26864449	Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease. 
26863340	African-Americans have been found to experience increased rates of post-traumatic stress disorder (PTSD), obesity, and flatter diurnal cortisol slopes compared to other demographic groups. Further exploration, however, is needed to understand how PTSD impacts diurnal cortisol activity in obese African-American women. The purpose of the current study is to examine the relationship between salivary cortisol levels and PTSD in a sample of obese young adult African-American women and to examine how depression and insomnia influence the relationship.Thirty-four young adult African-American women (mean age = 24.0 years; mean BMI = 37.4 kg/m(2), 6/34 of the sample had a score of 40 or above on the PTSD Checklist (PCL) representing clinically significant PTSD) filled out questionnaires assessing PTSD, lifetime exposure to traumatic events, insomnia severity, and depression. A home-based assessment of salivary cortisol was provided upon awakening at 30 min and 1, 3, 6, and 12 h.	There was a significant interaction between PTSD status and diurnal cortisol activity (p < 0.04). There were trends for higher cortisol levels at awakening (p < 0.051) and 30 min post-awakening (p < 0.059) with PTSD. The significance of the interaction between PTSD and cortisol was attenuated by co-varying for depression and insomnia (p > 0.05).	PTSD, influenced by depression and insomnia symptoms, has an impact on diurnal cortisol activity in obese young adult African-American women.	
26863205	The horseshoe crab Tachypleus tridentatus is critically endangered in Japan due to rapidly decreasing numbers resulting from the loss of tidal flats and sandy beaches, and the deterioration of coastal environments. We monitored the year-round migratory patterns and residency of this species in a coastal embayment at Tsuyazaki, Japan, using acoustic telemetry. Total 20 adult crabs (15 males and 5 females) were tagged with ultrasonic transmitters and tracked during two periods (2006-2008; n = 10 and 2007-2009; n = 10). Adult crabs were more active during periods of higher water temperatures and their activity peaked in July, during the spawning period. Water temperature appeared to be one of the key factors influencing the movement patterns for the species. Moreover, the crabs tended to be more active at night than in the day. The nocturnal activity pattern was clearly evident before and during the reproductive period (May-August). Tracking data also showed that one pair-bond was maintained for a maximum of 17 days after the pair-bonded female had spawned. Overall, 11 males (73% of 15 individuals) remained in the bay area over winter, whereas three females (60% of 5 individuals) overwintered outside of the bay. Telemetry data showed that over 60% (13 of 20) of tagged crabs overwintered within the bay where there are sandy beaches, mudflats, and scattered seagrass beds. This year-round residence by adult T. tridentatus in the bay area identifies it as a critical habitat for the management of this species, regardless of life-stage. Not only is it a comprehensive management strategy that effectively reflects this species' habitat use patterns but also its implementation, such as the establishment of a protected area, would contribute to its conservation. 
26862173	Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization. 
26862003	Circadian rhythms are biological rhythms with a period of around 24 hours. In this study, we compared the metabolome of the liver of medaka during the day and night. To comprehensively analyze the circadian variations in the levels of metabolites in the liver, livers were isolated from Zeitgeber time (ZT)4 and ZT16, and the variations in metabolite levels were evaluated. Inosinemonophosphate (IMP) and uridinemonophosphate (UMP) were found to be increased at night, indicating that nucleotide synthesis is most active during the night. Furthermore, the levels of metabolites of the tricarboxylic acid cycle were also reduced at night. In addition, the levels of many amino acids were reduced during the night, suggesting that the amino acids had been degraded. Moreover, the citrulline/ornithine ratio, which is related to arginine consumption, was lower during the day than at night. This pattern suggests that the urea cycle is activated during the day, whereas large amounts of nitric oxide and citrulline may be produced from arginine via nitric oxide synthase during the night. The results of this metabolomic analysis may be useful in future fundamental research to provide insight into chronobiology as well as applied research on drug evaluations using medaka as a model species.
26861419	The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network. Here we review the current understanding of communication among SCN clock cells and highlight a collection of formal assays where changes in SCN interactions provide for plasticity in the waveform of circadian rhythms in behavior. Future studies that pair analytical behavioral assays with modern neuroscience techniques have the potential to provide deeper insight into SCN circuit mechanisms. 
26860578	Injection anaesthesia is commonly used in laboratory mice; however, a disadvantage is that post-anaesthesia recovery phases are long. Here, we investigated the potential for shortening the recovery phase after injection anaesthesia with fentanyl-midazolam-medetomidine by antagonization with naloxone-flumazenil-atipamezole. In order to monitor side-effects, the depth of anaesthesia, heart rate (HR), core body temperature (BT) and concentration of blood gases, as well as reflex responses, were assessed during a 50 min anaesthesia. Mice were allowed to recover from the anaesthesia in their home cages either with or without antagonization, while HR, core BT and spontaneous home cage behaviours were recorded for 24 h. Mice lost righting reflex at 330 ± 47 s after intraperitoneal injection of fentanyl-midazolam-medetomidine. During anaesthesia, HR averaged 225 ± 23 beats/min, respiratory rate and core BT reached steady state at 131 ± 15 breaths/min and 34.3 ± 0.25℃, respectively. Positive pedal withdrawal reflex, movement triggered by tail pinch and by toe pinch, still occurred in 25%, 31.2% and 100% of animals, respectively. Arterial blood gas analysis revealed acidosis, hypoxia, hypercapnia and a marked increase in glucose concentration. After anaesthesia reversal by injection with naloxone-flumazenil-atipamezole, animals regained consciousness after 110 ± 18 s and swiftly returned to physiological baseline values, yet they displayed diminished levels of locomotion and disrupted circadian rhythm. Without antagonization, mice showed marked hypothermia (22 ± 1.9℃) and bradycardia (119 ± 69 beats/min) for several hours. Fentanyl-midazolam-medetomidine provided reliable anaesthesia in mice with reasonable intra-anaesthetic side-effects. Post-anaesthetic period and related adverse effects were both reduced substantially by antagonization with naloxone-flumazenil-atipamezole. 
26859736	Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common sleep-related breathing disorder. Hypertension is frequently a concomitant disorder in patients with OSAHS.This study investigates the prevalence and clinical features of hypertension in patients with OSAHS and explores the related nursing strategies.	Three thousand six hundred seven patients were included in this study. Subjects were divided into four groups that were categorized according to apnea-hypopnea index (AHI) scores as follows: control group (control, n = 354) with AHI < 5, mild OSAHS (mild, n = 658) with 5 ≤ AHI < 15, moderate OSAHS (moderate, n = 753) with 15 ≤ AHI < 30, and severe OSAHS (severe, n = 1842) with AHI ≥ 30. Blood pressure (BP) values were measured at four time points (daytime, evening, nighttime, and morning). The prevalence of hypertension and BP values in the different groups were compared at four time points. Finally, the nighttime-to-daytime mean BP (MBP; RN/D) and morning-to-evening MBP (RM/E) ratios were calculated.	The prevalence of hypertension in the control group, mild group, moderate group, and severe group were 22.32%, 34.65%, 39.04%, and 55.37%, respectively. AHI positively correlated with the prevalence of hypertension (r = .191, p < .001). The daytime, nighttime, evening, and morning MBP rose as AHI increased. The ratios of nighttime-to-daytime MBP (RN/D) and morning-to-evening MBP (RM/E) increase with the severity of the illness (F = 9.821 and 18.957; p < .001). The daytime BP correlates significantly with AHI and lowest oxygen saturation (LSaO2; systolic BP, r = .195 and -.206; diastolic BP, rs = .248 and -.251, p < .01). Daytime MBP increases gradually in small fluctuations concurrent with increases in AHI until 61-65.	OSAHS is an independent risk factor for hypertension. Patients with OSAHS have a significant increase in nighttime and morning BP, which means they lose normal BP diurnal rhythm. Therefore, nurses should take necessary measures based on the clinical features of hypertension in patients with OSAHS to minimize the risk of cardiocerebral vascular incidents.	
26859701	The hypothalamic-pituitary-adrenal (HPA) axis is a critical component of the body's stress-response neurobiological system, and its development and functioning are shaped by the social environment. Much of our understanding of the effects of the caregiving environment on the HPA axis is based on (a) parenting in young children and (b) individual maternal stressors, such as depression. Yet, less is known about how parenting behaviors and maternal stressors interact to influence child cortisol regulation, particularly in older children. With an ethnically diverse sample of 199 mothers and their early adolescent children (M=11.00years; 54% female), a profile analytic approach was used to investigate how multiple phenotypes of maternal stress co-occur and moderate the relation between parenting behaviors and youths' diurnal cortisol rhythms. Latent profile analysis yielded 4 profiles: current parenting stress, concurrent parenting and childhood stress, childhood stress, and low stress. For mothers with the concurrent parenting and childhood stress profile, inconsistent discipline, poor parental supervision, and harsh caregiving behaviors each were related to flattened diurnal cortisol rhythms in their adolescents. For mothers with the current parenting stress and childhood stress profiles, their use of inconsistent discipline was associated with flattened diurnal cortisol rhythms in their adolescents. For mothers with the low stress profile, none of the parenting behaviors was related to their adolescents' cortisol regulation. Findings suggest that based on mothers' stress profile, parenting behaviors are differentially related to youths' diurnal cortisol rhythms. Implications for parenting interventions are discussed. 
26858968	In terms of reproductive and social functions, vasoactive intestinal polypeptide (VIP) is best known as a major regulator of prolactin secretion in vertebrates and hence, as an essential contributor to parental care. However, VIP and its cognate VPAC receptors are distributed throughout the social behavior network in the brain, suggesting that VIP circuits may play important roles in a variety of behaviors. With the exception of VIP neuronal populations in the suprachiasmatic nucleus and tuberal hypothalamus (which regulate circadian rhythms and prolactin secretion, respectively), we have known very little about the functional properties of VIP circuits until recently. The present review highlights new roles for VIP signaling in avian social behaviors such as affiliation, gregariousness, pair bonding and aggression, and discusses recent advances in VIP's role as a regulator of biological rhythms, including the potential timing of ovulation, photoperiodic response and seasonal migration.
26858795	The influences of obstructive sleep apnea hypopnea syndrome (OSAHS) on blood pressure and C-reactive protein (CRP) were observed, and the underlying mechanism was investigated.Respiratory sleep monitoring was performed on 188 male patients who were newly diagnosed with hypertension. Based on the apnea hypopnea index (AHI) results, patients were divided into a normal control group (AHI ≤ 5, n = 35), a mild OSAHS group (5 < AHI ≤ 15, n = 28), a moderate OSAHS group (15 < AHI ≤ 30, n = 57), and a severe OSAHS group (AHI > 30, n = 68). Ambulatory blood pressure monitoring was conducted on patients in each group, and blood samples were collected to detect indicators, including fasting blood glucose (FBG), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and high-sensitivity CRP (hs-CRP).	TG and hs-CRP in patients in the moderate and severe OSAHS groups were higher than those in the normal control group (P < 0.01, P < 0.05). Additionally, their mean nocturnal systolic blood pressure (nSBP) and nocturnal diastolic blood pressure (nDBP) were higher than those in the normal control group (P < 0.01, P < 0.05). However, the percentage of blood pressure reduction at night was significantly lower than that in the normal control group (P < 0.01). AHI and hs-CRP positively correlated with nSBP (adjusted R(2) = 0.46) and nDBP (adjusted R(2) = 0.38) and negatively correlated with the nocturnal blood pressure reduction percentage (adjusted R(2) = 0.48).	Moderate and severe OSAHS induced increases in nocturnal blood pressure and CRP content in the body, resulting in further damage to the circadian rhythms of blood pressure.	
26858652	Circadian rhythms in organisms are involved in many aspects of metabolism, physiology, and behavior. In many animals, these rhythms are produced by the circadian system consisting of a central clock located in the brain and peripheral clocks in various peripheral tissues. The oscillatory machinery and entrainment mechanism of peripheral clocks vary between different tissues and organs. The relationship between the central and peripheral clocks is also tissue-dependent. Here we review the heterogeneous nature of peripheral circadian clocks in the fruit fly Drosophila melanogaster and their dependence on the central clock, and discuss their significance in the temporal organization of physiology in peripheral tissues/organs. 
26858531	Previous studies have reported an association between circadian disturbances and age-related cognitive impairment. The aim was to study the 24-hour profiles of melatonin and cortisol in relation to cognitive function in middle-aged male subjects. Fifty healthy middle-aged males born in 1953 were recruited from a population-based cohort based on previous cognitive assessments in young adulthood and late midlife. The sample included 24 cognitively high-functioning and 26 cognitively impaired participants. Saliva samples were collected every 4 hours over a 24-hour period and analyzed for cortisol and melatonin levels by immunoassay. All participants exhibited clear circadian rhythms of salivary melatonin and cortisol. Salivary melatonin concentrations had a nocturnal peak at approximately 4 am. The median nocturnal melatonin response at 4 am was significantly lower in the cognitively impaired group than in the high-functioning group (-4.6 pg/mL, 95% CI: -7.84, -1.36, P=0.006). The 24-hour mean melatonin concentration (high-functioning group: 4.80±0.70 pg/mL, vs cognitively impaired group: 4.81±0.76 pg/mL; P>0.05) (or the area under the curve, AUC) was not significantly different between the two groups. Cortisol levels were low during the night, and peaked at approximately 8 am. Median cortisol concentrations were similar at all times, as were the 24-hour mean cortisol concentrations and AUC. To the best of our knowledge, ours is the first study to assess circadian measures (ie, melatonin and cortisol) in healthy middle-aged men with different cognitive trajectories in midlife. We found evidence of altered circadian rhythms with a reduced nocturnal melatonin response at 4 am in men with cognitive impairment. The 24-hour concentration and AUC of melatonin and cortisol were similar in the cognitively high-functioning group and in the cognitively impaired. 
26858432	Daily variations in the environment have shaped life on Earth, with circadian cycles identified in most living organisms. Likewise, seasons correspond to annual environmental fluctuations to which organisms have adapted. However, little is known about seasonal variations in human brain physiology. We investigated annual rhythms of brain activity in a cross-sectional study of healthy young participants. They were maintained in an environment free of seasonal cues for 4.5 d, after which brain responses were assessed using functional magnetic resonance imaging (fMRI) while they performed two different cognitive tasks. Brain responses to both tasks varied significantly across seasons, but the phase of these annual rhythms was strikingly different, speaking for a complex impact of season on human brain function. For the sustained attention task, the maximum and minimum responses were located around summer and winter solstices, respectively, whereas for the working memory task, maximum and minimum responses were observed around autumn and spring equinoxes. These findings reveal previously unappreciated process-specific seasonality in human cognitive brain function that could contribute to intraindividual cognitive changes at specific times of year and changes in affective control in vulnerable populations. 
26858430	Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk. 
26857333	We investigated how the diagnosis of postural orthostatic tachycardia syndrome (POTS) would be changed due to diurnal variability in orthostatic tachycardia. The orthostatic vital sign test was administered to each patient twice, in the afternoon of the day of admission and the next morning (n = 113). Forty-six patients were diagnosed with POTS, and the remaining 67 patients were assigned to non-POTS group. Heart rate increments after standing were larger in the morning than in the afternoon in every group (all P < .001). Among the POTS patients, 82.6% fulfilled the diagnostic criteria for POTS in the morning and 52.2% in the afternoon. Most POTS group (65.2%) displayed normal result on single orthostatic vital sign test. Orthostatic intolerance symptoms were provoked in only 45.7% of the POTS patients, more frequently in the morning. In conclusion, diurnal variability in hemodynamic parameters and provoked symptoms significantly challenged the diagnosis of POTS.
26856993	Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance. 
26856902	We aimed to analyze nocturnal sleep characteristics of patients with narcolepsy type 1 (narcolepsy with cataplexy) measured by actigraphy in respect to cerebrospinal fluid hypocretin-1 levels of the same patients.Actigraphy recording of 1-2 w and hypocretin-1 concentration analysis were done to thirty-six unmedicated patients, aged 7 to 63 y, 50% female. Twenty-six of them had hypocretin-1 levels under 30 pg/mL and the rest had levels of 31-79 pg/mL.	According to actigraphy, patients with very low hypocretin levels had statistically significantly longer sleep latency (P = 0.033) and more fragmented sleep, indicated by both the number of immobile phases of 1 min (P = 0.020) and movement + fragmentation index (P = 0.049). There were no statistically significant differences in the actual sleep time or circadian rhythm parameters measured by actigraphy.	Actigraphy gives additional information about the stabilization of sleep in patients with narcolepsy type 1. Very low hypocretin levels associate with more wake intruding into sleep.	
26856096	Twenty-four hour blood pressure monitoring in groups of patients of elderly age with bronchial asthma and hypertension was conducted. The study showed an increased variability of blood pressure and insufficient reduction in night time that leads to development of cardiovascular complications.
26856086	The present review summarizes the current knowledge of gradual deterioration of temporal order in aging humans and other mammals. An obvious consequence of age-dependent circadian disruption in complex mechanisms is extra-circadian dissemination (ECD) that can be observed in overt rhythmic functions. ECD is a variance transposition from circadian to ultradian and infradian frequencies accompanied by a loss of interdaily phase stability. Moreover, heterochronic changes in central and peripheral tissue-specific cellular mechanisms are involved in circadian desychronization. A multitude of internal factors accounts for cumulative clockwork misalignment. Age-related circadian disruption is a consequence of weaker rhythm generation and the loss of proper orchestration on molecular, tissue and systemic levels, disabling their circadian synchrony and resonance.
26855609	Narcolepsy with cataplexy (NC) is a neurological sleep disorder characterized by very low or undetectable concentration of hypocretin-1 in the cerebrospinal fluid. It has been recently found that patients with NC have disturbed circadian pattern of blood pressure, with more frequent non-dipping, compared to healthy controls. It has been hypothesized that lack of hypocretin may lead to increase in nocturnal blood pressure. This increase may result also from disturbed sleep architecture regardless of the deficiency of hypocretin. The aim of this study was to compare changes in values of daytime and nighttime blood pressure in NC patients and in patients with disturbed nocturnal sleep due to other sleep disorders. We have retrospectively compared polysomnographic and clinical data of 8 NC patients and 7 age- and sex controls suffering from insomnia. We have compared sleep architecture, mean blood pressure values and dipping pattern in both groups. The groups did not differ in terms of disturbances of sleep architecture. We have not found any statistical differences in values of daytime and nocturnal blood pressure. Non-dipping was equally frequent in both groups (87.5 and 85.7 %). Our results suggest that observed abnormalities in circadian changes of blood pressure values result from disturbed sleep architecture than from deficiency of hypocretin. Patients with sleep disorders should be carefully observed for the presence of increased blood pressure and other vascular risk factors.
26855448	Cartilage tissues possess intrinsic circadian oscillators, which influence chondrocyte function and chondrocyte specific gene expression. However, it is not fully understood how chondrogenesis influences the circadian clock, and vice versa. Thus, we established ATDC5 cells which were stably transfected with the Bmal1:luc reporter and revealed robust circadian rhythms in ATDC5 cells during differentiation. Moreover, the circadian clock in ATDC5 cells was strongly reset by PTH in a circadian time-dependent manner. This assay system is expected to be useful for investigating the role of the circadian clock in chondrogenic differentiation and the precise molecular mechanisms underlying PTH action on the chondrocyte circadian clock. 
26855193	In order to decipher the disease etiology, progression and treatment of multifactorial human brain diseases we utilize a host of different experimental models. Recently, patient-derived human dermal fibroblast (HDF) cultures have re-emerged as promising in vitro functional system for examining various cellular, molecular, metabolic and (patho)physiological states and traits of psychiatric disorders. HDF studies serve as a powerful complement to postmortem and animal studies, and often appear to be informative about the altered homeostasis in neural tissue. Studies of HDFs from patients with schizophrenia (SZ), depression, bipolar disorder (BD), autism, attention deficit and hyperactivity disorder and other psychiatric disorders have significantly advanced our understanding of these devastating diseases. These reports unequivocally prove that signal transduction, redox homeostasis, circadian rhythms and gene*environment (G*E) interactions are all amenable for assessment by the HDF model. Furthermore, the reported findings suggest that this underutilized patient biomaterial, combined with modern molecular biology techniques, may have both diagnostic and prognostic value, including prediction of response to therapeutic agents. 
26854928	Beyond image formation, the light that is detected by retinal photoreceptors influences subcortical functions, including circadian timing, sleep, and arousal. The physiology of nonimage-forming (NIF) photoresponses in humans is not well understood; therefore, the development of therapeutic interventions based on this physiology, such as bright light therapy to treat chronobiological disorders, remains challenging.Thirty-nine participants were exposed to 60 minutes of either continuous light (n = 8) or sequences of 2-millisecond light flashes (n = 31) with different interstimulus intervals (ISIs; ranging from 2.5 to 240 seconds). Melatonin phase shift and suppression, along with changes in alertness and sleepiness, were assessed.	We determined that the human circadian system integrates flash sequences in a nonlinear fashion with a linear rise to a peak response (ISI = 7.6 ± 0.53 seconds) and a power function decrease following the peak of responsivity. At peak ISI, flashes were at least 2-fold more effective in phase delaying the circadian system as compared with exposure to equiluminous continuous light 3,800 times the duration. Flashes did not change melatonin concentrations or alertness in an ISI-dependent manner.	We have demonstrated that intermittent light is more effective than continuous light at eliciting circadian changes. These findings cast light on the phenomenology of photic integration and suggest a dichotomous retinohypothalamic network leading to circadian phase shifting and other NIF photoresponses. Further clinical trials are required to judge the practicality of light flash protocols.	National Heart, Lung, and Blood Institute (1R01HL108441-01A1) and Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center.	
26854556	A radon-based nocturnal stability classification scheme is developed for a flat inland site near Bucharest, Romania, characterised by significant local surface roughness heterogeneity, and compared with traditional meteorologically-based techniques. Eight months of hourly meteorological and atmospheric radon observations from a 60 m tower at the IFIN-HH nuclear research facility are analysed. Heterogeneous surface roughness conditions in the 1 km radius exclusion zone around the site hinder accurate characterisation of nocturnal atmospheric mixing conditions using conventional meteorological techniques, so a radon-based scheme is trialled. When the nocturnal boundary layer is very stable, the Pasquill-Gifford "radiation" scheme overestimates the atmosphere's capacity to dilute pollutants with near-surface sources (such as tritiated water vapour) by 20% compared to the radon-based scheme. Under these conditions, near-surface wind speeds drop well below 1 m s(-1) and nocturnal mixing depths vary from ∼ 25 m to less than 10 m above ground level (a.g.l.). Combining nocturnal radon with daytime ceilometer data, we were able to reconstruct the full diurnal cycle of mixing depths. Average daytime mixing depths at this flat inland site range from 1200 to 1800 m a.g.l. in summer, and 500-900 m a.g.l. in winter. Using tower observations to constrain the nocturnal radon-derived effective mixing depth, we were able to estimate the seasonal range in the Bucharest regional radon flux as: 12 mBq m(-2) s(-1) in winter to 14 mBq m(-2) s(-1) in summer.
26854277	Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K(+) , after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound. The amounts of endogenous K(+) are kept constant by balancing intake and loss of exogenous K(+) . Food and ingestion of KCl-containing medicines are sources for exogenous K(+) . In the pharmacokinetic context exogenous K(+) from KCl-containing medicines, K(+) exo,dose , is of primary interest. The distinction between the different K(+) entities is critical for obtaining unbiased estimates of the kinetic parameters for K(+) exo,dose . A literature search using prespecified acceptance criteria was performed. Publications were selected that reported plasma and urine data of K(+) exo,dose directly or provided information allowing their determination. Additional criteria applied included that the studies used a randomized design and controlled for the important covariates. Most of the selected publications reported urinary excretion data. Only 2 publications also reported plasma concentrations. The excursions of the plasma concentrations of K(+) exo,dose were considered too small to be of use by most investigators. The aggregate results indicate that urinary recovery data have the potential for providing reliable estimates for bioavailability and bioequivalence of K(+) exo,dose with KCl-containing formulations. Absorption efficiency, peak rates, and corresponding times of K(+) exo,dose with liquid formulations are fairly consistent among studies. The mean absorption efficiency of K(+) exo,dose with solid and liquid formulations of KCl ranges between 70% and 90%. The absorption rate of liquid formulations is rapid, whereas the solid formulations show extended release characteristics. The time-averaged renal clearance of K(+) exo,dose is about 200 mL/min during daytime and significantly smaller around midnight. Circadian rhythm and delayed homeostatic control of potassium make the pharmacokinetics of K(+) exo,dose time dependent. The impact of these endogenous controls makes the pharmacokinetics of K(+) exo,dose unusual. 
26854132	Although the literature has documented associations between sleep problems and internet addiction, the temporal direction of these relationships has not been established. The purpose of this study is to evaluate the bidirectional relationships between sleep problems and internet addiction among children and adolescents longitudinally. A four-wave longitudinal study was conducted with 1253 children and adolescents in grades 3, 5 and 8 from March 2013 to January 2014. The sleep problems of the student participants were measured by parental reports on the Sleep Habit Questionnaire, which catalogues early insomnia, middle insomnia, disturbed circadian rhythm, periodic leg movements, sleep terrors, sleepwalking, sleep talking, nightmares, bruxism, snoring and sleep apnoea. The severity of internet addiction was measured by students' self-reports on the Chen Internet Addiction Scale. Based on the results of time-lag models, dyssomnias (odds ratio = 1.31), especially early and middle insomnias (odds ratio = 1.74 and 2.24), sequentially predicted internet addiction, and internet addiction sequentially predicted disturbed circadian rhythm (odds ratio = 2.40), regardless of adjustment for gender and age. This is the first study to demonstrate the temporal relationship of early and middle insomnia predicting internet addiction, which subsequently predicts disturbed circadian rhythm. These findings imply that treatment strategies for sleep problems and internet addiction should vary according to the order of their occurrence. 
26854032	To test the hypothesis that a 24-hour recording of intraocular pressure (IOP)-related measurements derived from a contact lens sensor (CLS) correlates to the rate of visual field progression in treated glaucomatous eyes.Prospective, cross-sectional study.	Forty treated glaucomatous patients with 8 or more 24-2 visual field tests.	Twenty-four-hour recording with a CLS that provides IOP-related measurements.	Rates of visual field mean deviation (MD) change before and at the time of CLS recording and CLS parameters, namely number of large peaks, mean peak ratio, wake-to-sleep slope, amplitude and area under the cosine curve, and variability from the mean.	When comparing the rate of MD change before and at the time of CLS recording of all patients, the average slope was -0.05 dB/year faster in the beginning compared with the end (P = 0.087), suggesting a deceleration of progression by the time of CLS recording. The number of long peaks and the mean peak ratio when patients were awake were the best predictors of faster progression. The combination of CLS parameters provided better measures of goodness of fit than Goldmann IOP parameters (mean, peak, and fluctuation) in the same period.	Intraocular pressure-related parameters obtained with 24-hour recording with a CLS were associated with the rate of visual field progression in treated glaucomatous eyes. This technology may be useful in detecting eyes at higher risk of glaucoma progression while receiving treatment.	
26853999	Disruptions to sleep and circadian rhythms have now been recognized as common comorbidities in patients with medical illnesses. We aimed to determine if the diurnal rhythms for rest and activity were disrupted in parallel with the development of diabetic complications. Ninety outpatients in our diabetes clinic who had a body mass index <25 kg m(2) wore an actigraph for 7 consecutive days (42 men; mean age 68.7 ± 8.2 years). Patients with neuropsychiatric diseases, liver cirrhosis, renal failure, chronic obstructive pulmonary disease or blindness, or those who performed shiftwork were excluded. We grouped the actigraph recordings into 1-h periods and counted the number of minutes that showed activity. Stepwise regression analysis showed an association between a diabetic clinical background and measurements of circadian rhythms such as daytime activity, night-time activity, phase, interdaily stability, intradaily variability and relative amplitude. Higher age, body mass index, total cholesterol levels and insulin usage were associated with lower daytime activity and higher intradaily variability, whereas higher haemoglobin A1c levels and the presence of neuropathy were associated with greater daytime activity. The presence of proliferative retinopathy and increased levels of microalbuminuria were associated with higher intradaily variability and lower interdaily stability and amplitude. The presence of cardiovascular disease was associated with advanced phase, whereas painful neuropathy was associated with delayed phase. Our study demonstrated that different diabetic complications were associated independently with a variety of alterations in the circadian rest and activity rhythms. Our findings have provided novel insights that may be helpful in developing interventions for sleep-wake disorders associated with diabetes. 
26853813	In preeclampsia and gestational diabetes, the sympathetic nerves are activated, leading to disrupted sleep. Melatonin, which transmits information to regulate the sleep-wake rhythm and other such biorhythms, has been implicated in insulin resistance, antioxidant behaviors, and metabolic syndrome. In addition, its reduced secretion increases the risk of hypertension and diabetes. The aim of this study was to elucidate the features of melatonin secretion, sleep quality, and sleep-wake rhythms in pregnant women with complications. Fifty-eight pregnant women with pregnancy complications (hypertensive or glucose metabolic disorders) and 40 healthy pregnant women completed questionnaires, including sleep logs and the Pittsburgh Sleep Quality Index (PSQI), during the second to third trimesters. Their salivary melatonin levels were also measured. Pregnant women with complications had significantly lower morning (p < 0.001), daytime (p < 0.01), evening (p < 0.001), night (p < 0.01), daily mean (p < 0.001), peak (p < 0.001), and bottom (p < 0.01) melatonin values than healthy pregnant women. Pregnant women with complications also had significantly smaller melatonin amplitudes than healthy pregnant women (p < 0.001). Among pregnant women with complications, the duration (p < 0.05) and frequency (p < 0.01) of wake after sleep-onset were significantly greater in the poor sleep group than in the favorable sleep group which was divided by PSQI cutoff value. Pregnant women with hypertensive or glucose metabolic disorder complications had smaller circadian variation in salivary melatonin secretion, and their values were lower throughout the day than healthy pregnant women. 
26853614	To examine the associations of the frequency and type of everyday discrimination with diurnal cortisol and whether those associations depend upon adolescents' ethnicity and gender.Adolescents (N=292, Mage=16. 39years, SD=0.74; 58% female) reported the frequency of perceived everyday discrimination and whether they attributed that discrimination to race, gender, age, or height and weight. Five saliva samples were collected per day across 3days and assayed for cortisol.	Higher frequency of everyday discrimination was associated with greater total daily cortisol output (area under the curve; AUC), lower wake and bedtime levels of cortisol, and less of a decline in cortisol across the day. These associations generally did not depend upon ethnicity or gender and attributions for the discrimination were not as consequential as the actual frequency of any type of unfair treatment.	Everyday discrimination, regardless of its type, may contribute to heightened HPA activity among adolescents of different ethnic backgrounds and genders.	
26852790	Therapy with oral anticoagulants (OACs) is a risk factor for cerebral hemorrhage (CH). Although different studies have been undertaken to investigate the timing of the onset of major cardiovascular events, no data exist on temporal patterns of the onset of CH in subjects treated with OACs. The aim of this study is to evaluate the timing of CH in patients treated with OACs. All patients who developed CH under OACs therapy and admitted to 28 Italian Emergency Departments (EDs) between September 2011 and July 2013 were enrolled. Age, sex, time and location of the hemorrhagic lesion, type of the bleeding events (idiopathic or post-traumatic), anticoagulant therapy (warfarin or new oral anticoagulants - NOAs) and time of ED admission (i.e., hour, day, month and season) were recorded. Five hundred and seventeen patients (63.2% male aged 80 ± 7.9 yrs) with CH were involved. Warfarin was taken by 494 patients (95.6%), and NOAs by 23 (4.4%). In-hospital mortality (IHM) was recorded in 208 cases (40.2%). Cosinor analysis showed a peak of CH arrival between 12:00 and 14:00 h both in the whole population (PR 73.9%, p = 0.002) and the male subgroup (PR 65.2%, p = 0.009), whereas females showed an anticipated morning peak between 08:00 and 10:00 h (PR 65.7%, p = 0.008). A further analysis between idiopathic and post-traumatic CH confirmed the presence of a 24 h pattern with a peak between 12:00 and 14:00 h (PR 58.5%, p = 0.019) and between 08:00 and 10:00 h (PR80.1%, p < 0.001) for idiopathic events and post-traumatic hemorrhages, respectively. Moreover, a seasonal winter peak was identified for idiopathic forms (PR 74%, p = 0.035), and a summer peak for post-traumatic forms (PR 77%, p = 0.025). The present study suggests the presence of a temporal pattern of ED arrivals in CH patients treated with OACs. 
26852745	The objective of this study was to investigate whether the pharmacokinetics of orally administered levofloxacin show 24 h variation. Levofloxacin was used as a model compound for solubility and permeability independent absorption and passive renal elimination.In this single centre, crossover, open label study, 12 healthy subjects received an oral dose of 1000 mg levofloxacin at six different time points equally divided over the 24 h period. Population pharmacokinetic modelling was used to identify potential 24 h variation in the pharmacokinetic parameters of this drug.	The pharmacokinetics of levofloxacin could be described by a one compartment model with first order clearance and a transit compartment to describe drug absorption. The fit of the model was significantly improved when the absorption rate constant was described as a cosine function with a fixed period of 24 h, a relative amplitude of 47% and a peak around 08.00 h in the morning. Despite this variation in absorption rate constant, simulations of a once daily dosing regimen showed that tmax , Cmax and the area under the curve at steady-state were not affected by the time of drug administration.	The finding that the absorption rate constant showed considerable 24 h variation may be relevant for drugs with similar physicochemical properties as levofloxacin that have a narrower therapeutic index. Levofloxacin, however, can be dosed without taking into account the time of day, at least in terms of its pharmacokinetics.	
26852551	The eyes are exposed to multiple environmental factors, which affect visual development, comfort, and visual health. While overexposure to sunlight can cause ocular surface and retinal pathologies, insufficient exposure to daylight could significantly contribute to myopia progression. New artificial lights, namely LED, have a higher risk of retinal phototoxicity, and could alter ocular circadian rhythm. The significant increase of prevalence of ocular allergies could be caused by the proliferation of environmental polluting substances, like tobacco smoke, fuel combustion by-products, or phtalates, which are found in many types of plastics. Finally, some dietary supplements could play a protective role in certain types of ocular pathologies, namely retinal pathologies.
26852486	The dynamics of circadian activity in adult frit flies of the Holarctic species Meromyza saltatrix (L) from Mongolian, Moscow, and Polish populations was studied. Synchronous peaks of activity were revealed with the periodicity multiple of three-four hours, which may depend on the level of light. The direct effect of temperature and humidity on the activity of flies outside the optimal values of these factors was found. It was detected that the peak of adult emergence falls on the beginning of a general increase in the abundance of flies, which indicates constant rejuvenation of the population. The sex ratio is close to 1, but the emergence of males and females is in antiphase. The synchronization of peaks of circadian activity in the populations from different regions confirms the presence of a circadian rhythm of activity. The rhythm synchronizing the reproductive activity of adults was found to be modified by the photoperiod under the optimum conditions of temperature and humidity.
26851993	Melatonin modulates central nervous system neuronal activity. We compared the melatonin levels of patients with febrile and afebrile seizures during and after seizure with those of healthy controls.We enrolled 59 individuals with afebrile and febrile seizures (mean age, 6.09 ± 4.46 years) and 28 age-, sex-, and weight-matched healthy children. Melatonin levels were measured near the time of a seizure (0 to 1 hour) and at 12 and 24 hours post-seizure, and control melatonin levels were measured from a single venous blood sample.	Plasma melatonin levels increased during seizures in the study group (P < 0.001). Post-seizure plasma melatonin levels were significantly lower in the study group than in the control group (P < 0.05). Plasma melatonin levels did not differ between patients with afebrile seizures who had and had not used antiepileptic drugs. Daytime (8 AM to 8 PM) and nighttime (8 PM to 8 AM) post-seizure melatonin levels were not significantly different.	Melatonin levels were lower in pediatric patients prone to seizures than in healthy children and increased during seizures. Further research is needed to test the role of melatonin in the pathophysiology and treatment of epilepsy.	
26851556	Chronic paradoxical sleep deprivation (CSD) can induce dramatic physiological and neurofunctional changes in rats, including decreased body weight, reduced learning and memory, and declined locomotor function. SKF38393, a dopamine D1 receptor agonist, can reverse the above damages. However, the mechanism of CSD syndrome and reversal role of SKF38393 remains largely unexplained. To preliminarily elucidate the mechanism of the neural dysfunction caused by CSD, in the present study we use gene chips to examine the expression profile of more than 28,000 transcripts in the prefrontal cortex (PFC). Rats were sleep deprived by modified multi-platform method for 3 weeks. Totally 59 transcripts showed differential expressions in CSD group in contrast to controls; they included transcripts coding for caffeine metabolism, circadian rhythm, drug metabolism and some amino acid metabolism pathway. Among the 59 transcripts, 39 increased their expression and 20 decreased. Two transcripts can be specifically reversed with SKF38393, one of them is Homer1, which is related to 20 functional classifications and coding for Glutamatergic synapse pathway. Our findings in the present study indicate that long-term sleep deprivation may trigger the changes of some certain functions and pathways in the PFC, and lead to the dysfunction of this advanced neuron, and the activation of D1 receptor by SKF38393 might ameliorate these changes via modulation of some transcripts such as Homer1, which is involved in the Ca(2+) pathway and MAPK pathway related to Glutamatergic synapse pathway. 
26851466	Shorter, more frequent rosters, such as 6h-on/6h-off split shifts, may offer promise to sleep, subjective sleepiness and performance by limiting shift length and by offering opportunities for all workers to obtain some sleep across the biological night. However, there exists a paucity of studies that have examined these shifts using objective measures of sleep and performance. The present study examined neurobehavioural performance, sleepiness and sleep during 6h-on/6h-off split sleep schedules. Sixteen healthy adults (6 males, 26.13 y ± 4.46) participated in a 9-day laboratory study that included two baseline nights (BL, 10h time in bed (TIB), 2200 h-0800 h), 4 days on one of two types of 6h-on/6h-off split sleep schedules with 5h TIB during each 'off' period (6h early: TIB 0300 h-0800 h and 1500 h-20000 h, or 6-h late: TIB 0900 h-1400 h and 2100 h-0200 h), and two recovery nights (10h TIB per night, 2200 h-0800 h). Participants received 10h TIB per 24h in total across both shift schedules. A neurobehavioural test bout was completed every 2 h during wake, which included the Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). Linear mixed effects models were used to assess the effect of day (BL, shift days 1-4), schedule (6h early, 6h late) and trial (numbers 1-6) on PVT lapses (operationalised as the number of reaction times >500 ms), PVT total lapse time, PVT fastest 10% of reaction times and KSS. Analyses were also conducted examining the effect of day and schedule on sleep variables. Overall, PVT lapses and total lapse time did not differ significantly between baseline and shift days, however, peak response speeds were significantly slower on the first shift day when compared to baseline, but only for those in the 6h-late condition. Circadian variations were apparent in performance outcomes, with individuals in the 6h-late condition demonstrated significantly more and longer lapses and slower peak reaction times at the end of their night shift (0730 h) than at any other time during their shifts. In the 6h-early condition, only response speed significantly differed across trials, with slower response speeds occurring at trial 1 (0930 h) than in trials 3 (1330 h) or 4 (2130 h). While subjective sleepiness was higher on shift days than at baseline, sleepiness did not accumulate across days. Total sleep was reduced across split sleep schedules compared to baseline. Overall, these results show that while there was not a cumulative cost to performance across days of splitting sleep, participants obtained less sleep and reported lowered alertness on shift days. Tests near the circadian nadir showed higher sleepiness and increased performance deficits. While this schedule did not produce cumulative impairment, the performance deficits witnessed during the biological night are still of operational concern for industry and workers alike.
26850841	Cell proliferation in mammals follows a circadian rhythm while disruption of clock gene expression has been linked to tumorigenesis. Expression of the c-Myc oncogene is frequently deregulated in tumors, facilitating aberrant cell proliferation. c-MYC protein levels display circadian rhythmicity, which is compatible with an in vitro repressive role of the clock-activating complex BMAL1/CLOCK on its promoter. In this report, we provide evidence for the in vivo binding of the core circadian factor BMAL1 on the human c-Myc promoter. In addition, analysis of protein synthesis and degradation rates, as well as post-translational acetylation, demonstrate that the clock tightly controls cellular MYC levels. The oncoprotein itself is a transcription factor that by responding to mitogenic signals regulates the expression of several hundred genes. c-MYC-driven transcription is generally exerted upon dimerization with MAX and binding to E-box elements, a sequence that is also recognized by the circadian heterodimer. Our reporter assays reveal that the MYC/MAX dimer cannot affect transcription of the circadian gene Per1. However, when overexpressed, c-MYC is able to repress Per1 transactivation by BMAL1/CLOCK via targeting selective E-box sequences. Importantly, upon serum stimulation, MYC was detected in BMAL1 protein complexes. Together, these data demonstrate a novel interaction between MYC and circadian transactivators resulting in reduced clock-driven transcription. Perturbation of Per1 expression by MYC constitutes a plausible alternative explanation for the deregulated expression of clock genes observed in many types of cancer. 
26850837	Previous studies on the relation between testosterone (T) levels and parenting have found ample evidence for the challenge hypothesis, demonstrating that high T levels inhibit parental involvement and that becoming a parent is related to a decrease in T levels in both mothers and fathers. However, less is known about the relation between T levels and more qualitative aspects of parenting. In the current study we examined basal T levels and diurnal variability in T levels in relation to mothers' and fathers' parenting quality. Participants included 217 fathers and 124 mothers with two children (3 and 5years of age). Evening and morning salivary T samples were analyzed with radio-immunoassays to determine circulating T levels. Parental sensitivity (i.e., child-centered responsiveness) and respect for children's autonomy were observed during free play in the family home. The results showed that higher evening T levels in mothers were associated with more sensitivity to the oldest and youngest child. Diurnal T variability was more consistently associated with parenting behavior towards their children than basal T levels. For fathers, more diurnal variability in T was associated with more sensitivity and more respect for autonomy with their youngest children. For mothers, more diurnal variability in T was associated with less sensitivity to both children and less respect for the youngest child's autonomy. These findings suggest that the T system might act differently in relation to parenting behavior in males and females. 
26848586	Plants have evolved a considerable number of intrinsic tolerance strategies to acclimate to ambient temperature increase. However, their molecular mechanisms remain largely obscure. Here we report a DEAD-box RNA helicase, TOGR1 (Thermotolerant Growth Required1), prerequisite for rice growth themotolerance. Regulated by both temperature and the circadian clock, its expression is tightly coupled to daily temperature fluctuations and its helicase activities directly promoted by temperature increase. Located in the nucleolus and associated with the small subunit (SSU) pre-rRNA processome, TOGR1 maintains a normal rRNA homeostasis at high temperature. Natural variation in its transcript level is positively correlated with plant height and its overexpression significantly improves rice growth under hot conditions. Our findings reveal a novel molecular mechanism of RNA helicase as a key chaperone for rRNA homeostasis required for rice thermotolerant growth and provide a potential strategy to breed heat-tolerant crops by modulating the expression of TOGR1 and its orthologs. 
26848280	To investigate the relationship between eating disorders, body mass index (BMI), sleep disorders, and daytime functioning.Survey.	The Netherlands.	N=574 Dutch young adults (18-35 years old).	Participants completed a survey on eating and sleep habits including the Eating Disorder Screen for Primary care (ESP) and SLEEP-50 questionnaire subscales for sleep apnea, insomnia, circadian rhythm disorder (CRD), and daytime functioning. SLEEP-50 outcomes of participants who screened negative (≤2) and positive (>2) on the ESP were compared. In addition, SLEEP-50 scores of groups of participants with different ESP scores (0-4) and different BMI groups (ie, underweight, healthy weight, overweight, and obese) were compared using nonparametric statistics.	Almost 12% (n=67) of participants screened positive for having an eating disorder. Relative to participants without eating disorders, participants who screened positive for eating disorders reported significantly higher scores on sleep apnea (3.7 versus 2.9, P=0.012), insomnia (7.7 versus 5.5, P<0.0001), CRD (2.9 versus 2.3, P=0.011), and impairment of daytime functioning (8.8 versus 5.8, P=0.0001). ESP scores were associated with insomnia (r=0.117, P=0.005), sleep apnea (r=0.118, P=0.004), sleep quality (r=-0.104, P=0.012), and daytime functioning (r=0.225, P<0.0001), but not with CRD (r=0.066, P=0.112). BMI correlated significantly with ESP scores (r=0.172, P<0.0001) and scores on sleep apnea (r=0.171, P<0.0001). When controlling for BMI, the partial correlation between ESP and sleep apnea remained significant (r=0.10, P=0.015).	Participants who score positive for eating disorders scored significantly higher on sleep disorder scales, and reported significantly more impairment of daytime functioning.	
26847974	Research indicates that physicians may frequently use pharmacotherapy to treat pediatric insomnia despite minimal safety data and very limited indications. Canadian data on the subject are lacking. This study aimed to determine physicians' views on and prescribing habits for sleep-promoting over-the-counter medication (OTCM) and prescription (RXM) medications for children.A modified 26-item version of the 'Pediatric Sleep Medication Survey', originally developed by Judith Owens and colleagues, was sent to 100 pediatricians and a random sample of 421 family physicians in Southwestern Ontario, Canada.	A total of 67 returned surveys were sufficiently complete for analysis. Sixty-one respondents indicated their specialty (28 pediatricians, 33 family physicians). In a typical 6-month period, 89% and 66% of respondents have recommended OTCM and RXM, respectively, for children with sleep problems. Only 20% have received any formal training on pediatric sleep disorders. The most common circumstances and sleep problems for which OTCM or RXM were recommended were mood disorders, developmental delay and attention deficit hyperactivity disorder (ADHD) (56, 40, and 39%, respectively), and insomnia, bedtime struggles/delayed sleep onset and circadian rhythm disorders (52, 48, and 28%, respectively). A total of 30% recommended OTCM or RXM to otherwise healthy children with sleep problems. Melatonin (73%), OTC antihistamines (41%), antidepressants (37%), and benzodiazepines (29%) were the most commonly recommended OTCM and RXM, respectively.	Respondents in our sample frequently use pharmacotherapy to treat pediatric sleep problems; few have received any training in this area. Our findings indicate the need for evidence-based guidelines and regular physician training in the management of pediatric sleep disorders.	
26847016	The dim light melatonin onset (DLMO) assists with the diagnosis and treatment of circadian rhythm sleep disorders. Home DLMOs are attractive for cost savings and convenience, but can be confounded by home lighting and sample timing errors. We developed a home saliva collection kit with objective measures of light exposure and sample timing. We report on our first test of the kit in a clinical population. Thirty-two participants with delayed sleep phase disorder (DSPD; 17 women, aged 18-52 years) participated in two back-to-back home and laboratory phase assessments. Most participants (66%) received at least one 30-s epoch of light >50 lux during the home phase assessments, but for only 1.5% of the time. Most participants (56%) collected every saliva sample within 5 min of the scheduled time. Eighty-three per cent of home DLMOs were not affected by light or sampling errors. The home DLMOs occurred, on average, 10.2 min before the laboratory DLMOs, and were correlated highly with the laboratory DLMOs (r = 0.93, P < 0.001). These results indicate that home saliva sampling with objective measures of light exposure and sample timing, can assist in identifying accurate home DLMOs. 
26846554	Human psychology and physiology are significantly altered by isolation and confinement. In light of planned exploration class interplanetary missions, the related adverse effects on the human body need to be explored and defined as they have a large impact on a mission's success. Terrestrial space analogs offer an excellent controlled environment to study some of these stressors during a space mission in isolation without the complex environment of the International Space Station. Participants subjected to these space analog conditions can encounter typical symptoms ranging from neurocognitive changes, fatigue, misaligned circadian rhythm, sleep disorders, altered stress hormone levels, and immune modulatory changes. This review focuses on both the psychological and the physiological responses observed in participants of long-duration spaceflight analog studies, such as Mars500 or Antarctic winter-over. They provide important insight into similarities and differences encountered in each simulated setting. The identification of adverse effects from confinement allows not only the crew to better prepare for but also to design feasible countermeasures that will help support space travelers during exploration class missions in the future. 
26843631	Signals from cones are recombined in postreceptoral channels [luminance, L + M; red-green, L - M; blue-yellow, S - (L + M)]. The melanopsin-containing retinal ganglion cells are also active at daytime light levels and recent psychophysical results suggest that melanopsin contributes to conscious vision in humans. Here, we measured BOLD fMRI responses to spectral modulations that separately targeted the postreceptoral cone channels and melanopsin. Responses to spatially uniform (27.5° field size, central 5° obscured) flicker at 0.5, 1, 2, 4, 8, 16, 32, and 64 Hz were recorded from areas V1, V2/V3, motion-sensitive area MT, and the lateral occipital complex. In V1 and V2/V3, higher temporal sensitivity was observed to L + M + S (16 Hz) compared with L - M flicker (8 Hz), consistent with psychophysical findings. Area MT was most sensitive to rapid (32 Hz) flicker of either L + M + S or L - M. We found S cone responses only in areas V1 and V2/V3 (peak frequency: 4-8 Hz). In addition, we studied an L + M modulation and found responses that were effectively identical at all temporal frequencies to those recorded for the L + M + S modulation. Finally, we measured the cortical response to melanopsin-directed flicker and compared this response with control modulations that addressed stimulus imprecision and the possibility of stimulation of cones in the shadow of retinal blood vessels (penumbral cones). For our stimulus conditions, melanopsin flicker did not elicit a cortical response exceeding that of the control modulations. We note that failure to control for penumbral cone stimulation could be mistaken for a melanopsin response.The retina contains cone photoreceptors and ganglion cells that contain the photopigment melanopsin. Cones provide brightness and color signals to visual cortex. Melanopsin influences circadian rhythm and the pupil, but its contribution to cortex and perception is less clear. We measured the response of human visual cortex with fMRI using spectral modulations tailored to stimulate the cones and melanopsin separately. We found that cortical responses to cone signals vary systematically across visual areas. Differences in temporal sensitivity for achromatic, red-green, and blue-yellow stimuli generally reflect the known perceptual properties of vision. We found that melanopsin signals do not produce a measurable response in visual cortex at temporal frequencies between 0.5 and 64 Hz at daytime light levels.	
26843619	Circadian clock in mammals is determined by a core oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronized peripheral clocks in other tissues. The coherent timing systems could sustain robust output of circadian rhythms in response to the entrainment controlled environmentally. Disparate approaches have discovered that clock genes and clock-controlled genes (CCGs) exist in nearly all mammalian cell types and are essential for establishing the mechanisms and complexity of internal time-keeping systems. Accumulating evidence demonstrates that the control of homeostasis and pathology in the liver involves intricate loops of transcriptional and post-translational regulation of clock genes expression. This review will focus on the recent advances with great importance concerning clock rhythms linking liver homeostasis and diseases. We particularly highlight what is currently known of the evolving insights into the mechanisms underlying circadian clock . Eventually , findings during recent years in the field might prompt new circadian-related chronotherapeutic strategies for the diagnosis and treatment of liver diseases by coupling these processes. 
26843191	The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock. 
26843038	To investigate and compare the 24-hr intra-ocular pressure (IOP) pattern among different severities of glaucomatous optic neuropathy (GON) together with different subtypes of primary open-angle glaucoma (POAG).The IOPs of untreated patients with POAG were measured every 2 hrs over a 24-hr period. Subjects were divided into mild, moderate and severe groups according to the glaucoma staging system 2. The two POAG subtypes, normal tension glaucoma (NTG) and hypertension glaucoma (HTG) were classified according to peak IOP values throughout the 24-hr period. The 24-hr IOP curves were obtained based on the average IOP value at each time-point. The mean, peak, trough and fluctuation of IOP together with the diurnal-to-nocturnal IOP change were calculated and compared among different groups.	A total of 160 POAG patients (84 NTG and 76 HTG) were enrolled in the study. Generally, IOP decreased in the diurnal period and increased progressively during the nocturnal period, with peak IOP occurring from 2:00 AM to 10:00 AM. The average IOP values at all time-points were significantly higher in the mild group compared to the moderate and severe groups (p < 0.05). Compared with the NTG subjects, the IOP parameters including mean, peak, trough and fluctuation were significantly higher in the HTG subjects (p < 0.001), and IOP increased more predominantly in the HTG subtype during the nocturnal period.	There was some regularity in the 24-hr IOP pattern in POAG, but different severities of GON and different subtypes might present different characteristics. Other non-IOP factors may lead to pathological IOP fluctuation and could be correlated with GON.	
26842252	Circadian rhythm disruption is a prevalent feature of modern day society that is associated with an increase in pro-inflammatory diseases, and there is a clear need for a better understanding of the mechanism(s) underlying this phenomenon. We have previously demonstrated that both environmental and genetic circadian rhythm disruption causes intestinal hyperpermeability and exacerbates alcohol-induced intestinal hyperpermeability and liver pathology. The intestinal microbiota can influence intestinal barrier integrity and impact immune system function; thus, in this study, we sought to determine whether genetic alteration of the core circadian clock gene, Clock, altered the intestinal microbiota community.Male Clock(Δ19) -mutant mice (mice homozygous for a dominant-negative-mutant allele) or littermate wild-type mice were fed 1 of 3 experimental diets: (i) a standard chow diet, (ii) an alcohol-containing diet, or (iii) an alcohol-control diet in which the alcohol calories were replaced with dextrose. Stool microbiota was assessed with 16S ribosomal RNA gene amplicon sequencing.	The fecal microbial community of Clock-mutant mice had lower taxonomic diversity, relative to wild-type mice, and the Clock(Δ19) mutation was associated with intestinal dysbiosis when mice were fed either the alcohol-containing or the control diet. We found that alcohol consumption significantly altered the intestinal microbiota in both wild-type and Clock-mutant mice.	Our data support a model by which circadian rhythm disruption by the Clock(Δ19) mutation perturbs normal intestinal microbial communities, and this trend was exacerbated in the context of a secondary dietary intestinal stressor.	
26842248	Circadian rhythms are essential for adapting to the environment. Chronic alcohol consumption often leads to sleep and circadian disruptions, which may impair the life quality of individuals with alcohol use disorders and contribute to the morbidity associated with alcoholism.We used a pair-feeding liquid diet alcohol exposure protocol (6 weeks duration) in PER1::LUC transgenic rats to examine the effects of chronic alcohol exposure on: (i) diurnal rhythms of core body temperature and locomotor activity, (ii) plasma corticosterone (CORT) concentrations, and (iii) rhythms of ex vivo Period1 (Per1) expression in the suprachiasmatic nucleus (SCN), pituitary, and adrenal glands. We followed multiple circadian outputs not only to examine individual components, but also to assess the relative phase relationships among rhythms.	We found that chronic alcohol consumption: (i) reduced 24-hour body temperature and locomotor activity counts in the dark period, (ii) advanced the acrophase of diurnal rhythms of body temperature and locomotor activity, (iii) abolished the phase difference between temperature and activity rhythms, (iv) blunted and advanced the diurnal CORT rhythm, and (v) advanced Per1 expression in the adrenal and pituitary glands but not in the SCN. We found that chronic alcohol altered the phase relationships among diurnal rhythms and between the central (SCN) and peripheral (adrenal and pituitary) molecular clocks.	Our findings suggest that desynchrony among internal rhythms is an important and overlooked aspect of alcohol-induced circadian disruptions. The misalignment of phases among rhythms may compromise normal physiological functions and put individuals with chronic alcohol use at greater risk for developing other physical and mental health issues. How this desynchrony occurs and the extent to which it participates in alcohol-related pathologies requires further investigation.	

26841283	A study was conducted to determine the circadian rhythms and trends of vitamin D metabolites including 25-hydroxyvitamin D3 , 25-hydroxyvitamin D2 , 1,25-dihydroxyvitamin D and parathyroid hormone, in addition to serum calcium, phosphorus and magnesium concentrations in horses over 48 h on the shortest and longest days of the year in 2013. Five healthy adult horses (Equus caballus) were on a constant pasture feeding regimen, and blood samples were collected from each horse every 3 h over a 48-h period, starting at 07:00 PM on day one and finishing at 07:00 PM on day three, for the measurement of calciotropic hormones and electrolytes. There was a significant difference between the serum concentration of calciotropic hormones, iCa, tCa, P and tMg between the shortest (winter) and longest (summer) days of the year in horses. Serum concentration of 25OHD3 was very low and mostly undetectable. Serum iCa, 1,25(OH)2 D and PTH concentrations clearly showed a circadian rhythm on the longest days of the year and serum tCa, P and tMg concentrations showed a diurnal pattern on the longest days (summer) of the year. None of the analytes showed any circadian rhythm on the shortest days (winter) of the year. The result of this study could have significant relevance to equine athletes travelling to international equestrian competitions and facing a huge time and seasonal differences that might affect their ability to adjust their circadian rhythms to new time zones.
26841172	The circadian clock controls many behavioral and physiological processes beyond daily rhythms. Circadian dysfunction increases the risk of cancer, obesity, and cardiovascular and metabolic diseases. Although clinical studies have shown that bone resorption is controlled by circadian rhythm, as indicated by diurnal variations in bone resorption, the molecular mechanism of circadian clock-dependent bone resorption remains unknown. To clarify the role of circadian rhythm in bone resorption, aryl hydrocarbon receptor nuclear translocator-like (Bmal1), a prototype circadian gene, was knocked out specifically in osteoclasts. Osteoclast-specific Bmal1-knockout mice showed a high bone mass phenotype due to reduced osteoclast differentiation. A cell-based assay revealed that BMAL1 upregulated nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (Nfatc1) transcription through its binding to an E-box element located on the Nfatc1 promoter in cooperation with circadian locomotor output cycles kaput (CLOCK), a heterodimer partner of BMAL1. Moreover, steroid receptor coactivator (SRC) family members were shown to interact with and upregulate BMAL1:CLOCK transcriptional activity. Collectively, these data suggest that bone resorption is controlled by osteoclastic BMAL1 through interactions with the SRC family and binding to the Nfatc1 promoter. © 2016 American Society for Bone and Mineral Research. 
26840869	Electrical status epilepticus in sleep is an age-dependent syndrome with the characteristic pattern of continuous spike and waves during non-rapid eye movement sleep. Most children can present developmental deterioration. The demonstration of the EEG pattern has to rely on all night long EEG recordings. A comprehensive neuropsychologic evaluation with periodic reassessment should be performed. For the idiopathic forms of electrical status epilepticus in sleep, clobazam could be considered as the first-line therapy; in the other cases, corticosteroids, in particular intravenous methylprednisolone pulse therapy, remain the most effective and should be considered the therapy of choice. 
26840337	There is a wealth of evidence that disrupted sleep and circadian rhythms, which are common in modern society even during the early stages of life, have unfavorable effects on brain function. Altered brain function can cause problem behaviors later in life, such as truancy from or dropping out of school, quitting employment, and committing suicide. In this review, we discuss findings from several large cohort studies together with recent results of a cohort study using the marshmallow test, which was first introduced in the 1960s. This test assessed the ability of four-year-olds to delay gratification and showed how this ability correlated with success later in life. The role of the serotonergic system in sleep and how this role changes with age are also discussed. The serotonergic system is involved in reward processing and interactions with the dorsal striatum, ventral striatum, and the prefrontal cortex are thought to comprise the neural basis for behavioral patterns that are affected by the quantity, quality, and timing of sleep early in life. 
26840324	Police officers have been reported to exhibit a high incidence of pathologies, which present prematurely in an otherwise healthy population. Shift work has also been associated with an increased risk of cardiovascular and sleep disorders, attributable to its propensity for circadian rhythm dysfunction. However, contention exists as to whether shift work has a direct effect upon blood pressure (BP) regulation.This cross-sectional study sought to determine changes in BP and associations with the overall sleep quality and fatigue in 206 general duties police officers (n = 140 males) of the New South Wales Police Force in Australia. The subjects' BP was assessed before and after their twelve hour shift, during which time they also completed the Lifestyle Appraisal Questionnaire, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale and Fatigue Severity Scale (FSS).	Poor sleep quality (PSQI) and fatigue severity (FSS) were found to predominate in the sample (69% and 51% respectively). Although there was no change in BP for male participants, female officers' systolic blood pressure (SBP) was found to increase significantly across the shift (p < 0.001), but with no change found in females' diastolic blood pressure (DBP). Finally, higher pre and post-shift SBP (r = -0.26, p = 0.001; r = -0.25, p = 0.001, respectively) and DBP (r = -0.26, p = 0.001; r = -0.26, p = 0.001, respectively) were significantly correlated with lower FSS scores after accounting for age, waist-hip ratio and lifestyle risk factors.	Based on these preliminary findings, there was a significant increase in SBP of female police officers after shift work, while BP and fatigue levels in all police officers were strongly related. Moreover, the predominating poor sleep quality and impact of fatigue in this sample remain a concern. Further research is required to ensure the physiological welfare of police officers, while strategies must be implemented to manage the detrimental effects shift work may be having upon their cardiovascular and sleep health.	
26840322	The impact of sleep restriction on the endogenous circadian rhythms of hunger and satiety were examined in 28 healthy young men. Participants were scheduled to 2 × 24-h days of baseline followed by 8 × 28-h days of forced desynchrony during which sleep was either moderately restricted (equivalent to 6 h in bed/24 h; n = 14) or severely restricted (equivalent to 4 h in bed/24 h; n = 14). Self-reported hunger and satisfaction were assessed every 2.5 h during wake periods using visual analogue scales. Participants were served standardised meals and snacks at regular intervals and were not permitted to eat ad libitum. Core body temperature was continuously recorded with rectal thermistors to determine circadian phase. Both hunger and satiety exhibited a marked endogenous circadian rhythm. Hunger was highest, and satiety was lowest, in the biological evening (i.e., ~17:00-21:00 h) whereas hunger was lowest, and satiety was highest in the biological night (i.e., 01:00-05:00 h). The results are consistent with expectations based on previous reports and may explain in some part the decrease in appetite that is commonly reported by individuals who are required to work at night. Interestingly, the endogenous rhythms of hunger and satiety do not appear to be altered by severe--as compared to moderate--sleep restriction.
26839375	Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. 
26839287	Plants react to seasonal change in day length through altering physiology and development. Factors that function to harmonize growth with photoperiod are poorly understood. Here we characterize a new protein that associates with both circadian clock and photoreceptor components, named PHOTOPERIODIC CONTROL OF HYPOCOTYL1 (PCH1). pch1 seedlings have overly elongated hypocotyls specifically under short days while constitutive expression of PCH1 shortens hypocotyls independent of day length. PCH1 peaks at dusk, binds phytochrome B (phyB) in a red light-dependent manner, and co-localizes with phyB into photobodies. PCH1 is necessary and sufficient to promote the biogenesis of large photobodies to maintain an active phyB pool after light exposure, potentiating red-light signaling and prolonging memory of prior illumination. Manipulating PCH1 alters PHYTOCHROME INTERACTING FACTOR 4 levels and regulates light-responsive gene expression. Thus, PCH1 is a new factor that regulates photoperiod-responsive growth by integrating the clock with light perception pathways through modulating daily phyB-signaling. 
26838474	The circadian system has endowed animals with the ability to anticipate recurring food availability at particular times of day. As daily food anticipation (FA) is independent of the suprachiasmatic nuclei, the central pacemaker of the circadian system, questions arise of where FA signals originate and what role components of the circadian clock might play. Here we show that liver-specific deletion of Per2 in mice abolishes FA, an effect that is rescued by viral overexpression of Per2 in the liver. RNA sequencing indicates that Per2 regulates β-hydroxybutyrate (βOHB) production to induce FA leading to the conclusion that liver Per2 is important for this process. Unexpectedly, we show that FA originates in the liver and not in the brain. However, manifestation of FA involves processing of the liver-derived βOHB signal in the brain, indicating that the food-entrainable oscillator is not located in a single tissue but is of systemic nature. 
26838238	We have reported a high prevalence of breast cancer in light-polluted areas in Korea. However, it is necessary to analyze the spatial effects of light polluted areas on breast cancer because light pollution levels are correlated with region proximity to central urbanized areas in studied cities. In this study, we applied a spatial regression method (an intrinsic conditional autoregressive [iCAR] model) to analyze the relationship between the incidence of breast cancer and artificial light at night (ALAN) levels in 25 regions including central city, urbanized, and rural areas. By Poisson regression analysis, there was a significant correlation between ALAN, alcohol consumption rates, and the incidence of breast cancer. We also found significant spatial effects between ALAN and the incidence of breast cancer, with an increase in the deviance information criterion (DIC) from 374.3 to 348.6 and an increase in R2 from 0.574 to 0.667. Therefore, spatial analysis (an iCAR model) is more appropriate for assessing ALAN effects on breast cancer. To our knowledge, this study is the first to show spatial effects of light pollution on breast cancer, despite the limitations of an ecological study. We suggest that a decrease in ALAN could reduce breast cancer more than expected because of spatial effects.
26835600	Circadian rhythms are a nearly universal feature of living organisms and affect almost every biological process. Our innate preference for mornings or evenings is determined by the phase of our circadian rhythms. We conduct a genome-wide association analysis of self-reported morningness, followed by analyses of biological pathways and related phenotypes. We identify 15 significantly associated loci, including seven near established circadian genes (rs12736689 near RGS16, P=7.0 × 10(-18); rs9479402 near VIP, P=3.9 × 10(-11); rs55694368 near PER2, P=2.6 × 10(-9); rs35833281 near HCRTR2, P=3.7 × 10(-9); rs11545787 near RASD1, P=1.4 × 10(-8); rs11121022 near PER3, P=2.0 × 10(-8); rs9565309 near FBXL3, P=3.5 × 10(-8). Circadian and phototransduction pathways are enriched in our results. Morningness is associated with insomnia and other sleep phenotypes; and is associated with body mass index and depression but we did not find evidence for a causal relationship in our Mendelian randomization analysis. Our findings reinforce current understanding of circadian biology and will guide future studies. 
26835539	The engineering of transcriptional networks presents many challenges due to the inherent uncertainty in the system structure, changing cellular context, and stochasticity in the governing dynamics. One approach to address these problems is to design and build systems that can function across a range of conditions; that is they are robust to uncertainty in their constituent components. Here we examine the parametric robustness landscape of transcriptional oscillators, which underlie many important processes such as circadian rhythms and the cell cycle, plus also serve as a model for the engineering of complex and emergent phenomena. The central questions that we address are: Can we build genetic oscillators that are more robust than those already constructed? Can we make genetic oscillators arbitrarily robust? These questions are technically challenging due to the large model and parameter spaces that must be efficiently explored. Here we use a measure of robustness that coincides with the Bayesian model evidence, combined with an efficient Monte Carlo method to traverse model space and concentrate on regions of high robustness, which enables the accurate evaluation of the relative robustness of gene network models governed by stochastic dynamics. We report the most robust two and three gene oscillator systems, plus examine how the number of interactions, the presence of autoregulation, and degradation of mRNA and protein affects the frequency, amplitude, and robustness of transcriptional oscillators. We also find that there is a limit to parametric robustness, beyond which there is nothing to be gained by adding additional feedback. Importantly, we provide predictions on new oscillator systems that can be constructed to verify the theory and advance design and modeling approaches to systems and synthetic biology. 
26834783	The toxicity and efficacy of more than 30 anticancer agents present very high variations, depending on the dosing time. Therefore, the biologists studying the circadian rhythm require a very precise method for estimating the periodic component (PC) vector of chronobiological signals. Moreover, in recent developments, not only the dominant period or the PC vector present a crucial interest but also their stability or variability. In cancer treatment experiments, the recorded signals corresponding to different phases of treatment are short, from 7 days for the synchronization segment to 2 or 3 days for the after-treatment segment. When studying the stability of the dominant period, we have to consider very short length signals relative to the prior knowledge of the dominant period, placed in the circadian domain. The classical approaches, based on Fourier transform (FT) methods are inefficient (i.e., lack of precision) considering the particularities of the data (i.e., the short length). Another particularity of the signals considered in such experiments is the level of noise: such signals are very noisy and establishing the periodic components that are associated with the biological phenomena and distinguishing them from the ones associated with the noise are difficult tasks. In this paper, we propose a new method for the estimation of the PC vector of biomedical signals, using the biological prior informations and considering a model that accounts for the noise. The experiments developed in cancer treatment context are recording signals expressing a limited number of periods. This is a prior information that can be translated as the sparsity of the PC vector. The proposed method considers the PC vector estimation as an Inverse Problem (IP) using the general Bayesian inference in order to infer the unknown of our model, i.e. the PC vector but also the hyperparameters (i.e the variances). The sparsity prior information is modeled using a sparsity enforcing prior law. In this paper, we propose a Student's t distribution, viewed as the marginal distribution of a bivariate normal-inverse gamma distribution. We build a general infinite Gaussian scale mixture (IGSM) hierarchical model where we assign prior distributions also for the hyperparameters. The expression of the joint posterior law of the unknown PC vector and hyperparameters is obtained via Bayes rule, and then, the unknowns are estimated via joint maximum a posteriori (JMAP) or posterior mean (PM). For the PM estimator, the expression of the posterior distribution is approximated by a separable one, via variational Bayesian approximation (VBA), using the Kullback-Leibler (KL) divergence. For the PM estimation, two possibilities are considered: an approximation with a partially separable distribution and an approximation with a fully separable one. Both resulting algorithms corresponding to the PM estimation and the one corresponding to the JMAP estimation are iterative algorithms. The algorithms are presented in detail and are compared with the ones corresponding to the Gaussian model. We examine the convergency of the algorithms and give simulation results to compare their performances. Finally, we show simulation results on synthetic and real data in cancer treatment applications. The real data considered in this paper examines the rest-activity patterns of KI/KI Per2::luc mouse, aged 10 weeks, singly housed in RealTime Biolumicorder (RT-BIO).
26834716	Yeast metabolism produces compounds derived from tryptophan, which are found in fermented beverages, such as wine and beer. In particular, melatonin and serotonin, may be relevant due to their bioactivity in humans. Indeed, the former is a neurohormone related to circadian rhythms, which also has a putative protective effect against degenerative diseases. Moreover, serotonin is a neurotransmitter itself, in addition to being a precursor of melatonin synthesis. This paper summarizes data reported on fermented beverages, to evaluate dietary intake. Additionally, the article reviews observed effects of yeast amino acid metabolites on the prevention of neurodegenerative diseases (Alzheimer's and Parkinson's) and angiogenesis, focusing on evidence of the molecular mechanism involved and identification of molecular targets. 
26834500	Sleep and circadian disorders in Alzheimer's disease (AD) are more frequent than in the general population and appear early in the course of the disease. Quality of sleep and quality of life are parallel in these patients, and such disorders also represent a heavy burden for caregivers. Although alterations in melatonin and hypocretins (orexins) seem to play a key role in the origin of these disturbances, the etiology of these disorders is multifactorial, including many factors such as environment, behavior, treatments, and comorbidities, among others. A comprehensive evaluation of sleep in each patient is essential in the design of the treatment that includes nonpharmacological and pharmacological approaches. One particularly interesting point is the possibility of a role of sleep disorders in the pathogenesis of AD, raising the possibility that treating the sleep disorder may alter the course of the disease. In this review, we present an update on the role of sleep disorders in AD, the bidirectional influence of sleep problems and AD, and treatment options. Behavioral measures, bright light therapy (BLT), melatonin, and other drugs are likely well known and correctly managed by the physicians in charge of these patients. In spite of the multiple treatments used, evidence of efficacy is scarce and more randomized double-blind placebo-controlled studies are needed. Future directions for treatment are the establishment of BLT protocols and the development of drugs with new mechanisms of action, especially hypocretin receptor antagonists, melatonin receptor agonists, and molecules that modulate the circadian clock. 
26833082	Although association of circadian clock properties with the timing of rhythmic behaviors (chronotype) has been extensively documented over several decades, recent studies on mice and Drosophila have failed to observe such associations. In addition, studies on human populations that examined effects of clock gene mutations/polymorphisms on chronotypes have revealed disparate and often contradictory results, thereby highlighting the need for a suitable model organism to study circadian clocks' role in chronotype regulation, the lack of which has hindered exploration of the underlying molecular-genetic bases. We used a laboratory selection approach to raise populations of Drosophila melanogaster that emerge in the morning (early) or in the evening (late), and over 14 years of continued selection, we report clear divergence of their circadian phenotypes. We also assessed the molecular correlates of early and late emergence chronotypes and report significant divergence in transcriptional regulation, including the mean phase, amplitude and levels of period (per), timeless (tim), clock (clk) and vrille (vri) messenger RNA (mRNA) expression. Corroborating some of the previously reported light-sensitivity and oscillator network coupling differences between the early and the late populations, we also report differences in mRNA expression of the circadian photoreceptor cryptochrome (cry) and in the mean phase, amplitude and levels of the neuropeptide pigment-dispersing factor (PDF). These results provide the first-ever direct evidence for divergent evolution of molecular circadian clocks in response to selection imposed on an overt rhythmic behavior and highlight early and late populations as potential models for chronotype studies by providing a preliminary groundwork for further exploration of molecular-genetic correlates underlying circadian clock-chronotype association. 
26833081	Delineating the factors that affect behavioral and neurological responses to alcohol is critical to facilitate measures for preventing or treating alcohol abuse. The high degree of conserved molecular and physiological processes makes Drosophila melanogaster a valuable model for investigating circadian interactions with alcohol-induced behaviors and examining sex-specific differences in alcohol sensitivity. We found that wild-type Drosophila exhibited rhythms in alcohol-induced sedation under light-dark and constant dark conditions with considerably greater alcohol exposure necessary to induce sedation during the late (subjective) day and peak sensitivity to alcohol occurring during the late (subjective) night. The circadian clock also modulated the recovery from alcohol-induced sedation with flies regaining motor control significantly faster during the late (subjective) day. As predicted, the circadian rhythms in sedation and recovery were absent in flies with a mutation in the circadian gene period or arrhythmic flies housed in constant light conditions. Flies lacking a functional circadian clock were more sensitive to the effects of alcohol with significantly longer recovery times. Similar to other animals and humans, Drosophila exhibit sex-specific differences in alcohol sensitivity. We investigated whether the circadian clock modulated the rhythms in the loss-of-righting reflex, alcohol-induced sedation, and recovery differently in males and females. We found that both sexes demonstrated circadian rhythms in the loss-of-righting reflex and sedation with the differences in alcohol sensitivity between males and females most pronounced during the late subjective day. Recovery of motor reflexes following alcohol sedation also exhibited circadian modulation in male and female flies, although the circadian clock did not modulate the difference in recovery times between the sexes. These studies provide a framework outlining how the circadian clock modulates alcohol-induced behaviors in Drosophila and identifies sexual dimorphisms in the circadian modulation of alcohol behaviors. 
26832835	Measuring changes in psychomotor activity is a potential tool in the monitoring of the course of affective states in bipolar disorder. Previous studies have been cross-sectional and only some have used objective measures. The aim was to investigate state-related differences in objectively-measured psychomotor activity in bipolar disorder. During a 12 weeks study, repeated measurements of heart rate and movement monitoring over several days were collected during different affective states from 19 outpatients with bipolar disorder. Outcomes included activity energy expenditure (AEE) and trunk acceleration (ACC). Symptoms were clinically assessed using Hamilton Depression Rating Scale (HDRS-17) and Young Mania Rating Scale (YMRS). Compared to patients in a euthymic state, patients in a manic state had significantly higher AEE. Compared to patients in a depressive state, patients in a manic state had significantly higher ACC and AEE. There was a significant diurnal variation in ACC and AEE between affective states. Finally, there was a significant correlation between the severity of manic symptoms and ACC and AEE, respectively. This first study measuring psychomotor activity during different affective states using a combined heart rate and movement sensor supports that psychomotor activity is a core symptom in bipolar disorder that is altered during affective states. 
26831808	Animal defense mechanisms against both endogenous and exogenous toxic compounds function mainly through receptor-type transcription factors, including the constitutive androstane receptor (CAR). Following xenobiotic stimulation, CAR translocates into the nucleus and transactivates its target genes including oxygenic and conjugative enzymes and transporters in hepatocytes. We identified subcellular localization signals in the rat CAR: two nuclear localization signals (NLS1 and 2); two nuclear export signals (NES1 and 2); and a cytoplasmic retention region. The nuclear import of CAR is regulated by the importin-Ran system and microtubule network. Five splice variants (SV1-5) were identified in rat liver in addition to wild-type CAR. When expressed in immortalized cells, their artificial transcripts were inactive as transcription factors. A CAR mutant with three consecutive alanine residues inserted into the ligand-binding domain of CAR showed ligand-dependent activation of target genes in immortalized cells, which is in marked contrast to the constitutive transactivating nature of wild-type CAR. Using this assay system, androstenol and clotrimazole, both of which are inverse agonists of CAR, were classified as an antagonist and weak agonist, respectively. A member of the DEAD box DNA/RNA helicase family (DP97) and protein arginine methyltransferase 5 (PRMT5) were found to be gene (or promotor)-specific coactivators of CAR. The expression of the CAR gene might be under the control of clock genes mediated by the nuclear receptor Rev-erb-α.
26831451	Peroxiredoxins (Prxs) are a very large and highly conserved family of peroxidases that reduce peroxides, with a conserved cysteine residue, designated the "peroxidatic" Cys (CP) serving as the site of oxidation by peroxides (Hall et al., 2011; Rhee et al., 2012). Peroxides oxidize the CP-SH to cysteine sulfenic acid (CP-SOH), which then reacts with another cysteine residue, named the "resolving" Cys (CR) to form a disulfide that is subsequently reduced by an appropriate electron donor to complete a catalytic cycle. This overview summarizes the status of studies on Prxs and relates the following 10 minireviews. 
26828650	A wide range of organisms features molecular machines, circadian clocks, which generate endogenous oscillations with ~24 h periodicity and thereby synchronize biological processes to diurnal environmental fluctuations. Recently, it has become clear that plants harbor more complex gene regulatory circuits within the core circadian clocks than other organisms, inspiring a fundamental question: are all these regulatory interactions between clock genes equally crucial for the establishment and maintenance of circadian rhythms? Our mechanistic simulation for Arabidopsis thaliana demonstrates that at least half of the total regulatory interactions must be present to express the circadian molecular profiles observed in wild-type plants. A set of those essential interactions is called herein a kernel of the circadian system. The kernel structure unbiasedly reveals four interlocked negative feedback loops contributing to circadian rhythms, and three feedback loops among them drive the autonomous oscillation itself. Strikingly, the kernel structure, as well as the whole clock circuitry, is overwhelmingly composed of inhibitory, rather than activating, interactions between genes. We found that this tendency underlies plant circadian molecular profiles which often exhibit sharply-shaped, cuspidate waveforms. Through the generation of these cuspidate profiles, inhibitory interactions may facilitate the global coordination of temporally-distant clock events that are markedly peaked at very specific times of day. Our systematic approach resulting in experimentally-testable predictions provides insights into a design principle of biological clockwork, with implications for synthetic biology. 
26828406	Melatonin (N-acetyl-5-methoxytryptamine) is an important regulator of circadian rhythms and immunity in animals. However, the diurnal changes of endogenous melatonin and melatonin-mediated diurnal change of downstream responses remain unclear in Arabidopsis. Using the publicly available microarray data, we found that the transcript levels of two melatonin synthesis genes (serotonin N-acetyltransferase (SNAT) and caffeate O-methyltransferase (COMT)) and endogenous melatonin level were regulated by diurnal cycles, with different magnitudes of change. Moreover, the transcripts of C-repeat-binding factors (CBFs)/Drought response element Binding 1 factors (DREB1s) were co-regulated by exogenous melatonin and diurnal changes, indicating the possible correlation among clock, endogenous melatonin level and AtCBFs expressions. Interestingly, diurnal change of plant immunity against Pst DC3000 and CIRCADIANCLOCK ASSOCIATED 1 (CCA1) expression were largely lost in AtCBFs knockdown line-amiR-1. Taken together, this study identifies the molecular pathway underlying the diurnal changes of immunity in Arabidopsis. Notably, the diurnal changes of endogenous melatonin may regulate corresponding changes of AtCBF/DREB1s expression and their underlying diurnal cycle of plant immunity and AtCCA1. 
26827443	It was analyzed the incidences of laryngotracheitis (LT) in children aged 0 to 14 years in Vinnytsya between 1995 and 2008. It was studied seasonal and circadian rhythms of LT in children. The seasonal variations of LT are characterized by two-wave curve with peaks in October and March, and with a significant decrease in July and August. The incidences of LT in October and March exceed the incidences of LT in July and August in 2.6 times. Circadian variation of LT is characterized by peak at night. The incidences of LT at night exceed the incidences in the morning in 2.6 times. The total number of the incidences of LT in the evening and at night exceed the total number of the incidences of LT in the morning and in the afternoon in 1.7 times. The maximum of incidences of LT to minimum of incidences of LT per hour ratio is 5:1 in girls compared to 4:1 in boys.

26827143	The daily photosynthetic performance of a natural biofilm of the extreme acidophilic Euglena mutabilis from Río Tinto (SW, Spain) under full solar radiation was analyzed by means of pulse amplitude-modulated (PAM) fluorescence measurements and metatrascriptomic analysis. Natural E. mutabilis biofilms undergo large-scale transcriptomic reprogramming during midday due to a dynamic photoinhibition and solar radiation stress. Photoinhibition is due to UV radiation and not to light intensity, as revealed by PAM fluorometry analysis. In order to minimize the negative effects of solar radiation, our data supports the presence of a circadian rhythm in this euglenophyte that increases their opportunity to survive. Differential gene expression throughout the day (at 12:00, 20:00 and night) was monitored by massive Illumina parallel sequencing of metatranscriptomic libraries. The transcription pattern was altered in genes involved in Photosystem II stability and repair, UV damaged DNA repair, non-photochemical quenching and oxidative stress, supporting the photoinhibition detected by PAM fluorometry at midday. 
26826022	The circadian system regulates biological rhythmicity in the human body. The role of the circadian system in neurological disorders is a theme that is attracting an increasing amount of interest from the scientific community. This has arisen, in part, from emerging evidence that disorders such as Parkinson's disease (PD) are multifactorial with many features exhibiting diurnal fluctuations, thereby suggestive of circadian involvement. Although the importance of fluctuating motor and nonmotor manifestations in PD have been well acknowledged, the role of the circadian system has received little attention until recently. It is proposed that intervening with circadian function provides a novel research avenue down which new strategies for improving symptomatic treatment and slowing of the progressive degenerative process can be approached to lessen the burden of PD. In this article we review the literature describing existing circadian research in PD and its experimental models.
26825619	The role of specific cortical regions in sleep-regulating circuits is unclear. The anterior insula (AI) has strong reciprocal connectivity with wake and sleep-promoting hypothalamic and brainstem regions, and we hypothesized that the AI regulates patterns of sleep and wakefulness. To test this hypothesis, we lesioned the AI in rats (n = 8) and compared sleep, wake, and activity regulation in these animals with nonlesioned controls (n = 8) with 24-h sleep recordings and chronic infrared activity monitoring. Compared to controls, animals with AI lesions had decreased wakefulness and increased rapid eye movement (REM) sleep and non-REM (NREM) sleep. AI-lesioned animals had shorter wake bouts, especially during the active dark phase. AI-lesioned animals also had more transitions from NREM to REM sleep, especially during the inactive light phase. Chronic infrared monitoring revealed that AI-lesioned animals also had a disturbed temporal organization of locomotor activity at multiple time scales with more random activity fluctuations from 4 to 12 h despite intact circadian rhythms. These results suggest that the AI regulates sleep and activity and contributes to the regulation of sleep and motor behavior rhythmicity across multiple time scales. Dysfunction of the AI may underlie changes in sleep-wake patterns in neurological diseases. 
26825618	Adolescent maturation is associated with delays of the endogenous circadian phase. Consequently, early school schedules may lead to a mismatch between internal and external time, which can be detrimental to adolescent sleep and health. In parallel, chronotype is known to play a role in adolescent health; evening chronotype adolescents are at higher risk for sleep problems and lower academic achievement. In the summer of 2008, Kénogami High School (Saguenay, Canada) was destroyed by fire. Kénogami students were subsequently relocated to Arvida High School (situated 5.3 km away) for the 2008-2009 academic year. A dual school schedule was implemented, with Arvida students attending a morning schedule (0740-1305 h) and Kénogami students an afternoon schedule (1325-1845 h). This study aimed to investigate the effects of such school schedules and chronotype on sleep, light exposure, and daytime functioning. Twenty-four morning and 33 afternoon schedule students wore an actigraph during 7 days to measure sleep and light exposure. Academic achievement was obtained from school. Subjects completed validated questionnaires on daytime sleepiness, psychological distress, social rhythms, school satisfaction, alcohol, and chronotype. Overall, afternoon schedule students had longer sleep duration, lower sleepiness, and lower light exposure than morning schedule students. Evening chronotypes (E-types) reported higher levels of sleepiness than morning chronotypes (M-types) in both morning and afternoon schedules. Furthermore, M-types attending the morning schedule reported higher sleepiness than M-types attending the afternoon schedule. No difference was found between morning and afternoon schedule students with regard to academic achievement, psychological distress, social rhythms, school satisfaction, and alcohol consumption. However, in both schedules, M-type had more regular social rhythms and lower alcohol consumption. In summary, this study emphasizes that an early school schedule is associated with detrimental effects in terms of sleep deprivation and daytime sleepiness, even for M-types. Furthermore, irrespective of school schedule, E-type adolescents face an increased risk for poor daytime functioning. 

26824606	Melatonin is rhythmically secreted by both the pineal gland and retina in a circadian fashion, with its peak synthesis occurring during the night. Once synthesized, melatonin exerts its effects by binding to two specific G-protein coupled receptors-melatonin receptor type 1(MT1) and melatonin receptor type 2(MT2). Recent studies suggest the involvement of MT1 and MT2 in the regulation of glucose homeostasis; however the ability of melatonin signaling to impart timing cues on glucose metabolism remains poorly understood. Here we report that the removal of MT1 or MT2 in mice abolishes the daily rhythm in blood glucose levels. Interestingly, removal of melatonin receptors produced small effects on the rhythmic expression patterns of clock genes within skeletal muscle, liver, and adipose tissue. Taken together, our data suggest that the loss of the daily rhythm in blood glucose observed in MT1(-/-) and MT2(-/-) mice does not occur as a consequence of 'disrupted' clocks within insulin sensitive tissues. Finally our results highlight a diurnal contribution of melatonin receptor signaling in the daily regulation of blood glucose levels.
26824045	We investigated the predictive value of morning blood pressure surge (MBPS) on the development of microalbuminuria in normotensive adults with a recent diagnosis of type 2 diabetes.Prospective assessments of 24-hour ambulatory blood pressure monitoring and urinary albumin excretion were performed in 377 adult patients. Multivariate-adjusted Cox regression models were used to assess hazard ratios (HRs) between baseline and changes over follow-up in MBPS and the risk of microalbuminuria. The MBPS was calculated as follows: mean systolic BP during the 2 hours after awakening minus mean systolic BP during the 1 hour that included the lowest sleep BP.	After a mean follow-up of 6.5 years, microalbuminuria developed in 102 patients. An increase in MBPB during follow-up was associated with an increased risk of microalbuminuria. Compared to individuals in the lowest tertile (-0.67 ± 1.10 mmHg), the HR and 95% CI for microalbuminuria in those in the highest tertile of change (24.86 ± 6.92 mmHg) during follow-up were 17.41 (95% CI 6.26-48.42); p for trend <0.001. Mean SD MBPS significantly increased in those who developed microalbuminuria from a mean [SD] of 10.6 [1.4] to 36.8 [7.1], p < 0.001.	An increase in MBPS is associated with the risk of microalbuminuria in normotensive adult patients with type 2 diabetes.	
26823445	Visible light on Earth largely comes from the sun, including light reflected from the moon. Predation risk is strongly determined by light conditions, and some animals are nocturnal to reduce predation. Artificial lights and its consequent light pollution may disrupt this natural behavior. Here, we used 13 years of attendance data to study the effects of sun, moon, and artificial light on the attendance pattern of a nocturnal seabird, the little penguin Eudyptula minor at Phillip Island, Australia. The little penguin is the smallest and the only penguin species whose activity on land is strictly nocturnal. Automated monitoring systems recorded individually marked penguins every time they arrived (after sunset) at or departed (before sunrise) from 2 colonies under different lighting conditions: natural night skylight and artificial lights (around 3 lux) used to enhance penguin viewing for ecotourism around sunset. Sunlight had a strong effect on attendance as penguins arrived on average around 81 min after sunset and departed around 92 min before sunrise. The effect of moonlight was also strong, varying according to moon phase. Fewer penguins came ashore during full moon nights. Moon phase effect was stronger on departure than arrival times. Thus, during nights between full moon and last quarter, arrival times (after sunset) were delayed, even though moonlight levels were low, while departure times (before sunrise) were earlier, coinciding with high moonlight levels. Cyclic patterns of moon effect were slightly out of phase but significantly between 2 colonies, which could be due to site-specific differences or presence/absence of artificial lights. Moonlight could be overridden by artificial light at our artificially lit colony, but the similar amplitude of attendance patterns between colonies suggests that artificial light did not mask the moonlight effect. Further research is indeed necessary to understand how seabirds respond to the increasing artificial night light levels. 
26822246	Shift work is often considered to be a factor that can negatively affect health and sleep quality. However, it is usually considered as a structural factor of the job and not as a perception of a work demand.The study aimed at analyzing the relationship between perception of shift work, burnout and sleep disturbances in a potentially stressful context, namely the call centre setting.	Call centre operators (N=510) completed a questionnaire encompassing the following scales: perceptions of shift work, monotony, time pressure, exhaustion, cynicism and sleep disturbances. We conducted two hierarchical regressions in order to analyze the contribution of the perception of shift work on burnout dimensions (exhaustion and cynicism), beyond the contribution of socio-demographical variables, and of two specific job stressors for call centre operators, namely monotony and time pressure. The mediating role of exhaustion and cynicism between the perception of shift work and sleep disturbances was also explored.	The perception of shift work was associated with operators' burnout, beyond the effect of socio-demographic variables and other job stressors. In addition, the relationship between the perception of shift work and sleep disturbances was fully mediated by exhaustion and partially mediated by cynicism.	Perceived shift work may represent a risk factor for the health of call centre operators that should be monitored and possibly managed through specific organizational interventions.	
26820297	Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed. 
26819638	Clock genes, major regulators of circadian rhythm, are involved in tumor progression. We have shown that clock genes basic helix-loop-helix (BHLH) transcription factors, differentiated embryonic chondrocyte gene 1 (DEC1/BHLHE40/Sharp2/Stra13) and DEC2 (BHLHE41/Sharp1) play important roles in circadian rhythm, cell proliferation, apoptosis, hypoxia response, various stresses, and epithelial-to-mesenchymal transition (EMT) of tumor cells. Various stresses, such as exposure to transforming growth factor-beta (TGF-β), hypoxia, cytokines, serum-free, and anti-tumor drugs affect DEC1 and DEC2 expression. An increased or decreased expression of DEC1 and DEC2 regulated tumor progression. However, DEC1 and DEC2 have opposite effects in tumor progression, where the reason behind remains unclear. We found that DEC2 has circadian expression in implanted mouse sarcoma cells, suggesting that DEC2 regulates tumor progression under circadian rhythm. In addition to that, we showed that DEC1 and DEC2 regulate target genes via positive or negative feedback system in tumor progression. We propose that DEC1 and DEC2 act as an accelerator or a brake in tumor progression. In this review, we summarize current progress of knowledge in the function of DEC1 and DEC2 genes in tumor progression. 
26819233	The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial.Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation.	Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes.	Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.	
26818960	This retrospective study tested the hypothesis that disease control and treatment-related toxicity in patients undergoing high-dose radiotherapy (HDRT) for prostate cancer varies in a circadian manner. Patients with localized prostate adenocarcinoma receiving HDRT (median 78 Gy) to the prostate and involved seminal vesicle(s) without elective pelvic irradiation were divided into a daytime treatment (before 5 PM) group (n = 267) and evening treatment (after 5 PM) group (n = 142). Biochemical failure (Phoenix definition), acute and late gastrointestinal (GI) and genitourinary toxicities (Common Terminology Criteria for Adverse Events version 4), biochemical failure-free survival (BFFS) and freedom from late toxicity were assessed. Analyses were performed by binary logistic regression and Cox proportional hazard regression. The median follow-up was 68 months, and 75% of patients were ≥70 years old. Evening HDRT was significantly associated with worse freedom from ≥grade 2 late GI complications (hazard ratio = 2.96; p < 0.001). The detrimental effect of evening HDRT was significant in patients older than 70 years old (p < 0.001) but not in younger patients (p = 0.63). In a subgroup of propensity score-matched cohort with T2b-T3 disease (n = 154), the 5-year BFFS was worse in the evening group than the daytime group (72% vs. 85%, hazard ratio = 1.95, p = 0.05). Our study indicates that evening HDRT may lead to more GI complications, especially in older patients, and worse BFFS in patients with T2b-T3 disease. 
26818941	It is known that office-hour measurements might not adequately estimate IOP mean, peaks and fluctuations in healthy subjects. The purpose of the present study is to verify whether office-hour measurements in patients in different body positions can estimate the characteristics of 24-hour intraocular pressure (IOP) in treated POAG patients.The 24-hour IOP curves of 70 eyes of 70 caucasian patients with treated glaucoma were analyzed. Measurements were taken at 9 AM; 12, 3, 6, and 9 PM; and 12, 3, and 6 AM, both in the supine (TonoPen XL) and sitting (Goldmann tonometer) positions. The ability of five strategies to estimate IOP mean, peak and fluctuation was evaluated. Each method was analyzed both with regression of the estimate error on the real value and with "hit or miss" analysis.	The least biased estimate of the Peak IOP was obtained using measurements from both supine and sitting positions, also yielding the highest rate of correct predictions (which was significantly different from 3 of the remaining 4 strategies proposed, p < 0.05). Strategies obtained from the combination of supine, sitting and peak measurements resulted to be least biased for the Mean IOP and the IOP Fluctuation estimate, but all strategies were not found significantly different in terms of correct prediction rate (the only significant difference being between the two strategies based on sitting or supine measurements only, with the former being the one with the highest correct prediction rate).	The results of this study remark the concept that IOP is a dynamic parameter and that intensive measurement is helpful in determining its characteristics. All office-hour strategies showed a very poor performance of in correctly predicting the considered parameters within the thresholds used in this paper, all scoring a correct prediction rate below 52%.	
26818921	Evidence on the association of nondipping pattern with carotid atherosclerosis is scarce. We performed a meta-analysis in order to provide comprehensive information on subclinical carotid alterations in nondipping as compared with dipping individuals. A computerized search was performed using PubMed, OVID, EMBASE and Cochrane library databases from 1 January 1990 up to 31 March 2015. Full articles providing data on carotid intima-media thickness (IMT) and plaque in nondipping and dipping individuals, as assessed by ultrasonography, were analyzed. A total of 2753 adult individuals (1003 nondipping and 1750 dipping) included in 13 studies were considered. Common carotid IMT was higher in nondipping than in dipping individuals [807 ± 36  μm vs. 746 ± 28  μm, standard means difference, SMD: 0.37 ± 0.09, confidence interval (CI): 0.19-0.56, P < 0.01]. From data on plaque prevalence provided by five studies, the odds ratio for carotid plaques resulted 67% higher in nondipping (95% CI: 1.26-2.21, P < 0.01) than in dipping individuals. Our findings support an association between nondipping pattern and increased risk of subclinical carotid alterations. In a practical perspective, the present meta-analysis reinforces the view that an effective blood pressure control over the entire 24-h period, in particular at night, may prevent the progression of vascular damage associated with nondipping phenotype.
26818910	Previously, we showed the acceleration of re-entrainment to 8-h phase-advanced light/dark cycles (LD) in the circadian Per1 expression rhythms of the mouse lung and skeletal muscle by 3-h wheel running (WR) at the beginning of shifted dark phase. In the present study, the effects of WR at the end of shifted dark phase were examined on the re-entrainment in mice. LD was advanced by shortening and was delayed by lengthening the first light period in the phase-advance and phase-delay protocol, respectively. Shifted LD was continued for 4 days, which was followed by constant darkness (DD). Per1 expression was measured in the cultured tissues obtained on the first day of DD from mice carrying a bioluminescence reporter of Per1 expression. In the phase-advance protocol, re-entrainment was not influenced by WR in any circadian rhythm examined. In the phase-delay protocol, re-entrainment of the circadian locomotor rhythm was not affected by WR. However, re-entrainment of circadian Per1 rhythm was significantly decelerated in the skeletal muscle and lung. These findings indicate that the effects of WR on re-entrainment depend on the time of day and the peripheral tissues. Mistimed WR interferes with re-entrainment of circadian rhythms in the lung and skeletal muscle.
26818846	Prokineticin 2 (PK2) has been indicated as an output signaling molecule for the suprachiasmatic nucleus (SCN) circadian clock. Most of these studies were performed with nocturnal animals, particularly mice and rats. In the current study, the PK2 and its receptor, PKR2, was cloned from a species of diurnal macaque monkey. The macaque monkey PK2 and PKR2 were found to be highly homologous to that of other mammalian species. The mRNA expression of PK2 and PKR2 in the macaque brain was examined by in situ hybridization. The expression patterns of PK2 and PKR2 in the macaque brain were found to be quite similar to that of the mouse brain. Particularly, PK2 mRNA was shown to oscillate in the SCN of the macaque brain in the same phase and with similar amplitude with that of nocturnal mouse brain. PKR2 expression was also detected in known primary SCN targets, including the midline thalamic and hypothalamic nuclei. In addition, we detected the expression of PKR2 mRNA in the dorsal raphe nucleus (DR) of both macaque and mouse brains. As a likely SCN to dorsal raphe projection has previously been indicated, the expression of PKR2 in the raphe nuclei of both macaque and mouse brain signifies a possible role of DR as a previously unrecognized primary SCN projection target. 
26818792	The aim of this study was to investigate the relationships among morningness-eveningness, impulsivity and anger in the general population. A total of 1000 community-dwelling subjects (500 males) aged 20-77 years (mean± SD age: 39.6 ± 11.6 years) completed the morningness-eveningness questionnaire (MEQ), Barratt impulsiveness scale (BIS), Spielberger State-Trait Anger Expression Inventory (STAXI) and Center for Epidemiologic Studies Depression Scale. Moderation and mediation analyses were performed to determine whether the relationship between two variables depended on the third variable, referred to as a moderator, and whether the third variable, known as a mediator, was associated with the other two variables establishing causation. The MEQ scores exhibited significant negative associations with BIS (p < 0.001) and STAXI (p < 0.001) scores, and high scores on the BIS were associated with high scores on the STAXI (p < 0.001). Impulsivity, as measured by the BIS, played a role as a moderator (p < 0.001) in the relationship between MEQ and STAXI, and anger, as measured by the STAXI, acted as moderator (p = 0.030) in the association between MEQ and BIS. However, after controlling for the interaction of the BIS and MEQ, the MEQ scores did not significantly predict STAXI scores (p = 0.070). Additionally, the effect size of the mediating effect of the BIS scores on the relationship between the MEQ and STAXI (percent mediation: 53.2%) was larger than that of the STAXI scores on the association between the MEQ and BIS (percent mediation: 31.8%). The present results demonstrate that morningness-eveningness was closely related with both impulsivity and anger in the general population. Furthermore, these findings suggest that impulsivity may exercise a great influence on the association between morningness-eveningness and anger in two ways: as a moderator by modulating this relationship based on the level of impulsivity and as a mediator by acting as an intermediary factor. 
26818772	Levels of cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, display a sharp increase immediately upon awakening, known as the cortisol awakening response (CAR). The daily stability of the CAR is potentially influenced by a range of methodological factors, including light exposure, participant adherence, sleep duration and nocturnal awakenings, making inferences about variations in the CAR difficult. The aim of the present study was to determine the daily stability of multiple measurement indices of the CAR in a highly-controlled sleep laboratory environment. A secondary aim was to examine the association between objective sleep continuity and sleep architecture, and the CAR.The CAR was assessed in 15 healthy normal sleepers (seven male, eight female, Mage = 23.67 ± 3.49 years) on three consecutive weekday mornings. Sleep was measured objectively using polysomnography. Saliva samples were obtained at awakening, +15, +30, +45 and +60 min, from which multiple CAR measurement indices were derived: cortisol levels at each time point, awakening cortisol levels, the mean increase in cortisol levels (MnInc) and total cortisol secretion during the measurement period. Morning 2 and Morning 3 awakening cortisol levels, MnInc and total cortisol secretion were compared and the relationship between Night 1 and Night 2 objective measures of sleep continuity and architecture, and the subsequent CAR, was also assessed.	There were no differences in cortisol levels at each time point, or total cortisol secretion during the CAR period, between Morning 2 and Morning 3. Awakening cortisol levels were lower, and the MnInc was higher, on Morning 3. Morning 2 and Morning 3 awakening levels (r = 0.77) and total cortisol secretion (r = 0.82), but not the magnitude of increase, were positively associated.	The stability of the CAR profile and total cortisol secretion, but not awakening cortisol levels or the magnitude of increase, was demonstrated across two consecutive mornings of measurement in a highly-controlled environment. Awakening cortisol levels, and the magnitude of increase, may be sensitive to differences in daily activities.	

26818652	Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states. 
26818410	The present cross-sectional study was aimed to identify pre-hypertension and masked hypertension rate in clinically normotensive adults in relation to socio-demographic, clinical and laboratory parameters.A total of 161 clinically normotensive adults with office blood pressure (OBP) <140/90 mmHg without medication were included in this single-center cross-sectional study. OBP, home BP (HBP) recordings and ambulatory BP monitoring (ABPM) were used to identify rates of true normotensives, true pre-hypertensives and masked hypertensives. Data on sociodemographic and clinical characteristics were collected in each subject and evaluated with respect to true normotensive vs. pre-hypertensive patients with masked hypertension or true pre-hypertensive. Target organ damage (TOD) was evaluated in masked hypertensives based on laboratory investigation.	Masked hypertension was identified in 8.7% of clinically normotensives. Alcohol consumption was significantly more common in masked hypertension than in true pre-hypertension (28.6 vs. 0.0%, p = 0.020) with risk ratio of 2.7 (95% CI 1.7-4.4). Patients with true pre-hypertension and masked hypertension had significantly higher values for body mass index, waist circumference, systolic and diastolic OBP and HBP (p < 0.05 for each) compared to true normotensive subjects. ABPM revealed significantly higher values for day-time and night-time systolic and diastolic BP (p = 0.002 for night-time diastolic BP, p < 0.001 for others) in masked hypertension than true pre-hypertension.	Given that the associations of pre-hypertension with TOD might be attributable to the high prevalence of insidious presentation of masked hypertension among pre-hypertensive individuals, ABPM seems helpful in early identification and management of masked hypertension in the pre-hypertensive population.	
26818054	Daily restricted access to food leads to the development of food anticipatory activity and metabolism, which depends upon an as yet unidentified food-entrainable oscillator(s). A premeal anticipatory peak in circulating hormones, including corticosterone is also elicited by daily restricted feeding. High-fat feeding is associated with elevated levels of corticosterone with disrupted circadian rhythms and a failure to develop robust meal anticipation. It is not clear whether the disrupted corticosterone rhythm, resulting from high-fat feeding contributes to attenuated meal anticipation in high-fat fed rats. Our aim was to better characterize meal anticipation in rats fed a low- or high-fat diet, and to better understand the role of corticosterone in this process. To this end, we utilized behavioral observations, hypothalamic c-Fos expression, and indirect calorimetry to assess meal entrainment. We also used the glucocorticoid receptor antagonist, RU486, to dissect out the role of corticosterone in meal anticipation in rats given daily access to a meal with different fat content. Restricted access to a low-fat diet led to robust meal anticipation, as well as entrainment of hypothalamic c-Fos expression, metabolism, and circulating corticosterone. These measures were significantly attenuated in response to a high-fat diet, and animals on this diet exhibited a postanticipatory rise in corticosterone. Interestingly, antagonism of glucocorticoid activity using RU486 attenuated meal anticipation in low-fat fed rats, but promoted meal anticipation in high-fat-fed rats. These findings suggest an important role for corticosterone in the regulation of meal anticipation in a manner dependent upon dietary fat content. 
26817828	We aimed at evaluating the relationship between the circadian blood pressure rhythm and UA level in young patients (30-40 years old) with newly diagnosed essential hypertension.The study included 62 essential hypertensive patients and 29 healthy controls (20 men, 35 ± 3 years) divided into two groups according to 24-hour ABPM results: 30 dippers and 32 nondippers.	Nondippers showed significantly higher both serum UA levels compared to dippers and controls (6.1 ± 0.7, 5.2 ± 0.9 and 4.1 ± 0.9 mg/dL, p < 0.001, respectively); and high sensitivity C-reactive protein (hsCRP) (4.1 ± 2.2 mg/L, 3.3 ± 1.9 mg/L, and 1.4 ± 0.9 mg/L, p < 0.001, respectively). After adjusting for age, sex, body mass index, smoking, creatinine levels, hsCRP and comorbidity, multivariate logistic regression analysis revealed an independent association between serum UA levels and nondipper pattern (OR 2.44, 95%CIs 1.4-4.1, p = 0.002).	Serum UA is independently associated with nondipper circadian pattern in young patients with newly diagnosed essential hypertension.	
26817496	Most of the research in the field of Chronobiology is focused on the problem of the circadian rhythms (CR) desynchronization. In travelers, it results mostly from the changes of surrounding: photoperiod, local climate conditions (radiation and thermal load) and behavior (e.g. type and place of tourism and activity level). Until now, it was not documented whether the changes in melatonin (MLT) secretion occur in effect of mid-distance transparallel travels (TpT), without complications arising due to time-zone transitions (e.g. jet-lag syndrome). To cope with this problem, a special field experiment was carried out. In the experiment, MLT characteristics were examined twice a year in real conditions through a group of young tourists (23-26 years old) at their place of habitual residence (Warsaw, Poland), and at their tourist destination (Tromso, Norway). Transition to circumpolar zone in summer has resulted in insignificant reduction in melatonin peak value (MPV) compared to preflight control (2 days before travel) and the melatonin peak time (MPT) was delayed. However, after traveling southward on the returning flight, MPV was lower compared to control and MPT was advanced. In winter, MPV was insignificantly higher in comparison to preflight control and MPT was almost unchanged. While changes in MPV do not depend on season, flight direction and day of stay after flight than MPT was differentiated seasonally and due to direction of flight. MPV and MPT were significantly modified by characteristics of individual light exposure during daytime and evening. The experiment showed also that in real conditions activity level is an important factor affected melatonin peak in tourists. In winter, greater daytime activity significantly influenced earlier MPT occurrence, both after northward and southward flights. 
26817403	At present, the measurement of circadian system status under free-living conditions by the use of sensors is a relatively new technique. The data obtained using these methods are influenced by strong environmental masking factors and artifacts that can affect its recording. Therefore, the use of integrative variables such as TAP, a measure that includes temperature, activity and position that reduces these drawbacks and the number of parameters obtained is necessary. However, the relative genetic contribution to this circadian marker is unknown. The aim of our study was to ascertain the relative importance of genetic influences in TAP, and for each of its components using classical twin models. The study was performed in 53 pairs of female twins [28 monozygotic (MZ) and 25 dizygotic (DZ)] with mean age 52 ± 6 years. Circadian patterns were studied by analyzing temperature, body position and activity for 1 week every 1 min with "Circadianware®.". Genetic influences affecting the variability of each of the measurements were estimated by comparing the observed data in twin pairs. MZ twins showed higher intrapair correlations than DZ twins for most of the parameters. Genetic factors (broad sense heritability) were responsible for about 40-72% of TAP variance in parameters such as mesor, acrophase, amplitude, Rayleigh test, percentage of rhythmicity and circadian function index. We found more homogeneous heritability estimates of the circadian system when using an integrative technique such as TAP than with individual variables alone, suggesting that this measurement can be more reliable and less subject to environmental artifacts. 
26817325	The aim of our study was to assess the morning and evening cortisol plasma levels in women with polycystic ovary syndrome (PCOS).95 patients gave their informed consent to participate in the study and were divided into 2 groups. Group A consisted of 40 PCOS patients and group B consisted of 55 women without features of PCOS. Between day 5 and 8 of the menstrual cycle, morning (7 am), fasting blood samples were taken for the assessment of luteinizng hormone (LH), follicle stimulating hormone (FSH), estradiol, cortisol, prolactin, thyreotropin (TSH), testosterone and dehydroepeiandrosterone (DHEAS). Evening (5 pm) blood samples were also taken for the evaluation of plasma cortisol level	There were no differences in mean age, body mass index (BMI), FSH, SHBG, PRL, estradiol and TSH levels between group A and group B. Mean plasma LH level was higher in group A compared to group B (10.7 ± 6.8 IU/l vs 6.6 ± 4.5 LU/l, p < 0.02). Mean plasma testosterone and DHEAS levels were also higher in PCOS patients (3.8 ± 0.6 nmol/l vs 1.63 ± 0.6 nmol/l; 427.7 ± 162.9 vs 236.6 ± 97.8 respectively, p < 0.001). Mean evening plasma cortisol level was higher in PCOS patients (11.8 ± 4.1 ug/dl vs 4.7 ± 1.3 ug/dl, p < 0.02). Mean morning plasma cortisol levels did not differ between groups.	PCOS women showed the increased evening plasma cortisol level with impacted diurnal secretion rate.	
26817220	The circadian rhythms in the suprachiasmatic nucleus (SCN), a central clock, are generated by autoregulatory network composed ofclock genes that encode transcriptionalfactors. There is a gradual development ofclock gene expression in the SCN during ontogenesis. Moreover clock genes are expressed in the adult hippocampus with circadian fashion.It is of interest to examine daily profiles ofthe clock gene mRNA and protein expressions in rat hippocampus during development.	Daily profiles ofthree clock genes (Per1, Per2, and Bmal1) mRNA, and their protein expressions were analyzed in the rat hippocampus ofpups at postnatal (P) day 4 and 8 (P4 and P8), pre-weaning stage (P16), early pubertal stage (P32), and adult (P60) by real-time PCR and immunohistochemistry.	The entire studied clock gene mRNAs and proteins did not exhibit circadian rhythm in early postnatal P4-P16. Rhythmic expression of Per1 and Per2 mRNA started at P32, whereas Bmal1 began at adult. However, their proteins showed circadian expression together at adult.	The present study suggests that rat hippocampal molecular clock works gradually develop after birth and slower than that in the central clock SCN. It was possible that ontogenetic development of clock gene in hippocampus was waitingfor central clocksynchronization.	
26814131	Caveolin-1 associates with the endo/lysosomal machinery of cells in culture, suggesting that it functions at these organelles independently of its contribution to cell surface caveolae. Here we explored mice lacking caveolin-1 specifically in the retinal pigment epithelium (RPE). The RPE supports neighboring photoreceptors via diurnal phagocytosis of spent photoreceptor outer segment fragments. Like mice lacking caveolin-1 globally, (RPE)CAV1(-/-) mice developed a normal RPE and neural retina but showed reduced rod photoreceptor light responses, indicating that lack of caveolin-1 affects photoreceptor function in a non-cell-autonomous manner. (RPE)CAV1(-/-) RPE in situ showed normal particle engulfment but delayed phagosome clearance and reversed diurnal profiles of levels and activities of lysosomal enzymes. Therefore, eliminating caveolin-1 specifically impairs phagolysosomal degradation by the RPE in vivo. Endogenous caveolin-1 was recruited to maturing phagolysosomes in RPE cells in culture. Consistent with these in vivo data, a moderate increase (to ∼ 2.5-fold) or decrease (by half) of caveolin-1 protein levels in RPE cells in culture was sufficient to accelerate or impair phagolysosomal digestion, respectively. A mutant form of caveolin-1 that fails to reach the cell surface augmented degradation like wild-type caveolin-1. Acidic lysosomal pH and increased protease activity are essential for digestion. We show that halving caveolin-1 protein levels significantly alkalinized lysosomal pH and decreased lysosomal enzyme activities. Taken together, our results reveal a novel role for intracellular caveolin-1 in modulating phagolysosomal function. Moreover, they show, for the first time, that organellar caveolin-1 significantly affects tissue functionality in vivo.
26814070	To identify the characteristics of blood pressure (BP) in the elderly hypertensive patients with chronic kidney disease (CKD).We retrospectively recruited 337 CKD patients who had been admitted into our renal unit during January 2010 to December 2012 and undergone clinical blood pressure (CBP) and ambulatory blood pressure (ABP) measurement with detailed clinical data. Those with age ≥ 60 years old (n = 94) were designated as elderly patients and their BP data were compared with those of young- and middle-aged patients (< 60 years old, n = 243). Logistic regression was adopted to analyze the independent risk factor for white-coat hypertension and reverse-dipper rhythm.	Compared to those < 60 y, the elder CKD patients had the following characteristics: (1) Higher prevalence of white-coat hypertension (24.5% vs 12.3%, P = 0.008). (2) Significantly lower diastolic blood pressure of average 24 h, daytime and nighttime by ambulatory monitoring of blood pressure (ABPM) (all P < 0.001). (3) Higher BP variability with significant difference (all P < 0.05) and more patients with morning surge (11.7% vs 3.7%, P = 0.009). (4) Higher prevalence of reverse-dipper circadian BP rhythm (41.5% vs 25.1%, P = 0.004). (5) Age was an independent predictor for white-coat hypertension (OR = 1.024, 95% CI: 1.004-1.044) and reverse-dipper circadian BP rhythm (OR = 1.016, 95% CI: 1.001-1.032).	The BP profile of elderly hypertensive CKD patients is different from that of young- and middle-aged patients. ABPM should be more commonly performed to improve BP treatment of elderly CKD patients.	
26812920	Fibromyalgia (FM) is a prevalent disorder defined by the presence of chronic widespread pain in association with fatigue, sleep disturbances and cognitive dysfunction. Recent studies indicate that bipolar spectrum disorders frequently co-occur in individuals with FM. Furthermore, shared pathophysiological mechanisms anticipate remarkable phenomenological similarities between FM and BD. A comprehensive search of the English literature was carried out in the Pubmed/MEDLINE database through May 10th, 2015 to identify unique references pertaining to the epidemiology and shared pathophysiology between FM and bipolar disorder (BD). Overlapping neural circuits may underpin parallel clinical manifestations of both disorders. Fibromyalgia and BD are both characterized by functional abnormalities in the hypothalamic-pituitary-adrenal axis, higher levels of inflammatory mediators, oxidative and nitrosative stress as well as mitochondrial dysfunction. An over-activation of the kynurenine pathway in both illnesses drives tryptophan away from the production of serotonin and melatonin, leading to affective symptoms, circadian rhythm disturbances and abnormalities in pain processing. In addition, both disorders are associated with impaired neuroplasticity (e.g., altered brain-derived neurotrophic factor signaling). The recognition of the symptomatic and pathophysiological overlapping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.
26812690	In this study we tested the use of salivary cortisol and cortisone as alternatives to serum cortisol. Salivary cortisol is often undetectable and contaminated by hydrocortisone. Salivary cortisone strongly reflects serum cortisol. 
26810072	Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redox-sensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian time-keeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological time-keeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping. 
26809638	We report the relationship between patterns of post-awakening salivary melatonin and cortisol secretion in healthy participants (n = 51; mean age 21.6 ± 5.0 years). Saliva samples were collected within the domestic setting, at 0-, 15-, 30-, and 45-min post-awakening on 2 consecutive typical weekdays. Analyses were undertaken on data with electronically verified sample timing accuracy (<5-min delay between awakening and the start of saliva sampling). Melatonin secretion declined linearly by an average of 29% within the first 45-min post-awakening. In contrast, there was a marked 112% surge in cortisol, characteristic of the cortisol awakening response. No day differences in melatonin or cortisol secretion were observed but melatonin concentrations were lower with later awakening. Despite contrasting post-awakening changes in these hormones, there was a lack of relationship between overall levels or patterns of melatonin and cortisol during this period. 
26808220	Disturbances of circadian rhythm and dysregulation of clock gene expression are involved in the induction of various neurological disorder states, including chronic pain. However, the relationship between the CNS circadian-clock gene system and nociception remains poorly defined. Significant circadian oscillations of Period (Per1, Per2), Bmal1 and Cryptochrome 1 (Cry1) mRNA expression have been observed in the lumbar spinal dorsal horn of naïve mice. The current study examined the expression of clock genes in the lumbar spinal dorsal horn of mice with neuropathic pain due to a partial sciatic nerve ligation (PSNL). Seven days after PSNL, the mice displayed a robust unilateral hind paw mechanical hypersensitivity. The normal circadian oscillations of Per1, Per2 and Cry1, but not Bmal1, mRNA expression were significantly suppressed in the ipsilateral lumbar spinal dorsal horn of PSNL mice 7days following surgery. The circadian expression of PER1 protein, in particular, was also significantly suppressed in the ipsilateral spinal dorsal horn of PSNL mice. Double-labeling immunohistochemistry revealed downregulation of PER1 in neurons and astrocytes, but not microglia. Knockdown of Per1 expression by intrathecal treatment with Per1 siRNA also induced mechanical hypersensitivity, phosphorylation of c-jun N-terminal kinase (JNK) and the upregulation of chemokine (C-C motif) ligand 2 (CCL2) production in the lumbar spinal dorsal horn. Per1 siRNA-induced mechanical hypersensitivity was attenuated with intrathecal treatment of either the JNK inhibitor SP600125 or the selective CCL2 receptor (CCR2) antagonist RS504393, indicating that these intracellular messengers are crucial in mediating the mechanical hypersensitivity following the downregulation of PER1 expression. These results suggest that the downregulation of the spinal dorsal horn clock genes such as Per1 expressed could be crucial in the induction of neuropathic pain following peripheral nerve injury. Modulating clock gene Per1 expression could be a novel therapeutic strategy in alleviating neuropathic pain. 
26807585	A potent angiotensin II type-1 receptor blocker, azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that azilsartan could also improve salt sensitivity; thus, we examined the effect of azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received azilsartan (1.0 mg/kg/day), candesartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; azilsartan or candesartan vs. vehicle). The azilsartan group also showed higher urinary fractional excretion of sodium during the dark period than the candesartan and vehicle groups (azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 azilsartan vs. candesartan or vehicle). A pressure-natriuresis curve demonstrated that azilsartan treatment restored salt sensitivity. Immunofluorescence and western blotting showed lower levels of Na+-H+ exchanger-3 (NHE3) protein (the major sodium transporter in renal proximal tubules) in the azilsartan group, but not in the candesartan or vehicle groups. However, azilsartan did not affect NHE3 transcription levels. Interestingly, we did not observe increased expression of downstream sodium transporters, which would have compensated for the increased flow of sodium and water due to non-absorption by NHE3. We also confirmed the mechanism stated above using cultured opossum kidney proximal tubular cells. Results revealed that a proteasomal inhibitor (but not a lysosomal inhibitor) blocked the azilsartan-induced decrease in NHE3 protein expression, suggesting that azilsartan increases NHE3 ubiquitination. In conclusion, azilsartan (but not candesartan) improved salt sensitivity possibly by decreasing NHE3 expression via ubiquitin-proteasomal degradation.
26807442	Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
26806862	Blue wavelength light has been used as an effective treatment for some types of mood disorders and circadian rhythm related sleep problems. We hypothesized that acute exposure to blue wavelength light would directly affect the functioning of neurocircuity implicated in emotion regulation (i.e., ventromedial prefrontal cortex, amygdala, insula, and anterior cingulate cortex [ACC]) during 'certain' and 'uncertain' anticipation of negative and positive stimuli. Thirty-five healthy adults were randomized to receive a thirty-minute exposure to either blue (active) or amber (placebo) light, immediately followed by an emotional anticipation task during functional magnetic resonance imaging (fMRI). In contrast to placebo, participants in the blue light group showed significantly reduced activation within the rostral ACC during 'uncertain' anticipation (i.e., uncertainty regarding whether a positive or negative stimulus would be shown) in comparison to 'certain' anticipation of a positive stimulus. These findings may be explicable in terms of interactions between blue light exposure and the influence of specific neuromodulators on ACC-mediated decision-making mechanisms.
26805535	To explore the effect of giving sedatives according to the circadian rhythm in prevention of occurrence of delirium and the prognosis of patients undergoing mechanical ventilation in intensive care unit (ICU).A prospective double-blinded randomized controlled trial (RCT) was conducted. The patients admitted to Department of Critical Care Medicine of the Second Hospital of Lanzhou University from July 2014 to February 2015, undergoing invasive mechanical ventilation over 12 hours were enrolled. All the patients were given fentanyl for analgesia, and they were randomly divided into simulated circadian clock group (study group, n = 35) and non-simulated circadian clock group (control group, n = 35). The patients in each group were subdivided into three subgroups according to the kinds of sedative drugs, namely dexmedetomidine group (n = 8), propofol group (n = 14), and dexmedetomidine combined with propofol group (combination group, n = 13). Visual analogue scale (VAS) standard and Richmond agitation-sedation scale (RASS) were used to control the analgesic and to quantify the depth of sedation by titrating the dose of sedative drugs, the simulated circadian clock was set to control the RASS score at 0-1 during the day, and -1 to -2 at night in study group. The RASS score in the control group was set at -1 to -2 day and night. The urine 6-hydroxy acid melatonin (aMT6s) levels at different time points in the first diurnal rhythm (06:00, 12:00, 18:00, 24:00) were determined by enzyme linked immunosorbent assay (ELISA). The incidence of delirium, severe hypotension, severe bradycardia and other adverse reactions, duration of mechanical ventilation and the time of extubation, length of ICU stay, amount of sedative and analgesic drugs used were recorded. The correlation between delirium and other indexes was analyzed by using Spearman correlation analysis.	(1) There were no significant differences in gender, age, acute physiology and chronic health evaluation II (APACHEII) score among groups. (2) Urine aMT6s levels did not show circadian rhythm in both groups, aMT6s level at 06:00 in study group showed an increasing tendency as compared with the control group, but the difference was not statistically significant. (3) Compared with the control group, the incidence of delirium was significantly lowered in the study group (14.3% vs. 37.1%, P = 0.029), but no significant differences were found in the incidence of severe hypotension or severe bradycardia (20.0% vs. 25.7%, 11.4% vs. 20.0%, both P > 0.05). In simulated circadian clock group, the incidence of delirium in dexmedetomidine group was significantly lower than that of the propofol group (6.3% vs. 32.1%, P < 0.05). (4) Compared with control group with the same sedative, the duration of mechanical ventilation, extubation time, length of ICU stay were significantly shortened, and the dosage of sedative drugs used was reduced in study group (all P < 0.05). In simulated circadian clock group, the duration of mechanical ventilation in dexmedetomidine group was significantly shorter than that of propofol group and combination group (hours: 75.75±26.78 vs. 102.00±26.31 and 100.31±25.38, both P < 0.05), and the length of ICU stay was significantly shorter than that of propofol group (days: 5.75±1.04 vs. 7.00±1.52, P < 0.05). (5) The occurrence of delirium was positively correlated with duration of mechanical ventilation (r = 0.705), extubation time (r = 0.704), length of ICU stay (r = 0.666, all P = 0.000), and no correlation was found between the occurrence of delirium and aMT6s level at 06:00, 12:00, 18:00, and 24:00 (r = -0.135, r = 0.163, r = 0.269, r = -0.077, all P > 0.05).	Administration of sedatives according to simulating circadian time could decrease the duration of mechanical ventilation, extubation time, and the length of ICU stay, decrease the dosage of sedative drugs, and reduce the incidence of delirium. Dexmedetomidine could reduce the incidence of delirium, and improve the prognosis of patients.	
26805404	Two experiments were conducted to elucidate the effect of increased concentrate allotment before evening grazing on herbage intake, nitrogen utilization and rumen fermentation in dairy cows. In experiment 1, nine lactating cows were grazed in the morning and evening sessions (2.5 h each). The cows were allocated to treatments of three concentrate allotment levels before the evening grazing session by altering proportions to daily total offered; 25%, 50% and 75%. Daily herbage dry matter intake quadratically decreased with increasing the concentrate allotment levels (P < 0.05). Nitrogen utilization was similar among treatments. To investigate diurnal changes in rumen fermentation, a second experiment was conducted where six ruminally cannulated non-lactating dairy cows grazed in the morning and evening sessions (3 h each) were subjected to the same treatments as experiment 1. Total volatile fatty acid concentration in the rumen linearly increased with increasing the concentrate allotment levels throughout the pre-evening grazing session to the post-morning grazing session (P < 0.01). The results indicate that dairy cows reduce daily herbage intake but do not alter nitrogen utilization with increasing concentrate allotment before evening grazing. © 2016 Japanese Society of Animal Science.
26804592	A synergistic-healing strategy that combines molecular targeting within a system-wide perspective is presented as the Multiple Integrated Complementary Healing Approaches: Energetics And Light (MICHAEL). The basis of the MICHAEL approach is the realization that environmental, nutritional and electromagnetic factors form a regulatory framework involved in bone and nerve healing. The interactions of light, energy, and nutrition with neural, hormonal and cellular pathways will be presented. Energetic therapies including electrical, low-intensity pulsed ultrasound and light based treatments affect growth, differentiation and proliferation of bone and nerve and can be utilized for their healing benefits. However, the benefits of these therapies can be impaired by the absence of nutritional, hormonal and organismal factors. For example, lack of sleep, disrupted circadian rhythms and vitamin-D deficiency can impair healing. Molecular targets, such as the Wnt pathway, protein kinase B and glucocorticoid signaling systems can be modulated by nutritional components, including quercetin, curcumin and Mg(2+) to enhance the healing process. The importance of water and water-regulation will be presented as an integral component. The effects of exercise and acupuncture on bone healing will also be discussed within the context of the MICHAEL approach. 
26804589	Pineal gland is an important organ for the regulation of the bio-clock in all vertebrate species. Its major secretory product is melatonin which is considered as the chemical expression of darkness due to its circadian peak exclusively at night. Pineal melatonin can be either released into the blood stream or directly enter into the CSF of the third ventricle via the pineal recess. We have hypothesized that rather than the peripheral circulatory melatonin circadian rhythm serving as the light/dark signal, it is the melatonin rhythm in CSF of the third ventricle that serves this purpose. This is due to the fact that melatonin circadian rhythm in the CSF is more robust in terms of its extremely high concentration and its precise on/off peaks. Thus, extrapineal-generated melatonin or diet-derived melatonin which enters blood would not interfere with the bio-clock function of vertebrates. In addition, based on the relationship of the pineal gland to the CSF and the vascular structure of this gland, we also hypothesize that pineal gland is an essential player for CSF production. We feel it participates in both the formation and reabsorption of CSF. The mechanisms associated with these processes are reviewed and discussed in this brief review. 
26803637	The importance of the 24-h daily cycle, termed circadian, on immune function has been highlighted by a number of recent studies. Immune parameters such as the response to bacterial challenge or immune cell trafficking change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. We are beginning to uncover that the key proteins that comprise the molecular clock, most notably BMAL1, CLOCK, and REV-ERBα, also control fundamental aspects of the immune response. Given the ubiquitous nature of the molecular clock in controlling many other types of physiologies such as metabolism and cardiovascular function, a more thorough understanding of the daily rhythm of the immune system may provide important insight into aspects of patient care such as vaccinations and how we manage infectious and inflammatory diseases. In this chapter, we describe a series of experiments to look at circadian expression and function in immune cells. The experiments described herein may provide an initial assessment of the role of the molecular clock on an immune response from any cell type of interest. 
26802736	The activity patterns and social interactions of two species of captive sifaka were observed during a 2-year period. Allogrooming was not observed in golden-crowned sifaka and they spent significantly more time resting than the Coquerel's sifaka. Females of both species were found to be dominant to males. The golden-crowned sifaka (Propithecus tattersalli) spent significantly less time feeding than the Coquerel's sifaka. Temperature, time of day, species, and interpair comparisons for the golden-crowned sifaka were found to affect activity and social interactions, while gender did not. Like the Coquerel's sifaka, the golden-crowned sifaka was found to be diurnal; however, they differed in that the golden-crowned sifaka did not descend to the ground.
26802726	Clock genes, such as period, which maintain an organism's circadian rhythm, can have profound effects on metabolic activity, including ethanol metabolism. In turn, ethanol exposure has been shown in Drosophila and mammals to cause disruptions of the circadian rhythm. Previous studies from our labs have shown that larval ethanol exposure disrupted the free-running period and period expression of Drosophila. In addition, a recent study has shown that arrhythmic flies show no tolerance to ethanol exposure. As such, Drosophila period mutants, which have either a shorter than wild-type free-running period (perS) or a longer one (perL), may also exhibit altered responses to ethanol due to their intrinsic circadian differences. In this study, we tested the initial sensitivity and tolerance of ethanol exposure on Canton-S, perS, and perL, and then measured their Alcohol Dehydrogenase (ADH) and body ethanol levels. We showed that perL flies had slower sedation rate, longer recovery from ethanol sedation, and generated higher tolerance for sedation upon repeated ethanol exposure compared to Canton-S wild-type flies. Furthermore, perL flies had lower ADH activity and had a slower ethanol clearance compared to wild-type flies. The findings of this study suggest that period mutations influence ethanol induced behavior and ethanol metabolism in Drosophila and that flies with longer circadian periods are more sensitive to ethanol exposure. 
26802541	The goal of this study was to characterize the light-dependent regulation of state transitions in gymnosperms. Two species of conifer were examined: eastern white pine (Pinus strobus L.) and white spruce [Picea glauca (Moench) Voss], as well as the angiosperm pumpkin (Cucurbita pepo L. subsp. pepo). Both diurnal time courses in the field and manipulated light experiments in growth chambers were conducted. Results from chlorophyll fluorescence analysis indicated that pumpkin was able to use a larger fraction of absorbed light to drive photochemistry and retain a lower reduction state at a given light intensity relative to the conifers. Results from western blots using anti-phosphothreonine demonstrate that in field conditions, conifers maintained higher light-harvesting complex II (LHCII) phosphorylation than pumpkin; however, this was likely due to a more variable light environment. Manipulated light experiments showed that general patterns of light-dependent LHCII phosphorylation were similar in conifers and pumpkin, with low levels of LHCII phosphorylation occurring in darkness and maximal levels occurring in low light conditions. However, high light-dependent dephosphorylation of LHCIII appears to be regulated differently in conifers, with conifers maintaining phosphorylation of LHCII proteins at higher excitation pressure compared with pumpkin. Additionally, spruce needles maintained relatively high phosphorylation of LHCII even in very high light conditions. Our results suggest that this difference in dephosphorylation of LHCII may be due to differences in the stromal redox status in spruce relative to pine and pumpkin. 
26802285	Abnormal circadian rhythm of blood pressure (BP) is closely related to target organ damage in hypertension. However, the association between abnormal circadian rhythm of BP and renal injury is not clear. We investigated whether renal injury is associated with nocturnal BP and circadian rhythm of BP in Chinese IgAN patients.Clinic and 24 h ambulatory BP monitoring data were obtained from 330 Chinese IgAN patients with mean 24 h BP < 130/80 and mean daytime BP < 135/85 mmHg. Renal histopathological injury was determined according to the Oxford classification of IgAN.	Among the 330 IgAN subjects, 35.8% suffered from nocturnal hypertension, 61.5% had abnormal circadian BP, and 27% had nocturnal hypertension with a nondipping pattern. Compared with nocturnal normotensive patients, patients with nocturnal hypertension had significantly higher levels of blood cystatin C, blood uric acid, and lower estimated glomerular filtration rate (eGFR), and significantly a higher mean renal tissue injury score. The nondipping hypertensive group had significantly higher nocturnal diastolic and systolic BP, blood uric acid, and glomerulosclerosis rates, whereas eGFR was lower. In nondipping hypertensive patients, urinary sodium excretion and renal tissue injury scores were significantly higher than dipping patients. Nocturnal hypertension and abnormal circadian BP correlated with renal tissue injury, renal interstitial fibrosis, and aortic arch atherosclerosis.	Abnormal circadian rhythm of BP and nocturnal hypertension are common clinical manifestations in Chinese IgAN patients with normal mean 24 h BP. Abnormal circadian BP and nocturnal hypertension may accelerate IgAN progression by inducing renal dysfunction and histopathological damage.	
26801650	The ventral subparaventricular zone (vSPVZ) receives direct retinal input and influences the daily patterning of activity in rodents, making it a likely candidate for the mediation of acute behavioral responses to light (i.e., masking). We performed chemical lesions aimed at the vSPVZ of diurnal grass rats (Arvicanthis niloticus) using N-methyl-D,L-aspartic acid (NMA), a glutamate agonist. Following NMA lesions, we placed grass rats in various lighting conditions (e.g., 12:12 light-dark, constant dark, constant light); presented a series of light pulses at circadian times (CT) 6, 14, 18, and 22; and placed them in a 7-h ultradian cycle to assess behavioral masking. Extensive bilateral lesions of the vSPVZ disrupted the expression of circadian rhythms of activity and abolished the circadian modulation of masking responses to light, without affecting light-induced masking behavior per se. We also found that in diurnal grass rats, NMA was capable of destroying not only neurons of the vSPVZ but also those of the suprachiasmatic nucleus (SCN), even though excitotoxins have been ineffective at destroying cells within the SCN of nocturnal rodents. The vulnerability of the grass rat's SCN to NMA toxicity raises the possibility of a difference in density of receptors for glutamate between nocturnal and diurnal species. In cases in which damage extended to the SCN, masking responses to light were present and similar to those displayed by animals with damage restricted to the vSPVZ. Thus, extensive bilateral lesions of the SCN and vSPVZ disrupted the expression of circadian rhythms without affecting acute responses to light in a diurnal species. Our present and previous results suggest that retinorecipient brain areas other than the SCN or vSPVZ, such as the intergeniculate leaflet or olivary pretectal nucleus, may be responsible for the mediation of masking responses to light in the diurnal grass rat. 
26801391	In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings. 
26800549	This paper presents a new system to measure the Intraocular Pressure (IOP) with very high accuracy (0.036 mbar) used for monitoring glaucoma. The system not only monitors the daily variation of the IOP (circadian IOP), but also allows to perform an spectral analysis of the pressure signal generated by the heartbeat (cardiac IOP). The system comprises a piezoresistive pressure sensor, an application-specific integrated circuit (ASIC) to read out the sensor data and an external reader installed on customized glasses. The ASIC readout electronics combines chopping modulation with correlated double sampling (CDS) in order to eliminate both the amplifier offset and the chopper ripple at the sampling frequency. In addition, programmable current sources are used to compensate for the atmospheric pressure ( 800-1200 mbar ) and the circadian component (± 7 mbar) thus allowing to read out the very weak cardiac signals (± 1.6 mbar) with a maximum accuracy of 0.036 mbar.
26799852	By and large, studies have reported moderate contributions of genetic factors to cortisol secreted in the early morning and even smaller estimates later in the day. In contrast, the cortisol awakening response (CAR) has shown much stronger heritability estimates, which prompted the hypothesis that the etiology of cortisol secretion may vary according to the time of day. A direct test of this possibility has, however, not yet been performed.To describe the specific and common etiology of the CAR, awakening level and cortisol change from morning to evening in an age-homogenous sample of twin adolescents.	A total of 592 participants of the Québec Newborn Twin Study, a population-based 1995-1998 cohort of families with twins in Canada, have collected saliva at awakening, 30 min later, at the end of afternoon and in the evening over four collection days.	Multivariate Cholesky models showed both specific and common sources of variance between the CAR, awakening and cortisol diurnal change. The CAR had the strongest heritability estimates, which, for the most part, did not overlap with the other indicators. Conversely, similar magnitudes of genetic and environmental contributions were detected at awakening and for diurnal change, which partially overlapped.	Our study unraveled differences between the latent etiologies of the CAR and the rest of the diurnal cycle, which may contribute to identify regulatory genes and environments and detangle how these indicators each relate to physical and mental health.	
26799851	Circadian rhythms are endogenous cycles of physiology and behavior that align with the daily rotation of the planet and resulting light-dark cycle. The circadian system ensures homeostatic balance and regulates many aspects of physiology, including the stress response and susceptibility to and/or severity of stress-related sequelae. Both acute and chronic stressors amplify neuroinflammatory responses to a subsequent immune challenge, however it is not known whether circadian timing of the stressor regulates the priming response. Here, we test whether stress-induced neuroinflammatory priming is regulated by the circadian system. As has been previously shown, exposure to 100 inescapable tails shocks (IS) increased hippocampal cytokines following a subsequent inflammatory challenge. However, this effect was limited to animals that experienced the stressor during the light phase. Rats exposed to stress during the dark phase did not alter inflammatory potential following lipopolysaccharide (LPS) challenge. To determine whether microglia might be involved in diurnal differences in neuroinflammatory priming, microglia were isolated 24h after stress that occurred either during the middle of the light or dark phase. Only microglia isolated from animals stressed during the light phase demonstrated an exaggerated inflammatory response when treated ex vivo with LPS. To determine possible circadian dependency of microglia responsiveness to glucocorticoids - the likely proximal mediator for stress associated neuroinflammatory priming - microglia were isolated during the middle of the light or dark phase and treated ex vivo with corticosterone. Glucocorticoids treatment downregulated CX3CR1 and CD200R, two genes involved in microglial inflammatory "off" signaling; however, there was no effect of time of day on expression of either gene. Importantly, while absolute concentrations of corticosterone were comparable following IS during the light and dark phase, the magnitude of change in corticosterone was greater during the light phase. This work highlights the importance of studying circadian rhythms to elucidate biological mechanisms of stress. 
26799849	Salivary alpha-amylase (sAA) is a stress-sensitive biomarker the shows promise as an indirect proxy of sympathetic-adrenal-medullary axis activities that are otherwise difficult to discern non-invasively. This comprehensive study investigated diurnal sAA in association with numerous psychosocial characteristics related to mental health, work stress, and non-work stress. Participants included 395 workers (56.1% women, age: M=41.3, SD=10.81) from across 34 distinct workplaces. Diurnal sAA was sampled over two non-consecutive work days at awakening, 30 min after awakening, 14h00, 16h00, and bedtime. Well-validated psychometrics and survey items were used to measure mental health (psychological distress, depression, burnout, work characteristics) (task design, demands, social relations, gratifications), and non-work characteristics (marital/parental status, economic statuses, marital and parental stress, work-family conflicts). Preliminary results revealed that men showed occasionally higher sAA concentrations than women. Multilevel regressions were used to analyze sAA concentrations nested according to levels (i) for each time-point, (ii) between workers, and (iii) across workplaces while covarying for time of awakening, sex, age, cigarette smoking, alcohol consumption, regular physical activity, psychotropic drug use, and body mass index. Main results revealed that psychological demands, support from colleagues, interpersonal conflicts, job recognition and job insecurity appear to be associated with diurnal sAA, while non-work factors did not. Our findings showing a distinct diurnal profile for sAA replicate and expand those of Nater et al. (2007, Psychoneuroendocrinology 32, 392-401), providing further evidence that sAA is associated to subjective psychosocial factors.
26799153	Distinguishing pediatric bipolar disorder (BD) from attention-deficit hyperactivity disorder (ADHD) can be challenging. Hyperactivity is a core feature of both disorders, but severely disturbed sleep and circadian dysregulation are more characteristic of BD, at least in adults. We tested the hypothesis that objective measures of activity, sleep, and circadian rhythms would help differentiate pediatric subjects with BD from ADHD and typically developing controls.Unmedicated youths (N = 155, 97 males, age 5-18) were diagnosed using DSM-IV criteria with Kiddie-SADS PL/E. BD youths (n = 48) were compared to typically developing controls (n = 42) and children with ADHD (n = 44) or ADHD plus comorbid depressive disorders (n = 21). Three-to-five days of minute-to-minute belt-worn actigraph data (Ambulatory Monitoring Inc.), collected during the school week, were processed to yield 28 metrics per subject, and assessed for group differences with analysis of covariance. Cross-validated machine learning algorithms were used to determine the predictive accuracy of a four-parameter model, with measures reflecting sleep, hyperactivity, and circadian dysregulation, plus Indic's bipolar vulnerability index (VI).	There were prominent group differences in several activity measures, notably mean 5 lowest hours of activity, skewness of diurnal activity, relative circadian amplitude, and VI. A predictive support vector machine model discriminated bipolar from non-bipolar with mean accuracy of 83.1 ± 5.4%, ROC area of 0.781 ± 0.071, kappa of 0.587 ± 0.136, specificity of 91.7 ± 5.3%, and sensitivity of 64.4 ± 13.6%.	Objective measures of sleep, circadian rhythmicity, and hyperactivity were abnormal in BD. Wearable sensor technology may provide bio-behavioral markers that can help differentiate children with BD from ADHD and healthy controls.	
26799067	Saliva is a biological fluid suitable for biomarker analysis, and differences in the salivary microbiota in oral health and disease have been reported. For such comparative analyses, time of sampling is critical since the bacterial composition may vary throughout the day, i.e., diurnal variation. The purpose of this study is to compare the salivary microbiome over time to determine the optimal time for sampling.Stimulated saliva samples were collected from 5 orally healthy individuals in 4 h intervals for 24 h, and collection was repeated 7 days later (number of samples per person, n = 12, total number of samples, n = 60). Salivary microbiota was analyzed using the Human Oral Microbe Identification using Next Generation Sequencing (HOMINGS), and statistical analysis was performed using the Kruskal-Wallis test with Benjamini-Hochberg's correction for multiple comparisons, cluster analysis, principal component analysis and correspondence analysis.	From a total of 60 saliva samples, 477 probe targets were collectively identified with a mean number of probes per sample of 207 (range: 153-307). Little or no variation in microbial profiles within subjects was observed over time.	Although there was considerable variation between subjects, microbial profiles within subjects were stable throughout a 24 hour period and after 1 week. Since there is little or no evidence of diurnal variation of the salivary microbiome, time of sampling of saliva is not critical for perturbation or other microbial studies.	
26797926	Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors RORs are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of RORs in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion (MI/R) injury pathogenesis. RORα and RORγ subtypes were detected in the adult mouse heart, and RORα but not RORγ was downregulated after MI/R. To determine the pathological consequence of MI/R-induced reduction of RORα, we subjected RORα-deficient staggerer mice and wild-type (WT) littermates to MI/R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, RORα deficiency promoted MI/R-induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, RORα deficiency augmented MI/R-induced oxidative/nitrative stress. Given the emerging evidence of RORα as an essential melatonin effects mediator, we further investigated the RORα roles in melatonin-exerted cardioprotection, in particular against MI/R injury, which was significantly attenuated in RORα-deficient mice, but negligibly affected by cardiac-specific silencing of RORγ. Finally, to determine cell type-specific effects of RORα, we generated mice with cardiomyocyte-specific RORα overexpression and they were less vulnerable to MI/R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor RORα is a novel endogenous protective receptor against MI/R injury and an important mediator of melatonin-exerted cardioprotection; melatonin-RORα axis signaling thus appears important in protection against ischemic heart injury. 
26797895	Population structure is a potential problem when testing for adaptive phenotypic differences among populations. The observed phenotypic differences among populations can simply be due to genetic drift, and if the genetic distance between them is not considered, the differentiation may be falsely interpreted as adaptive. Conversely, adaptive and demographic processes might have been tightly associated and correcting for the population structure may lead to false negatives. Here, we evaluated this problem in the cosmopolitan weed Capsella bursa-pastoris. We used RNA-Seq to analyse gene expression differences among 24 accessions, which belonged to a much larger group that had been previously characterized for flowering time and circadian rhythm and were genotyped using genotyping-by-sequencing (GBS) technique. We found that clustering of accessions for gene expression retrieved the same three clusters that were obtained with GBS data previously, namely Europe, the Middle East and Asia. Moreover, the three groups were also differentiated for both flowering time and circadian rhythm variation. Correction for population genetic structure when analysing differential gene expression analysis removed all differences among the three groups. This may suggest that most differences are neutral and simply reflect population history. However, geographical variation in flowering time and circadian rhythm indicated that the distribution of adaptive traits might be confounded by population structure. To bypass this confounding effect, we compared gene expression differentiation between flowering ecotypes within the genetic groups. Among the differentially expressed genes, FLOWERING LOCUS C was the strongest candidate for local adaptation in regulation of flowering time.
26797483	A 50-year-old man was diagnosed with Parkinson's disease at the age of 43 years. The patient was hospitalized because of frozen gait and tendency to fall and showed abnormal postures of marked antecollis and stooped posture. The angle of the abnormal posture dramatically fluctuated, and the fluctuation coincided with the motor symptoms over the course of a 24-hour period. Treatment with rotigotine was started, and diurnal fluctuations in the gait disorder and abnormal posture were recorded. The time recorded in the Timed Up & Go test decreased after treatment with rotigotine in a dose-dependent manner, particularly early in the morning. The angle of the abnormal posture improved with a 4 mg/24 hr dose of rotigotine but worsened with a dose of 8 mg/24 hr. Because abnormal posture is a known side effect of dopamine agonists such as rotigotine, it is possible that high-dose rotigotine worsened the abnormal posture, whereas the low-dose improved the abnormal posture because of undertreatment. This case highlights the importance of observing the diurnal fluctuation in abnormal posture for developing a strategy for the treatment of Parkinson's disease.
26797245	Serotonin leads to reduced food intake and satiety. Disrupted circadian rhythms lead to hyperphagia and obesity. The serotonergic and circadian systems are intertwined, as the central brain clock receives direct serotonergic innervation and, in turn, makes polysynaptic output back to serotonergic nuclei. Our objective was to test the hypothesis that peripherally serotonin alters circadian rhythms leading to a shift towards fat synthesis and weight gain. We studied the effect of serotonin and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on the circadian clock and metabolic gene and protein expression in mouse liver, muscle and white adipose tissue (WAT) and cell culture. We found that serotonin and/or the SSRI fluvoxamine led to fat accumulation in mouse liver and hepatocytes by shifting metabolism towards fatty acid synthesis mainly through low average levels of phosphorylated acetyl CoA carboxylase (pACC) and phosphorylated protein phosphatase 2A (pPP2A). This shift towards fat synthesis was also observed in adipose tissue. Muscle cells were only slightly affected metabolically by serotonin or fluvoxamine. In conclusion, although centrally it leads to increased satiety, in peripheral tissues, such as the liver and WAT, serotonin induces fat accumulation. 
26797126	Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found thatIrp2mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCK(Δ19)) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor. 
26795436	Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122 ± 2; GR 119 ± 2; control-OVX 116 ± 3; GR-OVX 126 ± 3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23 ± 7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40 ± 25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension.
26795189	The present study aimed to examine diurnal variation of the diving bradycardia responses on the same day.Eighteen young men (age 26 ± 2 years; height 174.2 ± 6.0 cm; body mass 70.2 ± 8.1 kg; body fat 18.0 ± 3.8 %; mean ± standard deviation) participated in this study. Oral temperature, heart rate variability (HRV) from 5-min of electrocardiogram data, and diving bradycardia responses were measured at 0900, 1300, and 1700 hours daily. All participants performed diving reflex tests twice in the sitting position with the face immersed in cold water (1.9-3.1 °C) and apnea at midinspiration for a minimum of 30 s and as long as possible, in consecutive order.	Oral temperature was found to be less in the morning (0900) than in the afternoon (1300) and evening (1700). In the frequency domain parameters of heart rate variability, the natural logarithms of high-frequency power were higher in the morning than in the evening. All participants showed bradycardia response to the two diving reflex tests. The peak values of R-R interval during the diving reflex test both for as long as possible and 30 s were longer in the morning than in the afternoon and evening.	Our results indicated that the maximal bradycardia during the diving reflex test exhibits a diurnal variation, with peak levels at morning and gradual decrease towards the evening. The HRV indexes show the same variation.	
26794149	Many of the elderly Kazakhs have been found to exhibit non-dipping blood pressure variations (BPV). Such variations are seen in both normotensive and hypertensive Kazakhs. The purpose of this study was (1) to determine whether middle-aged Kazakhs also include large numbers of non-dippers, (2) to compare the characteristics of non-dipping and dipping, and (3) to clarify the mechanisms responsible for non-dipping type BPV by examining the autonomic nervous activity and physical activity. We performed ambulatory blood pressure (BP) monitoring. The subjects were divided into two groups (dipping and non-dipping type). We monitored the subjects' physical activity with accelerometry and assessed their autonomic nerve activity by performing a frequency domain analysis of their heart rate variability (HRV). The power spectral density (PSD) of the HRV was calculated using fast Fourier transformation. We analyzed the systolic blood pressure (SBP) variations with the maximum entropy method (MEM). The dippers and non-dippers accounted for 48% and 52% of the subjects, respectively. MEM analysis revealed that the SBP variations of the non-dippers exhibited a 24 hour periodicity with a very weak PSD as well as an ultradian periodicity. The non-dippers exhibited higher low-frequency/high-frequency (LF/HF) ratio and lower HF/(LF + HF) ratios than the dippers, particularly during the nighttime. In addition, the non-dippers performed less physical activity than the dippers. These differences in cardiac autonomic function and physical activity might contribute to the generation of a weak circadian rhythm in SBP, and thus, ultimately lead to the non-dipping SBP variations observed in non-dipper Kazakhs. 
26793210	Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule with pleiotropic actions in different organisms. It performs many important functions in human, animals, and plants; these range from regulating circadian rhythms in animals to controlling senescence in plants. In this review, we summarize the available information regarding the presence of melatonin in different plant species, along with highlighting its biosynthesis and mechanisms of action. We also collected the available information on the effects of melatonin application on commercially important crops to improve their growth and development. Additionally, we have identified many new aspects where melatonin may have possible roles in plants, for example, its function in improving the storage life and quality of fruits and vegetables, its role in vascular reconnection during the grafting process and nutrient uptake from roots by modifying root architecture. Another potentially important aspect is the production of melatonin-rich food crops (cereals, fruits, and vegetables) through combination of conventional and modern breeding approaches, to increase plant resistance against biotic and abiotic stress, leading to improved crop yields, and the nutraceutical value of produce to solve food security issues. 
26793129	Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward-related behavior. 
26793115	Circadian rhythms are oscillations in behavior, metabolism and physiology that have a period close to 24 h. These rhythms are controlled by an internal pacemaker that evolved under strong selective pressures imposed by environmental cyclical changes, mainly of light and temperature. The molecular nature of the circadian pacemaker was extensively studied in a number of organisms under controlled laboratory conditions. But although these studies were fundamental to our understanding of the circadian clock, most of the environmental conditions used resembled rather crudely the relatively constant situation at lower latitudes. At higher latitudes light-dark and temperature cycles vary considerably across different seasons, with summers having long and hot days and winters short and cold ones. Considering these differences and other external cues, such as moonlight, recent studies in more natural and semi-natural situations revealed unexpected features at both molecular and behavioral levels, highlighting the dramatic influence of multiple environmental variables in the molecular clockwork. This emphasizes the importance of studying the circadian clock in the wild, where seasonal environmental changes fine-tune the underlying circadian mechanism, affecting population dynamics and impacting the geographical variation in clock genes. Indeed, latitudinal clines in clock gene frequencies suggest that natural selection and demography shape the circadian clock over wide geographical ranges. In this review we will discuss the recent advances in understanding the molecular underpinnings of the circadian clock, how it resonates with the surrounding variables (both in the laboratory and in semi-natural conditions) and its impact on population dynamics and evolution. In addition, we will elaborate on how next-generation sequencing technologies will complement classical reductionist approaches by identifying causal variants in natural populations that will link genetic variation to circadian phenotypes, illuminating how the circadian clock functions in the real world. 
26792047	Lithium is the first line treatment for maintenance treatment of bipolar disorder. Among the long term adverse effects, weight gain is likely to affect a subset of patients. There is no specific guideline for the treatment of lithium-induced weight gain. We report a young male with bipolar disorder who had significant weight gain with lithium (25 kg), which responded to metformin treatment at 500 mg twice daily. The proposed mechanism of weight lowering effect of metformin includes changes in hypothalamic physiology, including leptin and insulin sensitivity, as well as circadian rhythm changes affecting food intake, regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. 
26791489	The pineal glands regulate circadian rhythm through the synthesis and secretion of melatonin. The stimulation of nicotinic acetylcholine receptor due to parasympathetic nerve activity causes an increase in intracellular Ca(2+) concentration and eventually downregulates melatonin production. Our previous report shows that rat pinealocytes have spontaneous and nicotine-induced Ca(2+) oscillations that are evoked by membrane depolarization followed by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs). These Ca(2+) oscillations are supposed to contribute to the inhibitory mechanism of melatonin secretion. Here we examined the involvement of large-conductance Ca(2+)-activated K(+) (BKCa) channel conductance on the regulation of Ca(2+) oscillation and melatonin production in rat pinealocytes. Spontaneous Ca(2+) oscillations were markedly enhanced by BKCa channel blockers (1 μM paxilline or 100 nM iberiotoxin). Nicotine (100 μM)-induced Ca(2+) oscillations were also augmented by paxilline. In contrast, spontaneous Ca(2+) oscillations were abolished by BKCa channel opener [3 μM 12,14-dichlorodehydroabietic acid (diCl-DHAA)]. Under whole cell voltage-clamp configurations, depolarization-elicited outward currents were significantly activated by diCl-DHAA and blocked by paxilline. Expression analyses revealed that the α and β3 subunits of BKCa channel were highly expressed in rat pinealocytes. Importantly, the activity of BKCa channels modulated melatonin secretion from whole pineal gland of the rat. Taken together, BKCa channel activation attenuates these Ca(2+) oscillations due to depolarization-synchronized Ca(2+) influx through VDCCs and results in a recovery of reduced melatonin secretion during parasympathetic nerve activity. BKCa channels may play a physiological role for melatonin production via a negative-feedback mechanism. 
26791158	Defective control of endogenous glucose production is an important factor responsible for hyperglycaemia in the diabetic individual. During the past decade, progressively more evidence has appeared indicating a strong and potentially causal relationship between disturbances of the circadian system and defects of metabolic regulation, including glucose metabolism. The detrimental effects of disturbed circadian rhythms may have their origin in disturbances of the molecular clock mechanisms in peripheral organs, such as the pancreas and liver, or in the central brain clock in the hypothalamic suprachiasmatic nuclei (SCN). To assess the role of SCN output per se on glucose metabolism, we investigated (i) the effect of several SCN neurotransmitters on endogenous glucose production and (ii) the effect of SCN neuronal activity on hepatic and systemic insulin sensitivity. We show that silencing of SCN neuronal activity results in decreased hepatic insulin sensitivity and increased peripheral insulin sensitivity. Furthermore, both oxytocin neurones in the paraventricular nucleus of the hypothalamus (PVN) and orexin neurones in the lateral hypothalamus may be important targets for the SCN control of glucose metabolism. These data further highlight the role of the central clock in the pathophysiology of insulin resistance. 
26790888	Fewer than 200 Indo-Pacific humpback dolphins (Sousa chinensis) occur in Hong Kong waters (though these are part of a much larger population in the Pearl River Estuary), with a decrease in the past about 10 years. They have partially overlapping individual ranges (mean=100km(2)), and two partially overlapping communities. Seasonal occurrence is higher in June-November than December-May, approximate wet and dry monsoon seasons, respectively. Group sizes tend to average three dolphins, a decrease from the past decade. Feeding often occurs in abruptly changing water depths and off rocky natural shores. The area immediately north of Hong Kong International Airport is largely used for travelling between locations to the west, east and further north. The area around Lung Kwu Chau Island in northwest Hong Kong is a "hot spot" for foraging and socializing. The area off Fan Lau, southwest Lantau Island, is largely used for foraging. A former foraging "hot spot" was located around the Brothers Islands east of the airport, now reduced, possibly due to increases in high-speed ferries (HSFs) and other activities. Sound recordings of dolphins from bottom-mounted hydrophones suggest that northwestern Hong Kong waters are used more at night than in daytime. Sexual activity and calving occur throughout the year, with a peak in late spring to autumn (wet monsoon season). Humpback dolphins communicate acoustically with each other and probably passively listen to prey in murky waters, and anthropogenic noises may be masking communication and affecting prey location. Increasing sounds of shipping, HSFs and industrial activities are likely to alter dolphin habitat use patterns and overall behaviours beyond the present already affected status. 
26786187	The current study was designed to determine if a relationship exists between acute and chronic blood pressure responses to aerobic exercise in pre-dialysis patients.Pre-dialysis kidney patients attended four sessions before being randomized to the treatment (n = 25) or control group (n = 21). In session 1, resting blood pressure was recorded, and these measurements were repeated during the second visit when peak oxygen uptake (VO2peak ) was assessed. In the third and fourth sessions, blood pressures were taken prior to a 40 min walk or period of seated rest. After the 40 min walk or seated rest, blood pressures were monitored for 60 min in the laboratory and for the subsequent 24 h. After session 4, subjects in the treatment group trained aerobically at a moderate intensity, three times per week for 16 weeks. Control subjects were asked to be sedentary. All measurements were repeated after 16 weeks of training or sedentary living.	Training increased VO2peak (mL/kg per minute) in the treatment group (baseline 19.6 ± 6.7 vs 21.2 ± 7.7, P < 0.05), with no change in the control (18.0 ± 6.0 vs 17.5 ± 5.7) group. Post-exercise hypotension occurred at baseline prior to training but was unaffected by 16 weeks of training.	Post-exercise hypotension occurs in pre-dialysis patients following aerobic exercise, but short-term moderate-intensity continuous aerobic training has no effect upon this response. There seems to be no relationship between the acute and chronic blood pressure responses to exercise in pre-dialysis kidney patients.	
26785837	The aim of this work was to study the sleep characteristics, blood pressure (BP) and heart rate (HR) of the police officers working during out-of-phase (OP) and in-phase (IP) duty schedules with respect to their chronotypes. Adult male and female police officers (n = 85) were asked to answer Hindi/English version of different questionnaires to assess their chronotype (morningness-eveningness questionnaire; MEQ), PSQI scores (Pittsburgh sleep quality index), daytime sleepiness (Epworth sleepiness scale, ESS) and fatigue levels (fatigue severity scale, FSS) and fill a sleep log. Based on their PSQI scores, the participating subjects (n = 85) were divided into two categories: good sleepers (58/85) and poor sleepers (27/85). Of these 85 subjects, 23 subjects (good sleepers n = 13; poor sleepers n = 10) volunteered for the next part of the study. At the beginning of the study, the existing duty schedule of these subjects was OP and lasted for 4 days (OP1). Thereafter, they were allotted their preferred (IP) duty schedule for 4 days, followed by OP2 for further 4 days. Over the 12-day period, subjects were monitored for their BP and sleep-wake cycle. Results showed that the poor sleepers improved their sleep quality and HR during IP duty schedule; however, good sleepers were not affected significantly. 
26785766	Dexras1 has been shown to exhibit clock-dependent rhythm in mice suprachiasmatic nucleus (SCN), and its genetic deletion modulates circadian responses to photic and nonphotic cues. We show that the rhythmic expression of Dexras1 mRNA and protein in rat SCN already oscillates with low amplitude at postnatal day 3 and can be detected as early as embryonic day 20. In contrast, its expression in peripheral tissues is not rhythmic in adult rats either. The Dexras1 protein is expressed predominantly in the dorsomedial part of the SCN and the light pulse has only a limited effect on its expression. Our data provide the descriptive basis for speculation about the Dexras1 involvement in the rat circadian physiology. 
26785726	Various characteristics of the sleep-wake cycle can determine the success or failure of individual adjustment to certain temporal conditions of the today's society. However, it remains to be explored how many such characteristics can be self-assessed and how they are inter-related one to another. The aim of the present report was to apply a three-dimensional structural representation of the sleep-wake adaptability in the form of "rugby cake" (scalene or triaxial ellipsoid) to explain the results of analysis of the pattern of correlations of the responses to the initial 320-item list of a new inventory with scores on the six scales designed for multidimensional self-assessment of the sleep-wake adaptability (Morning and Evening Lateness, Anytime and Nighttime Sleepability, and Anytime and Daytime Wakeability). The results obtained for sample consisting of 149 respondents were confirmed by the results of similar analysis of earlier collected responses of 139 respondents to the same list of 320 items and responses of 1213 respondents to the 72 items of one of the earlier established questionnaire tools. Empirical evidence was provided in support of the model-driven prediction of the possibility to identify items linked to as many as 36 narrow (6 core and 30 mixed) adaptabilities of the sleep-wake cycle. The results enabled the selection of 168 items for self-assessment of all these adaptabilities predicted by the rugby cake model. 
26785632	Alzheimer's patients suffer from circadian dysregulation. The aim of this study was to examine the evolution of balance control and gait at different times of the day (11:00, 14:00, 18:00) in order to identify whether Alzheimer's patients were more likely to fall at certain periods of the day. Spatio-temporal parameters of centre of foot pressure displacements were measured with a force platform and spatio-temporal parameters of walking were evaluated with a gait analysis device. The results highlighted that balance control was worse in the evening and the afternoon than in the morning. Furthermore, the walking speed was faster and support duration, swing duration and cycle duration were shorter in the evening than in the morning and afternoon. The combined analysis of balance control and gait parameters revealed that balance control and walking are concomitantly altered in the evening which increases the fall risk in the evening, in comparison with the morning, for Alzheimer's patients. 
26784927	Specific neurons in the hypothalamus are regulated by peripheral hormones and nutrients to maintain proper metabolic control. It is unclear if nutrients can directly control clock gene expression. We have therefore utilized the immortalized, hypothalamic cell line mHypoE-37, which exhibits robust circadian rhythms of core clock genes. mHypoE-37 neurons were exposed to 0.5 or 5.5 mM glucose, comparable to physiological levels in the brain. Per2 and Bmal1 mRNAs were assessed every 3 hours over 36 hours. Incubation with 5.5 mM glucose significantly shortened the period and delayed the phase of Per2 mRNA levels, but had no effect on Bmal1. Glucose had no significant effect on phospho-GSK3β, whereas AMPK phosphorylation was altered. Thus, the AMPK inhibitor Compound C was utilized, and mRNA levels of Per2, Bmal1, Cryptochrome1 (Cry1), agouti-related peptide (AgRP), carnitine palmitoyltransferase 1C (Cpt1c), and O-linked N-acetylglucosamine transferase (Ogt) were measured. Remarkably, Compound C dramatically reduced transcript levels of Per2, Bmal1, Cry1, and AgRP, but not Cpt1c or Ogt. Because AMPK was not inhibited at the same time or concentrations as the clock genes, we suggest that the effect of Compound C on gene expression occurs through an AMPK-independent mechanism. The consequences of inhibition of the rhythmic expression of clock genes, and in turn downstream metabolic mediators, such as AgRP, could have detrimental effects on overall metabolic processes. Importantly, the effects of the most commonly used AMPK inhibitor Compound C should be interpreted with caution, considering its role in AMPK-independent repression of specific genes, and especially clock gene rhythm dysregulation. 
26782716	The physiology and metabolism of poikilothermic insects are under the control of environmental temperature. Temperature is the primary cue for the circadian rhythm. Reports on the timing mechanisms of temperature in lepidopterans are limited. This study used Bombyx mori BmN ovarian cells to investigate the effect of temperature on expression of the main circadian clock genes in a negative feedback loop. A 37°C, 30-min high-temperature stimulation induced transcription of the circadian clock genes Cry1, Cry2, Per, and Tim. The gene expression profiles showed rhythmic oscillations, with shortened oscillatory periods for Cry1 and altered oscillatory phases for Cry1 and Per. Cyclical increases in temperature of 2°C starting at 26°C, 5°C starting at 20 or 25°C, or 10°C starting at 20°C induced cyclical changes in expression and protein from the four circadian clock genes. Cyclical temperature changes with a difference of 10°C had the most influence. In conclusion, cyclical changes in temperature with differences from 2 to 10°C reset and synchronized the circadian clock of silkworm BmN cells. Transcription of the genes for and protein from Cry2 and Per showed a better reset and synchronization with cyclical temperature changes. 
26781276	Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. 

26780675	Pharmacokinetic-pharmacodynamic (PKPD) modelling can improve safety assessment, but few PKPD models describing drug-induced QRS and PR prolongations have been published. This investigation aims to develop and evaluate PKPD models for describing QRS and PR effects in routine safety studies.Exposure and telemetry data from safety pharmacology studies in conscious beagle dogs were acquired. Mixed effects baseline and PK-QRS/PR models were developed for the anti-arrhythmic compounds AZD1305, flecainide, quinidine and verapamil and the anti-muscarinic compounds AZD8683 and AZD9164. RR interval correction and circadian rhythms were investigated for predicting baseline variability. Individual PK predictions were used to drive the pharmacological effects evaluating linear and non-linear direct and effect compartment models.	Conduction slowing induced by the tested anti-arrhythmics was direct and proportional at low exposures, whilst time delays and non-linear effects were evident for the tested anti-muscarinics. AZD1305, flecainide and quinidine induced QRS widening with 4.2, 10 and 5.6% μM(-1) unbound drug. AZD1305 and flecainide also prolonged PR with 13.5 and 11.5% μM(-1). PR prolongations induced by the anti-muscarinics and verapamil were best described by Emax models with maximal effects ranging from 55 to 95%. RR interval correction and circadian rhythm improved PR but not QRS modelling. However, circadian rhythm had minor impact on estimated drug effects.	Baseline and drug-induced effects on QRS and PR intervals can be effectively described with PKPD models using routine data, providing quantitative safety information to support drug discovery and development.	
26780151	Mammals typically display alternating active and resting phases and, in most species, these rhythms follow a circadian pattern. The active and resting phases often are accompanied by corresponding physiological changes. In humans, blood pressure decreases during the resting phase of the activity cycle, and the magnitude of that "nocturnal dipping" has been used to stratify patients according to the risk for cardiovascular disease. However, in contrast to most mammals, prairie voles (Microtus ochrogaster) have periods of activity and rest that follow an ultradian rhythm with period lengths significantly <24h. While rhythmic changes in blood pressure across a circadian activity cycle have been well-documented, blood pressure patterns in species that display ultradian rhythms in activity are less well-studied. In the current study, we implanted pressure-sensitive radiotelemetry devices in male prairie voles and recorded activity, mean arterial pressure (MAP), and heart rate (HR) continuously for 3days. Visualization of the ultradian rhythms was enhanced using a 1h running average to filter the dataset. Positive correlations were found between activity and MAP and between activity and HR. During the inactive period of the ultradian cycle, blood pressure decreased by about 15%, which parallels the nocturnal dipping pattern seen in healthy humans. Further, the duration of inactivity did not affect any of the cardiovascular measures, so the differences in blood pressure values between the active and inactive periods are likely driven by ultradian oscillations in hormones and autonomic function. Finally, specific behavioral patterns also were examined. Both the instrumented animal and his non-instrumented cagemate appeared to show synchronized activity patterns, with both animals displaying sleep-like behavior for more than 90% of the inactive period. We propose that the prairie vole ultradian rhythm in blood pressure is an analogue for circadian blood pressure variability and can be used to study the long-term effects of commonly prescribed drugs on blood pressure dipping. 
26779042	Drug addiction is a brain disease involving alterations in anatomy and functional neural communication. Drug intake and toxicity show daily rhythms in both humans and rodents. Evidence concerning the role of clock genes in drug intake has been previously reported. However, the implication of a timekeeping brain locus is much less known. The epithalamic lateral habenula (LHb) is now emerging as a key nucleus in drug intake and addiction. This brain structure modulates the activity of dopaminergic neurons from the ventral tegmental area, a central part of the reward system. Moreover, the LHb has circadian properties: LHb cellular activity (i.e., firing rate and clock genes expression) oscillates in a 24-h range, and the nucleus is affected by photic stimulation and has anatomical connections with the main circadian pacemaker, the suprachiasmatic nucleus. Here, we describe the current insights on the role of the LHb as a circadian oscillator and its possible implications on the rhythmic regulation of the dopaminergic activity and drug intake. These data could inspire new strategies to treat drug addiction, considering circadian timing as a principal factor. 
26778372	Comprehensive cardiovascular assessment in conscious rodents by utilizing telemetry has been limited by the restriction of current devices to one pressure channel. The purpose of this study was to test and validate a dual pressure transmitter that allows the simultaneous measurement of arterial pressure (AP) and left ventricular pressure (LVP) in conscious freely moving rats. Six rats were surgically implanted with dual pressure transmitters. Baseline hemodynamics and circadian rhythm were observed to return within 7days. AP, heart rate (HR), LVP and indices of left ventricular contractility were stable and demonstrated a prominent circadian rhythm over a two-week period of uninterrupted recordings. Administration of the vasodilator nifedipine produced the anticipated dose-dependent decrease in AP which was accompanied by a baroreflex mediated increase in HR and cardiac contractility. The negative inotrope verapamil produced the expected dose-dependent decreases in AP and cardiac contractility. Finally, a terminal validation of the dual pressure transmitter was performed under anesthesia by measuring AP and LVP simultaneously via telemetry and from a fluid filled arterial catheter and an intraventricular Millar catheter, respectively. A range of pressures and cardiac contractility were studied by administering sequential intravenous infusions of the positive inotrope dobutamine followed by verapamil. Linear regression analysis revealed a high level of agreement between pressures measured by the dual pressure transmitter and the exteriorized catheters. Histopathologic analysis of the heart revealed mild peri-catheter fibrosis. In conclusion, the simultaneous measurement of AP and LVP offers the potential for more detailed cardiovascular assessment in conscious rats. 
26778202	Acute and sustained activation of the sympathetic nervous system are clinical hallmarks of both obstructive and central sleep apnea. Conversely, their treatment has been shown to reverse these abnormalities. The objectives of this brief review are to summarize: 1) present knowledge concerning the mechanisms, magnitude and consequences of night- and day-time sympathetic nervous system activation in patients with these sleep-related breathing disorders; and 2) the impact on the sympathetic nervous system and on blood pressure of their specific treatment. 
26778201	Obstructive sleep apnea (OSA) places an enormous pressure load on the cardiovascular system by inducing a temporary blood pressure (BP) surge during apnea episodes. This pressure load is regarded as a potential mechanism of development of cardiovascular diseases such as stroke. Therefore, accurate measurement of such BP surges would be valuable for the risk stratification of OSA patients. Recently we developed a new triggered nocturnal BP monitoring system (TNP) based on oxygen desaturation and have achieved success to detect BP surges with OSA. TNP would be a promising tool for assessment of cardiovascular risks in sleep apnea syndrome. 
26778054	Melatonin is a hormone mainly involved in the regulation of circadian and seasonal rhythms in both invertebrates and vertebrates. Despite the identification of melatonin in many insects, its involvement in the insect seasonal response remains unclear. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for melatonin analysis in aphids (Acyrthosiphon pisum) for the first time. After comparing two different procedures and five extraction solvents, a sample preparation procedure with a mixture of methanol/water (50:50) was selected for melatonin extraction. The method was validated by analyzing melatonin recovery at three spiked concentrations (5, 50 and 100 pg/mg) and showed satisfactory recoveries (75-110%), and good repeatability, expressed as relative standard deviation (<10%). Limits of detection (LOD) and quantitation (LOQ) were 1 pg/mg and 5 pg/mg, respectively. Eight concentration levels were used for constructing the calibration curves which showed good linearity between LOQ and 200 times LOQ. The validated method was successfully applied to 26 aphid samples demonstrating its usefulness for melatonin determination in insects. This is -to our knowledge- the first identification of melatonin in aphids by LC-MS/MS.
26777427	Bright nocturnal light has been shown to suppress melatonin secretion. However, bright light exposure during the day might reduce light-induced melatonin suppression at night. The human circadian system is sensitive to short wavelength light. This study evaluated the preventive effect of different wavelengths of daytime light on light-induced melatonin suppression at night. Twelve male subjects were exposed to various light conditions (dim, white, and bluish white light) between the hours of 09:00 and 10:30 (daytime light conditions). They were then exposed to light (300lx) again between 01:00 and 02:30 (night-time light exposure). Subjects provided saliva samples before (00:55) and after night-time light exposure (02:30). A two-tailed paired t-test yielded significant decrements in melatonin concentrations after night-time light exposure under daytime dim and white light conditions. No significant differences were found in melatonin concentrations between pre- and post-night-time light exposure with bluish-white light. Present findings suggest that daytime blue light exposure has an acute preventive impact on light-induced melatonin suppression in individuals with a general life rhythm (sleep/wake schedule). These findings may be useful for implementing artificial light environments for humans in, for example, hospitals and underground shopping malls to reduce health risks.
26776516	In the core mammalian circadian negative feedback loop, the BMAL1-CLOCK complex activates the transcription of the genes Period (Per) and Cryptochrome (Cry). To close the negative feedback loop, the PER-CRY complex interacts with the BMAL1-CLOCK complex to repress its activity. These two processes are separated temporally to ensure clock function. Here, we show that histone deacetylase 3 (HDAC3) is a critical component of the circadian negative feedback loop by regulating both the activation and repression processes in a deacetylase activity-independent manner. Genetic depletion of Hdac3 results in low-amplitude circadian rhythms and dampened E-box-driven transcription. In subjective morning, HDAC3 is required for the efficient transcriptional activation process by regulating BMAL1 stability. In subjective night, however, HDAC3 blocks FBXL3-mediated CRY1 degradation and strongly promotes BMAL1 and CRY1 association. Therefore, these two opposing but temporally separated roles of HDAC3 in the negative feedback loop provide a mechanism for robust circadian gene expression. 
26776097	Soil temperature cycles are considered to play an important role in the entrainment of circadian clocks of underground insects. However, because of the low conductivity of soil, temperature cycles are gradually dampened and the phase of the temperature cycle is delayed with increasing soil depth. The onion fly, Delia antiqua, pupates at various soil depths, and its eclosion is timed by a circadian clock. This fly is able to compensate for the depth-dependent phase delay of temperature change by advancing the eclosion time with decreasing amplitude of the temperature cycle. Therefore, pupae can eclose at the appropriate time irrespective of their location at any depth. However, the mechanism that regulates eclosion time in response to temperature amplitude is still unknown. To understand whether this mechanism involves the circadian clock or further downstream physiological processes, we examined the expression patterns of period (per), a circadian clock gene, of D. antiqua under temperature cycles that were square wave cycles of 12-h warm phase (W) and 12-h cool phase (C) with the temperature difference of 8 °C (WC 29:21 °C) and 1 °C (WC 25.5:24.5 °C). The phase of oscillation in per expression was found to commence 3.5h earlier under WC 25.5:24.5 °C as compared to WC 29:21 °C. This difference was in close agreement with the eclosion time difference between the two temperature cycles, suggesting that the mechanism that responds to the temperature amplitude involves the circadian clock.
26776072	Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterised by impulsivity, inattention and hyperactivity. Aside from these core psychopathologies, sleep disturbances are found to be highly comorbid with ADHD, and indeed dysregulated sleep may contribute to some of the symptoms of the disorder. It is not clear how sleep disturbances come to be so common in ADHD, but one putative mechanism is through the circadian timekeeping system. This system underpins the generation of near 24-hour rhythms in a host of physiological, behavioural and psychological parameters, and is a key determinant of the sleep/wake cycle. In this paper we review the evidence for sleep and circadian rhythm disturbance in ADHD, examine the possible mechanistic links between these factors and the disorder and discuss future directions through which the circadian clock can be targetted for ADHD symptom relief. 
26775078	There is evidence that a decrease in alertness is associated with a rightward shift of attention. Alertness fluctuates throughout the day and peak times differ between individuals. Some individuals feel most alert in the morning; others in the evening. Our aim was to investigate the influence of morningness/eveningness and time of testing on spatial attention. It was predicted that attention would shift rightwards when individuals were tested at their non-optimal time as compared to tests at peak times. A crowdsourcing internet marketplace, Amazon Mechanical Turk (AMT) was used to collect data. Given questions surrounding the quality of data drawn from such virtual environments, this study also investigated the sensitivity of data to demonstrate known effects from the literature. Five-hundred and thirty right-handed participants took part between 6 am and 11 pm. Participants answered demographic questions, completed a question from the Horne and Östberg Morningness/Eveningness Scale, and performed a spatial attentional task (landmark task). For the landmark task, participants indicated whether the left or right segment of each of 72 pre-bisected lines was longer (longer side counterbalanced). Response bias was calculated by subtracting the 'number of left responses' from the 'number of right responses', and dividing by the number of trials. Negative values indicate a leftward attentional bias, and positive values a rightward bias. Well-supported relationships between variables were reflected in the dataset. Controlling for age, there was a significant interaction between morningness/eveningness and time of testing (morning=6 am-2.30 pm, evening=2.30 pm-11 pm) (p<0.05) such that there was a relative rightward shift of attention from peak to off-peak times of testing for those identifying as morning types, but not evening types. Findings support the utility of crowdsourcing internet marketplaces as data collection vehicles for research. Results also suggest that the deployment of spatial attention is modulated by an individual's peak time (morningness/eveningness) and time of testing.
26774754	Huntington's disease (HD) is an inherited neurodegenerative disorder that is well recognised as producing progressive deterioration of motor function, including dyskinetic movements, as well as deterioration of cognition and ability to carry out activities of daily living. However, individuals with HD commonly suffer from a wide range of additional symptoms, including weight loss and sleep disturbance, possibly due to disruption of circadian rhythmicity. Disrupted circadian rhythms have been reported in mice models of HD and in humans with HD. One way of assessing an individual's circadian rhythmicity in a community setting is to monitor their sleep/wake cycles, and a convenient method for recording periods of wakefulness and sleep is to use accelerometers to discriminate between varied activity levels (including sleep) during daily life. Here we used Actiwatch(®) Activity monitors alongside ambulatory EEG and sleep diaries to record wake/sleep patterns in people with HD and normal volunteers. We report that periods of wakefulness during the night, as detected by activity monitors, agreed poorly with EEG recordings in HD subjects, and unsurprisingly sleep diary findings showed poor agreement with both EEG recordings and activity monitor derived sleep periods. One explanation for this is the occurrence of 'break through' involuntary movements during sleep in the HD patients, which are incorrectly assessed as wakeful periods by the activity monitor algorithms. Thus, care needs to be taken when using activity monitors to assess circadian activity in individuals with movement disorders. 
26774585	Glucose metabolism is subjected to diurnal variation, which might be mediated by alterations in the transcription pattern of clock genes and regulated by hormonal factors, as has been demonstrated for insulin. However, whether also glucagon is involved in the diurnal variation of glucose homeostasis is not known. We therefore examined glucagon secretion after meal ingestion (meal tolerance test) and during hypoglycemia (hyperinsulinemic hypoglycemic clamp at 2.5mmol/L glucose) and in vitro from isolated islets at ZT3 versus ZT15 in normal C57BL/6J mice and, furthermore, glucose levels and the insulin response to meal ingestion were also examined at these time points in glucagon receptor knockout mice (GCGR-/-) and their wildtype (wt) littermates. We found in normal mice that whereas the glucagon response to meal ingestion was not different between ZT3 and ZT15, the glucagon response to hypoglycemia was lower at ZT3 than at ZT15 and glucagon secretion from isolated islets was higher at ZT3 than at ZT15. GCGR-/- mice displayed lower basal glucose, a lower insulin response to meal and a higher insulin sensitivity than wt mice at ZT3 but not at ZT15. We conclude that there is a time dependent variation in glucagon secretion in normal mice, which is dependent both on intraislet and extraislet regulatory mechanisms and that the phenotype characteristics of a lower glucose and reduced insulin response to meal in GCGR-/- mice are evident only during the light phase. These findings suggest that glucagon signaling is a plausible contributor to the diurnal variation in glucose homeostasis which may explain that the phenotype of the GCGR-/- mice is dependent on the time of the day when it is examined. 
26773916	The present study aimed to evaluate the relationship between the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and major depressive episodes in the remote postpartum period.The sample (mean age, 28.0±5.3 years) consisted of 37 depressed postpartum women (DPP), 42 euthymic postpartum women (EPP) and 25 non-postpartum healthy women (HC). Salivary cortisol samples were collected immediately after awakening and 30min, 3 and 12h later, at approximately the sixth month postpartum (mean, 169.6±60.3 days).	Differences in cortisol levels were observed at awakening (DPP<EPP=HC), at 30min (DPP<EPP<HC), at 3h (DPP=EPP<HC) and at 12h (DPP>EPP=HC). The relative increment in the cortisol awakening response (CARi%) was significantly higher in HC (113.5±94.3) than in EPP (63.1±69.8) and DPP (32.2±49.6). The relative reduction in diurnal variation (DVr%) was lower in DPP (56.5±41.8) than in EPP (75.6±22.4) and HC (75.1±13.0).	The main limitation was cortisol collection on a single day and without measurement at midnight.	Our findings suggest that the remote postpartum period involves attenuation of HPA axis reactivity; this dysregulation is more pronounced in the presence of DPP, which is associated with a reduction in cortisol diurnal variation. Abnormalities in the neuroendocrine system related to stress processing, present even several months after delivery, can represent vulnerability to mental disorders. Thus, improvements in the mental health care of postpartum women are needed.	
26773673	The occurrence of seizures in specific types of epilepsies can follow a 24-hour nonuniform or nonrandom pattern. We described the 24-hour pattern of clinical seizures in patients with focal refractory epilepsy who underwent video-electroencephalography monitoring. Only patients who were candidates for epilepsy surgery with an unequivocal seizure focus were included in the study. A total of 544 seizures from 123 consecutive patients were analyzed. Specific time of seizures were distributed along 3- or 4-hour time blocks or bins throughout the 24-hour period. The mean age of the subjects was 37.7 years, with standard deviation of 11.5 years, median of 37. The majority were females (70/56%). The majority of patients had a seizure focus located in the mesial temporal lobe (102/83%) and in the neocortical temporal lobe (13/11%). The remaining patients had a seizure focus located in the extratemporal lobe (8/6%). The most common etiology was mesial temporal sclerosis (86/69.9%). Nonuniform seizure distribution was observed in seizures arising from the temporal lobe (mesial temporal lobe and neocortical temporal lobe), with two peaks found in both 3- and 4-hour bins: 10:00-13:00/16:00-19:00 and 08:00-12:00/16:00-20:00 respectively (p=0.004). No specific 24-hour pattern was identified in seizures from extratemporal location. The 24-hour rhythmicity of seizure distribution is recognized in certain types of epilepsy, but studies on the topic are scarce. Their replication and validation is therefore needed. Our study confirms the bimodal pattern of temporal lobe epilepsy independently of the nature of the lesion. However, peak times differ between different studies, suggesting that the ambient, rhythmic exogenous factors or environmental/social zeitgebers, may modulate the 24-hour rhythmicity of seizures. Characterization of these 24-hour patterns of seizure occurrence can influence diagnosis and treatment in selected types of epilepsy, such as the case of temporal lobe epilepsy, the most common drug-resistant epilepsy.
26773465	Disturbed light-dark (LD) cycles are associated with circadian disruption of physiological and behavioural rhythms and in turn with an increased risk of disease development. However, direct causal links and underlying mechanisms leading to negative health consequences still need to be revealed. In the present study, we exposed male Wistar rats to repeated phase shifts of LD cycle and analysed their ability to cope with mild emotional stressors. In experiment 1, rats were submitted to either a regular 12:12 LD cycle (CTRL rats) or 8-h phase delay shifts applied every 2days for 5weeks (SHIFT rats). Subsequently, the behaviour was examined in the open-field, black-white box and elevated plus maze tests. In experiment 2, changes in blood pressure (BP), heart rate (HR) as well as the activity of autonomic nervous system were measured in telemeterised rats in response to open-field and black-white box tests before and after 5-week exposure to shifted LD regime. Locomotor activity was consistently higher in SHIFT than CTRL rats in in the open-field and black-white box tests. Interestingly, in the elevated plus maze, SHIFT rats displayed increased risk assessment and decreased grooming compared to CTRL rats. Anxiety measures were affected only in the black-white box, where SHIFT rats displayed reduced anxiety-like behaviour compared to CTRL rats. Differences in behavioural reactivity between SHIFT and CTRL rats did not correspond with BP and HR changes. However, exposure to phase shifts increased the sympathovagal reactivity in the black-white box. Together, our results demonstrated that disturbed LD conditions decreased emotional reactivity of rats and affected their ability to cope with emotional stressors denoting an additional risk mechanism linking disrupted circadian organisation to adverse health effects. 
26772885	Since the discovery of human somatic cell reprogramming, human induced pluripotent stem cells (hiPSC) have been increasingly recognized as the landmark for development of organs-on-chip. hiPSCs show a remarkable plasticity that is related to their ability to promptly respond to the surrounding environment. In vitro, the soluble culture microenvironment, with its critical balance between exogenous and cell-secreted factors, plays a great role in inducing hiPSC response, for both preserving pluripotency and controlling differentiation stages. Exploring the complexity of hiPSC microenvironment requires new experimental tools, as a tight control is limited within conventional culture dishes. Microfluidic technology is particularly attractive in hiPSC research because of its ability to mimic specific environmental cues by accurate control of soluble factors with high spatiotemporal resolution and in a high-throughput fashion. In this review, we highlight recent progress in hiPSC research enabled by microfluidic technology as well as new emerging scenarios. 
26772201	In bilaterian animals, the circadian clock is intimately involved in regulating energetic metabolism. Although cnidarians exhibit diel behavioral rhythms including cycles in locomotor activity, tentacle extension and spawning, daily cycles in cnidarian metabolism have not been described. To explore a possible circadian metabolic cycle, we maintained the anemone Nematostella vectensis in a 12 h light/dark cycle, a reversed light cycle, or in constant darkness. Oxygen consumption rates were measured at intervals using an optical oxygen meter. Respiration rates responded to entrainment with higher rates during light periods. During a second experiment with higher temporal resolution, respiration rates peaked late in the light period. The diel pattern could be detected after six days in constant darkness. Together, our results suggest that respiration rates in Nematostella exhibit a daily cycle that may be under circadian control and that the cycle in respiration rate is not driven by the previously described nocturnal increase in locomotor activity in this species. 
26771705	Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and 24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown.The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects.	A randomized, crossover study with two 3-day laboratory visits.	Center for Clinical Investigation at Brigham and Women's Hospital.	Healthy chronic shift workers.	The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment).	Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols.	Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early and late phase insulin; both P ≤ .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38).	Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.	
26770548	The aim of this study was to explore the influence of combination therapy in different administration time on antihypertensive efficacy and blood pressure variability in patients with essential hypertension. A total of 86 patients with stage II to III essential hypertension were randomly divided into 4 groups: taking indapamide and losartan potassium together in the morning or in the evening 2 to 4 hours before sleep, indapamide in the morning and losartan potassium in the evening, losartan potassium in the morning and indapamide in the evening. Ambulatory blood pressure monitoring was performed before and 12 weeks after the medication. The result showed that statistically significant reductions from baseline of systolic blood pressure/diastolic blood pressure occurred in all treatment groups. There was no significant difference of the reductions or SI among the four groups, neither the rate of decline of BP in the night or the circadian rhythm. In group B, the numbers of rapid rise in BP in the morning hours were significantly less after the medication, while not in the other groups. It is concluded that independent of the administration time, both once-daily treatment and component-based dual therapy had significant antihypertensive effect, but the night taken-together combination resulted in reductions of BP, SI and morning blood pressure peak that may have advantages over the other combinations, without the increased incidence of hypotension at night. Medicines should be taken 2 to 4 hours before sleep. 
26769470	The effect of temperature on radial root hydraulic specific resistance (Rp) is a known phenomenon; however, the impact ofRpvariations expected from soil temperature changes over the tree root system is unknown. The present article analyses the relations hip ofRpwith temperature in olive 'Picual' and a hybrid rootstock, GF677, at five different temperatures, showing that a variation of 3- and 4.5-folds exists for olive 'Picual' and GF677 in the range from 10 to 20 °C. The functions obtained were scaled up to show the theoretical changes of total radial root system resistance in a common tree orchard in a Mediterranean climate at a daily and seasonal scale, using recorded soil temperature values: a difference between summer and winter of 3.5-fold for olive 'Picual' and 9-fold for GF677 was observed. Nevertheless,Rpchanges are not only related to temperature, as cavitation or circadian rhythms in aquaporin expression may also play a role. The results obtained from an experiment with the two cultivars submitted to constant pressure and temperature during several hours exhibited a variation inRp, but this was of lower magnitude than that observed due to temperature changes. Finally, a comparison ofRpat 25 °C between GF677 and GN15 (another rootstock obtained from the same parental as GF677) showed significant differences. According to our results, diurnal and seasonal changes inRpdue to temperature variations are of significant importance, and it would therefore be advisable to assess them explicitly into soil-plant-atmosphere continuum models. 
26768600	Timing of flowering is not only an interesting topic in developmental biology, but it also plays a significant role in agriculture for its effects on the maturation time of seed. The hexaploid wheat (Triticum aestivum) is one of the most important crop species whose flowering time, i.e. heading time, greatly influences yield. However, it remains unclear whether and how microRNAs regulate heading time in it. In our current study, we identified the tae-miR408 in wheat and its targets in vivo, including Triticum aestivum TIMING OF CAB EXPRESSION-A1 (TaTOC-A1), TaTOC-B1, and TaTOC-D1. The tae-miR408 levels were reciprocal to those of TaTOC1s under long-day and short-day conditions. Wheat plants with a knockdown of TaTOC1s via RNA interference and overexpression of tae-miR408 showed early-heading phenotype. Furthermore, TaTOC1s expression was down-regulated by the tae-miR408 in the hexaploid wheat. In addition, other important agronomic traits in wheat, such as plant height and flag leaf angle, were regulated by both tae-miR408 and TaTOC1s. Thus, our results suggested that the tae-miR408 functions in the wheat heading time by mediating TaTOC1s expression, and the study provides important new information on the mechanism underlying heading time regulation in wheat. 

26766786	A high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of NAD(+) in human whole blood using a surrogate analyte approach was developed and validated. Human whole blood was acidified using 0.5N perchloric acid at a ratio of 1:3 (v:v, blood:perchloric acid) during sample collection. 25μL of acidified blood was extracted using a protein precipitation method and the resulting extracts were analyzed using reverse-phase chromatography and positive electrospray ionization mass spectrometry. (13)C5-NAD(+) was used as the surrogate analyte for authentic analyte, NAD(+). The standard curve ranging from 0.250 to 25.0μg/mL in acidified human blood for (13)C5-NAD(+) was fitted to a 1/x(2) weighted linear regression model. The LC-MS/MS response between surrogate analyte and authentic analyte at the same concentration was obtained before and after the batch run. This response factor was not applied when determining the NAD(+) concentration from the (13)C5-NAD(+) standard curve since the percent difference was less than 5%. The precision and accuracy of the LC-MS/MS assay based on the five analytical QC levels were well within the acceptance criteria from both FDA and EMA guidance for bioanalytical method validation. Average extraction recovery of (13)C5-NAD(+) was 94.6% across the curve range. Matrix factor was 0.99 for both high and low QC indicating minimal ion suppression or enhancement. The validated assay was used to measure the baseline level of NAD(+) in 29 male and 21 female human subjects. This assay was also used to study the circadian effect of endogenous level of NAD(+) in 10 human subjects. 
26765251	Determining the time a biological trace was left at a scene of crime reflects a crucial aspect of forensic investigations as - if possible - it would permit testing the sample donor's alibi directly from the trace evidence, helping to link (or not) the DNA-identified sample donor with the crime event. However, reliable and robust methodology is lacking thus far. In this study, we assessed the suitability of mRNA for the purpose of estimating blood deposition time, and its added value relative to melatonin and cortisol, two circadian hormones we previously introduced for this purpose. By analysing 21 candidate mRNA markers in blood samples from 12 individuals collected around the clock at 2h intervals for 36h under real-life, controlled conditions, we identified 11 mRNAs with statistically significant expression rhythms. We then used these 11 significantly rhythmic mRNA markers, with and without melatonin and cortisol also analysed in these samples, to establish statistical models for predicting day/night time categories. We found that although in general mRNA-based estimation of time categories was less accurate than hormone-based estimation, the use of three mRNA markers HSPA1B, MKNK2 and PER3 together with melatonin and cortisol generally enhanced the time prediction accuracy relative to the use of the two hormones alone. Our data best support a model that by using these five molecular biomarkers estimates three time categories, i.e. night/early morning, morning/noon, and afternoon/evening with prediction accuracies expressed as AUC values of 0.88, 0.88, and 0.95, respectively. For the first time, we demonstrate the value of mRNA for blood deposition timing and introduce a statistical model for estimating day/night time categories based on molecular biomarkers, which shall be further validated with additional samples in the future. Moreover, our work provides new leads for molecular approaches on time of death estimation using the significantly rhythmic mRNA markers established here. 
26765037	To compare the 24-hour ocular perfusion pressure (OPP) among patients with primary open angle glaucoma (POAG) and those with suspected POAG identified in a population-based study in China.Forty-seven patients with POAG and 35 with suspected POAG attended the 24-hour OPP study. Intraocular pressure (IOP) and blood pressure (BP) were measured at 2, 6, and 10 AM and 2, 6, and 10 PM. Subjects were not taking any medications to lower IOP, which was measured with Goldmann applanation in an upright sitting position. Blood pressure was measured in a supine position using a digital automatic BP monitor (OMRON, model HEM-907). Mean arterial pressure was calculated as diastolic BP + 1[Fraction Slash]3 × (systolic BP - diastolic BP). Mean OPP (MOPP) was defined as 2[Fraction Slash]3 × mean arterial pressure - IOP, systolic OPP (SOPP) was defined as 2[Fraction Slash]3 × systolic BP - IOP, and diastolic OPP (DOPP) was defined as 2[Fraction Slash]3 × diastolic BP - IOP.	After adjustment for age, sex, and IOP, the maximum, mean, and minimum SOPP, DOPP, and MOPP were statistically significantly lower in subjects with POAG than in those with suspected POAG (P < 0.05). The minimum MOPP, SOPP, and DOPP occurred from 10 AM to 2 PM in approximately 60% of eyes with POAG and between 20% and 30% of minimum MOPP, SOPP, and DOPP occurred around 10 PM.	Systolic OPP, DOPP, and MOPP were consistently lower in eyes with POAG than in those with suspected POAG, providing further evidence that OPP plays a role in the development of glaucoma.	
26763505	Circadian rhythm disturbances overlap with the symptoms of mood episodes and may trigger or prolong mood symptoms. There is limited research on the role of circadian disturbances in mood disorders in young people and/or first episode cases of unipolar and bipolar disorders.Actigraphy was undertaken for about 14 days in 63 post-pubertal individuals aged 13-25 years with a recent onset of a mood disorder meeting recognised diagnostic criteria. We examined associations between three easily interpretable markers of circadian rhythm activity (amplitude, acrophase and rhythmicity index) and demography and clinical characteristics. Then, circadian markers were compared between diagnostic groups, controlling for potential confounders.	Longer duration of illness was correlated with reduced circadian rhythmicity and lower levels of activity over 24 h. A delay in the timing of maximum activity was associated with the level of manic but not depressive symptoms. The circadian rhythmicity index differentiated unipolar from bipolar cases, and in bipolar but not unipolar disorder, the rhythmicity was less robust in those with more severe manic or depressive symptoms.	Less robust circadian rhythmicity, especially associated with increasing symptom severity, may represent a more specific or a trait marker of young people with mood disorders who are at higher risk of a bipolar course of illness.	
26763504	This review will discuss the role of childhood trauma in bipolar disorders. Relevant studies were identified via Medline (PubMed) and PsycINFO databases published up to and including July 2015. This review contributes to a new understanding of the negative consequences of early life stress, as well as setting childhood trauma in a biological context of susceptibility and discussing novel long-term pathophysiological consequences in bipolar disorders. Childhood traumatic events are risk factors for developing bipolar disorders, in addition to a more severe clinical presentation over time (primarily an earlier age at onset and an increased risk of suicide attempt and substance misuse). Childhood trauma leads to alterations of affect regulation, impulse control, and cognitive functioning that might decrease the ability to cope with later stressors. Childhood trauma interacts with several genes belonging to several different biological pathways [Hypothalamic-pituitary-adrenal (HPA) axis, serotonergic transmission, neuroplasticity, immunity, calcium signaling, and circadian rhythms] to decrease the age at the onset of the disorder or increase the risk of suicide. Epigenetic factors may also be involved in the neurobiological consequences of childhood trauma in bipolar disorder. Biological sequelae such as chronic inflammation, sleep disturbance, or telomere shortening are potential mediators of the negative effects of childhood trauma in bipolar disorders, in particular with regard to physical health. The main clinical implication is to systematically assess childhood trauma in patients with bipolar disorders, or at least in those with a severe or instable course. The challenge for the next years will be to fill the gap between clinical and fundamental research and routine practice, since recommendations for managing this specific population are lacking. In particular, little is known on which psychotherapies should be provided or which targets therapists should focus on, as well as how childhood trauma could explain the resistance to mood stabilizers. 
26763012	In the article by Guessous et al (Guessous I, Pruijm M, Ponte B, Ackermann D, Ehret G, Ansermot N, Vuistiner P, Staessen J, Gu Y, Paccaud F, Mohaupt M, Vogt B, Pechère-Bertschi A, Martin PY, Burnier M, Eap CB, Bochud M. Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions. Hypertension. 2015;65:691–696. doi: 10.1161/HYPERTENSIONAHA.114.04512), which published online ahead of print December 8, 2014, and appeared in the March 2015 issue of the journal, a correction was needed.One of the author surnames was misspelled. Antoinette Pechère-Berstchi has been corrected to read Antoinette Pechère-Bertschi.The authors apologize for this error.
26762786	Extensive studies focus on the cognitive and motor impairments after perinatal hypoxic-ischemia (HI). Sleep problems, although reported to be associated with cerebral palsy (CP), are often overlooked in non-severe HI patients. Here, by investigating the sleep qualities of children with different degrees of HI, we discovered that sleep initiation and maintenance, sleep-related breathing problems, or circadian rhythmic issues were highly associated with children of moderate or mild HI, respectively. Follow-up MRI studies in 2-year old patients showed that periventricular white matter lesions including periventricular leukomalacia (PVL) were prevalent in moderate, but not mild, HI children. In contrast, the occurrence of pineal cysts had a high risk in children with mild HI. Our study provides novel insights into the mechanisms of distinctive sleep problems associated with children of different degrees of HI, and therefore sheds light on the studies of targeted therapeutic treatments for sleep disorders in children who suffer from HI. 
26762333	Obesity and consequent insulin resistance are known risk factors for type 2 diabetes. A compensatory increase in beta cell function and mass in response to insulin resistance permits maintenance of normal glucose homeostasis, whereas failure to do so results in beta cell failure and type 2 diabetes. Recent evidence suggests that the circadian system is essential for proper metabolic control and regulation of beta cell function. We set out to address the hypothesis that the beta cell circadian clock is essential for the appropriate functional and morphological beta cell response to insulin resistance.We employed conditional deletion of the Bmal1 (also known as Arntl) gene (encoding a key circadian clock transcription factor) in beta cells using the tamoxifen-inducible CreER(T) recombination system. Upon adulthood, Bmal1 deletion in beta cells was achieved and mice were exposed to either chow or high fat diet (HFD). Changes in diurnal glycaemia, glucose tolerance and insulin secretion were longitudinally monitored in vivo and islet morphology and turnover assessed by immunofluorescence. Isolated islet experiments in vitro were performed to delineate changes in beta cell function and transcriptional regulation of cell proliferation.	Adult Bmal1 deletion in beta cells resulted in failed metabolic adaptation to HFD characterised by fasting and diurnal hyperglycaemia, glucose intolerance and loss of glucose-stimulated insulin secretion. Importantly, HFD-induced beta cell expansion was absent following beta cell Bmal1 deletion indicating impaired beta cell proliferative and regenerative potential, which was confirmed by assessment of transcriptional profiles in isolated islets.	Results of the study suggest that the beta cell circadian clock is a novel regulator of compensatory beta cell expansion and function in response to increased insulin demand associated with diet-induced obesity.	
26762288	Proanthocyanidins (PAs) are the most abundant flavonoids in the human diet. Several epidemiological studies connect PA consumption and health benefits and the designation of PAs as healthy compounds started at the early stages of the 20th century. The beneficial health properties of PAs are attributed to their conjugated and colonic metabolites. Therefore, gut microbial compositions can determine the effectiveness of PAs. Reciprocally, dietary polyphenols can act as prebiotics. Recently, it has also been described that PAs modulate the circadian rhythm. Biochemical and epigenetic mechanisms, including the modulation of microRNAs, allow PAs to modulate cell functionality. PA effects in metabolic diseases are also reviewed.
26762182	In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle. 
26761645	Ocean soundscapes convey important sensory information to marine life. Like many mid-to-low latitude coastal areas worldwide, the high-frequency (>1.5 kHz) soundscape of oyster reef habitat within the West Bay Marine Reserve (36°N, 76°W) is dominated by the impulsive, short-duration signals generated by snapping shrimp. Between June 2011 and July 2012, a single hydrophone deployed within West Bay was programmed to record 60 or 30 seconds of acoustic data every 15 or 30 minutes. Envelope correlation and amplitude information were then used to count shrimp snaps within these recordings. The observed snap rates vary from 1500-2000 snaps per minute during summer to <100 snaps per minute during winter. Sound pressure levels are positively correlated with snap rate (r = 0.71-0.92) and vary seasonally by ~15 decibels in the 1.5-20 kHz range. Snap rates are positively correlated with water temperatures (r = 0.81-0.93), as well as potentially influenced by climate-driven changes in water quality. Light availability modulates snap rate on diurnal time scales, with most days exhibiting a significant preference for either nighttime or daytime snapping, and many showing additional crepuscular increases. During mid-summer, the number of snaps occurring at night is 5-10% more than predicted by a random model; however, this pattern is reversed between August and April, with an excess of up to 25% more snaps recorded during the day in the mid-winter. Diurnal variability in sound pressure levels is largest in the mid-winter, when the overall rate of snapping is at its lowest, and the percentage difference between daytime and nighttime activity is at its highest. This work highlights our lack of knowledge regarding the ecology and acoustic behavior of one of the most dominant soniforous invertebrate species in coastal systems. It also underscores the necessity of long-duration, high-temporal-resolution sampling in efforts to understand the bioacoustics of animal behaviors and associated changes within the marine soundscape. 
26760592	Insomnia affects 10% to 30% of the population with a total cost of $92.5 to $107.5 billion annually. Short-term, chronic, and other types of insomnia are the three major categories according to the International Classification of Sleep Disorders, 3rd ed. The criteria for diagnosis are difficulty falling asleep, difficulty staying asleep, or early awakening despite the opportunity for sleep; symptoms must be associated with impaired daytime functioning and occur at least three times per week for at least one month. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy arousability, poor self-reported health, and chronic pain. Insomnia is more common in women, especially following menopause and during late pregnancy, and in older adults. A comprehensive sleep history can confirm the diagnosis. Psychiatric and medical problems, medication use, and substance abuse should be ruled out as contributing factors. Treatment of comorbid conditions alone may not resolve insomnia. Patients with movement disorders (e.g., restless legs syndrome, periodic limb movement disorder), circadian rhythm disorders, or breathing disorders (e.g., obstructive sleep apnea) must be identified and treated appropriately. Chronic insomnia is associated with cognitive difficulties, anxiety and depression, poor work performance, decreased quality of life, and increased risk of cardiovascular disease and all-cause mortality. Insomnia can be treated with nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies include sleep hygiene, cognitive behavior therapy, relaxation therapy, multicomponent therapy, and paradoxical intention. Referral to a sleep specialist may be considered for refractory cases. 
26759012	Sleep is an essential physiologic process that helps to restore normal body homeostasis. Sleep disturbances have been shown to be associated with poor clinical outcomes, such as a greater risk of cardiovascular disease and increasing mortality. Critically ill patients, particularly those receiving mechanical ventilation, may be more susceptible to sleep disruption.Mechanical ventilation is an important factor influencing sleep in critically ill patients as it may have positive or negative effects, depending on patient population, mode, and specific settings. Other causes of sleep disruption include the acute illness itself, the daily routine care, and the effects of medications. Improving sleep in patients admitted to an intensive care unit has the potential to improve both short- and long-term clinical outcomes. In this article we review the specific aspects of sleep in critically ill mechanically ventilated patients, including abnormal sleep patterns and loss of circadian rhythm, as well as the effects of mechanical ventilation and intravenous sedatives on sleep quality and quantity.	We provide recommendations for clinicians regarding optimal ventilatory settings and discuss fields for future research.	

26757391	Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging-related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases. 
26757053	Light signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) entrain the circadian clock and regulate negative masking. Two neurotransmitters, glutamate and Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), found in the ipRGCs transmit light signals to the brain via glutamate receptors and the specific PACAP type 1 (PAC1) receptor. Light entrainment occurs during the twilight zones and has little effect on clock phase during daytime. When nocturnal animals have access to food only for a few hours during the resting phase at daytime, they adapt behavior to the restricted feeding (RF) paradigm and show food anticipatory activity (FAA). A recent study in mice and rats demonstrating that light regulates FAA prompted us to investigate the role of PACAP/PAC1 signaling in the light mediated regulation of FAA. PAC1 receptor knock out (PAC1-/-) and wild type (PAC1+/+) mice placed in running wheels were examined in a full photoperiod (FPP) of 12:12 h light/dark (LD) and a skeleton photoperiod (SPP) 1:11:1:11 h L:DD:L:DD at 300 and 10 lux light intensity. Both PAC1-/- mice and PAC1+/+ littermates entrained to FPP and SPP at both light intensities. However, when placed in RF with access to food for 4-5 h during the subjective day, a significant change in behavior was observed in PAC1-/- mice compared to PAC1+/+ mice. While PAC1-/- mice showed similar FAA as PAC1+/+ animals in FPP at 300 lux, PAC1-/- mice demonstrated an advanced onset of FAA with a nearly 3-fold increase in amplitude compared to PAC1+/+ mice when placed in SPP at 300 lux. The same pattern of FAA was observed at 10 lux during both FPP and SPP. The present study indicates a role of PACAP/PAC1 signaling during light regulated FAA. Most likely, PACAP found in ipRGCs mediating non-image forming light information to the brain is involved. 
26756747	To assess the noninferiority of a dorzolamide-timolol fixed combination (DTFC) versus latanoprost in terms of intraocular pressure (IOP) and to compare blood pressure (BP), ocular perfusion pressure (OPP) and diastolic ocular perfusion pressure (DOPP) between the latanoprost and DTFC groups in patients with normal-tension glaucoma (NTG).Prospective, interventional, randomized, single-blinded, crossover design study. Patients with newly diagnosed NTG that had not been treated with a glaucoma medication in the most recent 2 months were recruited. In total, 44 patients with NTG were randomly allocated to one of two groups. Patients in group A were treated with DTFC, lubricant, and latanoprost for 4 weeks each, whereas patients in group B were treated with latanoprost, lubricant, and DTFC for 4 weeks each. Patients were examined on day 1 (without medication), week 4 (under medication), week 8 (without medication), and week 12 (under medication). At weeks 4 and 12, diurnal IOP, systolic and diastolic BP, and OPP were measured at 8:00 AM, 10:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM.	Baseline demographic characteristics showed no difference in terms of age, sex, central corneal thickness, spherical equivalent, or stage of glaucoma between the groups. The between-group difference was -0.19 ± 0.18 mmHg (mean ± SE, upper bound of one-sided 95% CI, 0.12). Diurnal IOP showed no difference between the groups with an average IOP reduction of 13.1% using latanoprost and 12.3% using DTFC. Diurnal systolic and diastolic BP were lower in the DTFC group than the latanoprost group; however, the difference between the groups was not statistically significant. Diurnal OPP and DOPP also showed no statistically significant difference between the groups.	IOP lowering efficacy of DTFC was noninferior to that of latanoprost in newly diagnosed NTG patients. There was no difference in BP, OPP, or DOPP between the latanoprost and DTFC groups. This prospective, randomized, single-blinded, crossover study demonstrated the noninferiority of DTFC versus latanoprost in terms of IOP in patients with NTG.	
26756164	The mammalian circadian clock influences most aspects of physiology and behavior through the transcriptional control of a wide variety of genes, mostly in a tissue-specific manner. About 20 clock-controlled genes (CCGs) oscillate in virtually all mammalian tissues and are generally considered as core clock components. One of them is Ubiquitin-Specific Protease 2 (Usp2), whose status remains controversial, as it may be a cogwheel regulating the stability or activity of core cogwheels or an output effector. We report here that Usp2 is a clock output effector related to bodily Ca2+ homeostasis, a feature that is conserved across evolution. Drosophila with a whole-body knockdown of the orthologue of Usp2, CG14619 (dUsp2-kd), predominantly die during pupation but are rescued by dietary Ca2+ supplementation. Usp2-KO mice show hyperabsorption of dietary Ca2+ in small intestine, likely due to strong overexpression of the membrane scaffold protein NHERF4, a regulator of the Ca2+ channel TRPV6 mediating dietary Ca2+ uptake. In this tissue, USP2-45 is found in membrane fractions and negatively regulates NHERF4 protein abundance in a rhythmic manner at the protein level. In clock mutant animals (Cry1/Cry2-dKO), rhythmic USP2-45 expression is lost, as well as the one of NHERF4, confirming the inverse relationship between USP2-45 and NHERF4 protein levels. Finally, USP2-45 interacts in vitro with NHERF4 and endogenous Clathrin Heavy Chain. Taken together these data prompt us to define USP2-45 as the first clock output effector acting at the post-translational level at cell membranes and possibly regulating membrane permeability of Ca2+. 
26755737	Heat stress (HS) dramatically disrupts the events in energy and nutrient metabolism, many of which requires zinc (Zn) as a cofactor. In this study, metabolic effects of HS and Zn supplementation were evaluated by examining growth performance, blood chemistry, and metabolomes of crossbred gilts fed with ZnNeg (no Zn supplementation), ZnIO (120 ppm ZnSO4), or ZnAA (60 ppm ZnSO4 + 60 ppm zinc amino acid complex) diets under diurnal HS or thermal-neutral (TN) condition. The results showed that growth performance was reduced by HS but not by Zn supplementation. Among measured serum biochemicals, HS was found to increase creatinine but decrease blood urea nitrogen (BUN) level. Metabolomic analysis indicated that HS greatly affected diverse metabolites associated with amino acid, lipid, and microbial metabolism, including urea cycle metabolites, essential amino acids, phospholipids, medium-chain dicarboxylic acids, fatty acid amides, and secondary bile acids. More importantly, many changes in these metabolite markers were correlated with both acute and adaptive responses to HS. Relative to HS-induced metabolic effects, Zn supplementation-associated effects were much more limited. A prominent observation was that ZnIO diet, potentially through its influences on microbial metabolism, yielded different responses to HS compared with two other diets, which included higher levels of short-chain fatty acids (SCFAs) in cecal fluid and higher levels of lysine in the liver and feces. Overall, comprehensive metabolomic analysis identified novel metabolite markers associated with HS and Zn supplementation, which could guide further investigation on the mechanisms of these metabolic effects. 
26754482	Recent research has documented the association between attachment and cortisol rhythms. During pregnancy, when attachment patterns are likely to be activated, elevated levels of cortisol are associated with negative effects for the mother and the foetus. The aim of the present study was to examine the association of adult attachment style and cortisol rhythms in pregnant women.Eighty women in the third trimester of pregnancy participated in the study. Adult attachment was assessed using the Adult Attachment Scale - Revised (AAS-R). Participants collected 4 samples of salivary cortisol at two different days; 3 samples were collected in the morning immediately after wakeup and one sample was collected by bedtime.	Results found group significant differences in the cortisol diurnal oscillation (F (1,71) =26.46, p < .001,), with secure women reporting a steep decrease in cortisol from awakening to bedtime, while women with fearful avoidant attachment reported no changes. No group differences were found regarding the cortisol awakening response.	These results highlight the importance of considering attachment patterns during pregnancy, suggesting fearful avoidant attachment style as a possible risk factor for emotional difficulties and dysregulation of the neuroendocrine rhythms.	
26754451	Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders.We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype.	This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.	
26754344	African Americans (AAs) have lower lung function, higher blood pressure variability (BPV) and increased risk for hypertension and cardiovascular disease (CVD) compared with whites. The mechanism through which reduced lung-function is associated with increased CVD risk is unclear.We evaluated the association between percent predicted lung-function and 24-hour BPV in 1008 AAs enrolled in the Jackson Heart Study who underwent ambulatory blood pressure (BP) monitoring. Lung-function was assessed as forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1-to-FVC during a pulmonary function test using a dry rolling sealed spirometer and grouped into gender-specific quartiles. The pairwise associations of these three lung-function measures with two measures of 24-hour BPV, (1) day-night standard deviation (SDdn) and (2) average real variability (ARV) were examined for systolic BP (SBP) and, separately, diastolic BP (DBP).	SDdn of SBP was not associated with FEV1 (mean ± standard deviation from lowest-to-highest quartile: 9.5 ± 2.5, 9.4 ± 2.4, 9.1 ± 2.3, 9.3 ± 2.6; p-trend = 0.111). After age and sex adjustment, the difference in SDdn of SBP was 0.0 (95% CI -0.4,0.4), -0.4 (95% CI -0.8,0.1) and -0.3 (95% CI -0.7,0.1) in the three progressively higher versus lowest quartiles of FEV1 (p-trend = 0.041). Differences in SDdn of SBP across FEV1 quartiles were not statistically significant after further multivariable adjustment. After multivariable adjustment, no association was present between FEV1 and ARV of SBP or SDdn and ARV of DBP or when evaluating the association of FVC and FEV1-to-FVC with 24-hour BPV.	Lung-function was not associated with increased 24-hour BPV.	
26753997	In development, morphogenetic processes are strictly coordinated in time. Cells in a developing tissue would need mechanisms for time-keeping. One such time-keeping mechanism is to use oscillations of gene expression. Oscillatory gene expression can be generated by transcriptional/translational feedback loops, usually referred to as a genetic oscillator. In this review article, we discuss genetic oscillators in the presence of developmental processes such as cell division, cell movement and cell differentiation. We first introduce the gene regulatory network for generating a rhythm of gene expression. We then discuss how developmental processes influence genetic oscillators. Examples include vertebrate somitogenesis and neural progenitor cell differentiation, as well as the circadian clock for comparison. To understand the behaviors of genetic oscillators in development, it is necessary to consider both gene expression dynamics and cellular behaviors simultaneously. Theoretical modeling combined with live imaging at single-cell resolution will be a powerful tool to analyze genetic oscillators in development. 
26753996	BMAL1 is a transcriptional activator of the molecular clock feedback network. Besides its role in generating circadian rhythms, it has also been shown to be involved in the modulation of cell proliferation, autophagy and cancer cell invasion. However, the role of BMAL1 in pulmonary fibrogenesis is still largely unknown. In this study, we investigated the crosstalk between BMAL1 and the signaling transduction and cellular activities of TGF-β1, a key player in lung fibrogenesis.Lungs from wild type and TGF-β1-adenovirus-infected mice were harvested and homogenized for isolation of RNA and protein. RT-PCR and Western Blotting were employed to measure the expression level of clock genes and TGF-β1-induced downstream target genes. siRNA against human BMAL1 gene was transfected by using lipofectamine RNAiMAX to knockdown the endogenous BMAL1 in both lung epithelial cells and fibroblasts.	Our results showed that TGF-β1 is able to up-regulate BMAL1 expression in both lung epithelial cells and normal lung fibroblasts. In animal models of pulmonary fibrosis, BMAL1 expression was also significantly higher in adenovirus-TGF-β1-infected mice than in the control group. Interestingly, BMAL1 was mostly found in a deacetylated form in the presence of TGF-β1. Importantly, siRNA-mediated knockdown of BMAL1 significantly attenuated the canonical TGF-β1 signaling pathway and altered TGF-β1-induced epithelial-mesenchymal transition and MMP9 production in lung epithelial cells. In addition, BMAL1 knockdown inhibited the fibroblast to myofibroblast differentiation of normal human lung fibroblasts.	Our results indicate that activation of TGF-β1 promotes the transcriptional induction of BMAL1. Furthermore, BMAL1 is required for the TGF-β1-induced signaling transduction and pro-fibrotic activities in the lung.	


26751779	Policy provision for naps is typical in child care settings, but there is variability in the practices employed. One practice that might modify children's early sleep patterns is the allocation of a mandatory nap time in which all children are required to lie on their beds without alternate activity permitted. There is currently limited evidence of the effects of such practices on children's napping patterns. This study examined the association between duration of mandatory nap times and group-level napping patterns in child care settings. Observations were undertaken in a community sample of 113 preschool rooms with a scheduled nap time (N = 2,114 children). Results showed that 83.5% of child care settings implemented a mandatory nap time (range = 15-145 min) while 14.2% provided alternate activities for children throughout the nap time period. Overall, 31% of children napped during nap times. Compared to rooms with ≤ 30 min of mandatory nap time, rooms with 31-60 min and > 60 min of mandatory nap time had a two-and-a-half and fourfold increase, respectively, in the proportion of children napping. Nap onset latency did not significantly differ across groups. Among preschool children, exposure to longer mandatory nap times in child care may increase incidence of napping.
26751571	Sleep disturbance is increasingly recognized as a major problem for patients with schizophrenia but it is rarely the direct focus of treatment. The main recommended treatment for insomnia is cognitive behavioural therapy, which we have been evaluating for patients with current delusions and hallucinations in the context of non-affective psychosis.In this article we describe the lessons we have learned about clinical presentations of sleep problems in schizophrenia and the adaptations to intervention that we recommend for patients with current delusions and hallucinations.	Twelve factors that may particularly contribute to sleep problems in schizophrenia are identified. These include delusions and hallucinations interfering with sleep, attempts to use sleep as an escape from voices, circadian rhythm disruption, insufficient daytime activity, and fear of the bed, based upon past adverse experiences. Specific adaptations for psychological treatment related to each factor are described.	Our experience is that patients want help to improve their sleep; sleep problems in schizophrenia should be treated with evidence-based interventions, and that the interventions may have the added benefit of lessening the psychotic experiences. A treatment technique hierarchy is proposed for ease of translation to clinical practice.	
26751389	Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host's circadian clock. However, it is not clear how the host's clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks. 
26750446	Despite the perceived importance of sleep for elite footballers, descriptions of the duration and quality of sleep, especially following match play, are limited. Moreover, recovery responses following sleep loss remain unclear. Accordingly, the present study examined the subjective sleep and recovery responses of elite footballers across training days (TD) and both day and night matches (DM and NM). Sixteen top division European players from three clubs completed a subjective online questionnaire twice a day for 21 days during the season. Subjective recall of sleep variables (duration, onset latency, time of wake/sleep, wake episode duration), a range of perceptual variables related to recovery, mood, performance and internal training loads and non-exercise stressors were collected. Players reported significantly reduced sleep durations for NM compared to DM (-157 min) and TD (-181 min). In addition, sleep restfulness (SR; arbitrary scale 1 = very restful, 5 = not at all restful) and perceived recovery (PR; acute recovery and stress scale 0 = not recovered at all, 6 = fully recovered) were significantly poorer following NM than both TD (SR: +2.0, PR: -2.6), and DM (SR: +1.5; PR: -1.5). These results suggest that reduced sleep quantity and quality and reduced PR are mainly evident following NM in elite players. 
26749455	The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients.The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C).	Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities.	The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.	
26749218	Low maternal socioeconomic position (SEP) has been associated with adverse neonatal outcomes, including preterm birth, low birthweight, intrauterine growth restriction, and infant mortality. A key biological mechanism that has been proposed to explain this association is hypothalamic-pituitary-adrenal (HPA) activity, yet the association between SEP and HPA activity in pregnancy has received little attention. In this study we aimed to examine the associations between SEP and 2 forms of maternal cortisol regulation-diurnal slope and wakening response-across pregnancy. Furthermore, we aimed to assess whether these associations differed by the sex of the fetus.A total of 217 pregnant women aged 18 to 40 years with singleton pregnancies participated. Women were excluded from participating if they were aged <18 or >40 years and if they were at risk for maternal or obstetric complications. Women provided information on socioeconomic characteristics of adults contributing to the participants' household to compute a Hollingshead Four Factor Index of Social Status score of SEP. Women provided salivary cortisol samples on awakening, 30 minutes after wakeup, and at bedtime, at 3 times over pregnancy and once 30 days postpartum to calculate the diurnal slope and cortisol awakening response (CAR). Using linear regression analyses, we examined the relationships between maternal SEP and maternal diurnal slope and CAR. We explored the relationships between maternal SEP and cortisol by fetal sex using linear regression analyses. We also explored links between maternal SEP, maternal cortisol, and infant birth outcomes.	Women of lower SEP displayed smaller awakening responses and less change over the day compared with women of higher SEP. SEP was significantly associated with attenuated diurnal slope only among women carrying female fetuses, whereas for CAR, the association between SEP and attenuated CAR was significant only for women carrying male fetuses. Lower SEP was associated with decreased birthweight, and this association was partially explained by maternal HPA activity in pregnancy.	Women of low SEP displayed attenuated HPA activity across the perinatal period, and patterns varied by fetal sex and cortisol metric. Findings are in need of replication. More research is needed to understand the links between SEP, HPA activity, and neonatal health.	
26748465	Salivary samples were collected over a 24-hr period from one group of six juvenile (7-12 years) and one group of three adult (24-25 years) African elephant females, Loxodonta africana, and the cortisol concentration was measured in unextracted samples by EIA. Samples were collected during May, June, and November 2012 (n = 147) using cotton swabs at 4-hr intervals from 20:00 to 20:00 of the next day (seven samples per animal in each trial). The animals are kept under standard zoo management: the herd is maintained in their indoor enclosures until 10:00 and then released into the outdoor enclosures until 21:00-21:30 (May/June) and 18:30-19:00 (November). No adult elephant bull was present at the zoo during this time. The results demonstrate a clear diurnal pattern of cortisol secretion with the lowest concentration observed at 20:00 (2.03 ± 0.08 ng/ml saliva) and the peak concentrations at 08:00 (5.26 ± 0.35 ng/ml saliva). Although the cortisol values were higher in the adult cows compared to the juvenile cows in the May-June period, the differences were not significant. However, the values obtained in November from the juvenile group were significantly higher (P < 0.05) than the concentrations measured in this group in June. In conclusion, salivary cortisol in zoo elephants follows a circadian rhythm (sleep-wake cycle) adapted to daily zoo husbandry routines.
26748146	Diurnal variation in the performance of rapid response systems has not been fully elucidated. Afferent limb failure (ALF) is a significant problem and is an important measure of performance of rapid response systems.To determine the diurnal variation in the detection and response to acute patient deterioration as measured by ALF, completeness of patient observations (Respiratory rate (RR); Pulse rate (PR) and Systolic blood pressure (SBP), and to explore the diurnal variation in the consequences of ALF in unanticipated admissions to the Intensive care unit (ICU) from the ward.	Point Prevalence study conducted on two days in 2012 in 41 ICUs in Australia and New Zealand, examining emergency (unanticipated) admissions to the ICU from the ward.	51 patients from the ward were admitted as an emergency to the ICU following a rapid response team call, of whom 48 patients had complete datasets and were enrolled; 32 (67%) were men. The prevalence of ALF was 37.5% (18/48). Median age was 62.5 (IQR 51.5-74.0), Median APACHE II score was 21.0 (IQR 17-26). There was no diurnal variation in the prevalence of ALF (day 28% versus night 28%; p=0.92), patient observations documented over time (p=0.78 for RR, p=0.95 for PR and p=0.74 for SBP) or 28-day mortality (p=0.24). There was a significant diurnal variation between the least recorded observation (SBP) and the most recorded observation (PR) (p<0.01). ALF was more likely (day and night) if a complete set of observations had been taken (p<0.01).	The prevalence of ALF amongst patients admitted to the ICU from the ward is high. SBP is the least recorded patient observation. This study was unable to identify a diurnal variation in the prevalence of ALF, its consequences (i.e. mortality) and the completeness of patient observations. Observational studies with a larger sample are required to explore this important problem.	
26746321	Bipolar disorder is a severe and complex multifactorial disease, characterized by alternance of acute episodes of depression and mania/hypomania, interspaced by euthymic periods. The etiological determinants of bipolar disorder yet, are still poorly understood. For the last 30 years, chronobiology is an important field of investigation to better understand the pathophysiology of bipolar disorder.We conducted a review using Medline, ISI Database, EMBase, PsyInfo up to January 2015, using the following keywords combinations: "mood disorder", "bipolar disorder", "depression", "unipolar disorder", "major depressive disorder", "affective disorder", for psychiatric conditions; and "circadian rhythms", "circadian markers", "circadian gene", "clock gene", "melatonin" for circadian rhythms. The search critera was presence of word in any field of the article.	Quantitative and qualitative circadian abnormalities are associated with bipolar disorders both during acute episodes and euthymic periods, suggesting that these altered circadian rhythms may represent biological trait markers of the disorder. These circadian dysfunctions were assessed by various validated tools including polysomnography, actigraphy, sleep diaries, chronotype assessments and blood melatonin/cortisol measures. Other altered endogenous circadian activities have also been reported in bipolar patients, such as hormones secretion, core body temperature or fibroblasts activity. Moreover, these markers were also altered in healthy relatives of bipolar patients, suggesting a degree of heritability. Several genetic association studies have also showed associations between multiple circadian genes and bipolar disorder, such as CLOCK, ARTNL1, GSK3β, PER3, NPAS2, NR1D1, TIMELESS, RORA, RORB, and CSNK1ε. Thus, these circadian gene variants may contribute to the genetic susceptibility of the disease. Furthermore, the study of the clock system may help to better understand some phenotypic aspects like the mechanisms of pharmacological treatments used in bipolar disorder, in particular lithium carbonate.	Several clinical, physiological and genetic data suggest that circadian rhythms dysregulations are involved in the pathophysiology of bipolar disorder. The circadian model has led to the development of new therapeutic strategies such as chronotherapeutics or Inter Personal Social and Rhythms Therapies. Further studies are needed in this promising research field to keep exploring the relationship between these circadian markers, genes and the clinical aspects of the disease.	
26746320	Suicidal behaviors are common in the general population and are so a major public health problem. In order to improve suicide prevention and to reduce the mortality by suicide, it appears essential to better identify suicide risk factors. Seasonality, circadian rhythms and sleep abnormalities have been already associated with numerous psychiatric disorders. This review aimed to characterize the associations between seasonality, circadian rhythms, sleep and suicidal behaviors including suicide attempts and completed suicides.We conducted a literature search between 1973 and 2015 in PubMed databases using the following terms: ("suicide" OR "suicidality" OR "suicide attempts" OR "suicidal behavior") AND ("circadian rhythms" OR "seasons" OR "sleep").	Many studies confirm a specific seasonality for suicide with a higher peak of suicides in spring for both sex and a lower peak in autumn especially for women. This distribution seems to correlate with depressive symptoms (especially for the autumn peak), gender and different types of suicide. Regarding gender and type of suicide differences, males more commonly commit violent suicide with a higher rate of suicides in spring. Suicide behaviors appear to be influenced by climatic and biological factors like sunshine, daylight cycles, temperature, air pollutants, viruses, parasites and aeroallergens. Circadian variations exist in suicide rates depending on age with a morning peak for elder and an evening peak for youth. In addition, completed suicide peak in early morning whereas suicide attempts peak rather in later afternoon. Several biomarkers dysregulation like melatonin, serotonin and cortisol may be implicated in suicide circadian variations. Furthermore, specific sleep disorders like insomnia, nightmares and sleep deprivation are common risk factors of suicide and possibly independently of the presence of depressive symptoms. Finally, the efficacy of chronotherapeutics (such as luminotherapy, dark therapy, sleep deprivation and melatonin drugs) has been suggested in the reduction of suicidal behaviors.	The suicide seasonality is very well documented showing a main peak in spring and another one in autumn. A suicide circadian distribution also exists depending of the suicidal behavior intensity and of the age. Numerous sleep disorders are also suicide risk factors and can be treated with chronotherapeutics. A better identification of seasonality, circadian rhythms and sleep abnormalities in suicidal behaviors could allow a better prevention in suicidal attempts and a reduction in death by suicide.	
26746317	Representations of time and time measurements depend on subjective constructs that vary according to changes in our concepts, beliefs, societal needs and technical advances. Similarly, the past, the future and the present are subjective representations that depend on each individual's psychic time and biological time. Therefore, there is no single, one-size-fits-all time for everyone, but rather a different, subjective time for each individual. We need to acknowledge the existence of different inter-individual times but also intra-individual times, to which different functions and different rhythms are attached, depending on the system of reference. However, the construction of these time perceptions and representations is influenced by objective factors (physiological, physical and cognitive) related to neuroscience which will be presented and discussed in this article. Thus, studying representation and perception of time lies at the crossroads between neuroscience, human sciences and philosophy. Furthermore, it is possible to identify several constants among the many and various representations of time and their corresponding measures, regardless of the system of time reference. These include the notion of movements repeated in a stable rhythmic pattern involving the recurrence of the same interval of time, which enables us to define units of time of equal and invariable duration. This rhythmicity is also found at a physiological level and contributes through circadian rhythms, in particular the melatonin rhythm, to the existence of a biological time. Alterations of temporality in mental disorders will be also discussed in this article illustrated by certain developmental disorders such as autism spectrum disorders. In particular, the hypothesis will be developed that children with autism would need to create discontinuity out of continuity through stereotyped behaviors and/or interests. This discontinuity repeated at regular intervals could have been fundamentally lacking in their physiological development due to possibly altered circadian rhythms, including arhythmy and asynchrony. Time measurement, based on the repetition of discontinuity at regular intervals, involves also a spatial representation. It is our own trajectory through space-time, and thus our own motion, including the physiological process of aging, that affords us a representation of the passing of time, just as the countryside seems to be moving past us when we travel in a vehicle. Chinese and Indian societies actually have circular representations of time, and linear representations of time and its trajectory through space-time are currently a feature of Western societies. Circular time is collective time, and its metaphysical representations go beyond the life of a single individual, referring to the cyclical, or at least nonlinear, nature of time. Linear time is individual time, in that it refers to the scale of a person's lifetime, and it is physically represented by an arrow flying ineluctably from the past to the future. An intermediate concept can be proposed that acknowledges the existence of linear time involving various arrows of time corresponding to different lifespans (human, animal, plant, planet lifespans, etc.). In fact, the very notion of time would depend on the trajectory of each arrow of time, like shooting stars in the sky with different trajectory lengths which would define different time scales. The time scale of these various lifespans are very different (for example, a few decades for humans and a few days or hours for insects). It would not make sense to try to understand the passage of time experienced by an insect which may live only a few hours based on a human time scale. One hour in an insect's life cannot be compared to one experienced by a human. Yet again, it appears that there is a coexistence of different clocks based here on different lifespans. Finally, the evolution of our society focused on the present moment and choosing the cesium atom as the international reference unit of time measurement (cesium has a transition frequency of 9.192.631.77000 oscillations per second), will be questioned. We can consider that focusing on the present moment, in particular on instantaneity rather than infinity, prevents us from facing our own finitude. In conclusion, the question is raised that the current representation of time might be a means of managing our fear of death, giving us the illusion of controlling the uncontrollable, in particular the passage of time, and a means of avoiding to represent what many regard as non-representable, namely our own demise. 
26745752	Sleep debt--together with circadian misalignment--is considered a central factor for adverse health outcomes associated with shift work. Here, we describe in detail sleep-wake behavior in a fast-forward rotating 12-h shift schedule, which involves at least 24 hours off after each shift and thus allows examining the role of immediate recovery after shift-specific sleep debt. Thirty-five participants at two chemical plants in Germany were chronotyped using the Munich ChronoType Questionnaire for Shift-Workers (MCTQ(Shift)) and wore actimeters throughout the two-week study period. From these actimetry recordings, we computed sleep and nap duration, social jetlag (a measure of circadian misalignment), and the daily timing of activity and sleep (center of gravity and mid-sleep, respectively). We observed that the long off-work periods between each shift create a fast alternation between shortened (mean ± standard deviation, 5h 17min ± 56min) and extended (8h 25min ± 72min) sleep episodes resulting in immanent reductions of sleep debt. Additionally, extensive napping of early chronotypes (up to 3 hours before the night shift) statistically compensated short sleep durations after the night shift. Partial rank correlations showed chronotype-dependent patterns of sleep and activity that were similar to those previously described in 8-h schedules; however, sleep before the day shift did not differ between chronotypes. Our findings indicate that schedules preventing a build-up of chronic sleep debt may reduce detrimental effects of shift work irrespective of shift duration. Prospective studies are needed to further elucidate the relationship between sleep, the circadian system, and health and safety hazards.
26745660	Circadian rhythms in mammals are driven by a central clock in the suprachiasmatic nucleus (SCN). In vitro, temperature cycles within the physiological range can act as potent entraining cues for biological clocks. We altered the body temperature (Tc) rhythm in rats by manipulating energy intake (EI) to determine whether EI-induced changes in Tc oscillations are associated with changes in SCN clock gene rhythms in vivo. Male Wistar rats (n = 16 per diet) were maintained on either an ad libitum diet (CON), a high energy cafeteria diet (CAF), or a calorie restricted diet (CR), and Tc was recorded every 30 min for 6-7 weeks. SCN tissue was harvested from rats at zeitgeber time (ZT) 0, ZT6, ZT12, or ZT18. Expression of the clock genes Bmal1, Per2, Cry1, and Rev-erbα, the heat shock transcription factor Hsf1, and the heat shock protein Hsp90aa1, were determined using qPCR. The circadian profile of gene expression for each gene was characterized using cosinor analysis. Compared to the CON rats, the amplitude of Tc was decreased in CAF rats by 0.1 °C (p < 0.001), and increased in CR rats by 0.3 °C (p < 0.001). The amplitude of Hsp90aa1 expression was lowest in CAF rats and highest in CR rats (p = 0.045), but the amplitude of all of the clock genes and Hsf1 were unaffected by diet (p > 0.25). Compared to CON, phase advances of the Tc, Bmal1, and Per2 rhythms were observed with CR feeding (p < 0.05), but CAF feeding elicited no significant changes in phase. The present results indicate that in vivo, the SCN is largely resistant to entrainment by EI-induced changes in the Tc rhythm, although some phase entrainment may occur.
26743744	Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients.We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb).	Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = -0.31, p = 0.044) and U-Alb (β = -0.25, p = 0.025) only at night.	Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.	
26742719	Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbβ and Pparα. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders. 
26741371	Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties. 
26740659	Rod photoreceptors are electrically coupled through gap junctions. Coupling is a key determinant of their light response properties, but whether rod electrical coupling is dynamically regulated remains elusive and controversial. Here, we have obtained direct measurements of the conductance between adjacent rods in mouse retina and present evidence that rod electrical coupling strength is dependent on the time of day, the lighting conditions, and the mouse strain. Specifically, we show in CBA/Ca mice that under circadian conditions, the rod junctional conductance has a median value of 98 pS during the subjective day and of 493 pS during the subjective night. In C57BL/6 mice, the median junctional conductance between dark-adapted rods is ∼140 pS, regardless of the time in the circadian cycle. Adaptation to bright light decreases the rod junctional conductance to ∼0 pS, regardless of the time of day or the mouse strain. Together, these results establish the high degree of plasticity of rod electrical coupling over the course of the day. Estimates of the rod coupling strength will provide a foundation for further investigations of rod interactions and the role of rod coupling in the ability of the visual system to anticipate, assimilate, and respond to the daily changes in ambient light intensity.Many cells in the CNS communicate via gap junctions, or electrical synapses, the regulation of which remains largely unknown. Here, we show that the strength of electrical coupling between rod photoreceptors of the retina is regulated by the time of day and the lighting conditions. This mechanism may help us understand some key aspects of day and night vision as well as some visual malfunctions.	
26739996	Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes.We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations.	We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43-0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63-1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model.	In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.	
26739872	We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin-angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP. 
26739645	Within populations, free-living birds display considerable variation in observable sleep behaviors, reflecting dynamic interactions between individuals and their environment. Genes are expected to contribute to repeatable between-individual differences in sleep behaviors, which may be associated with individual fitness. We identified and genotyped polymorphisms in nine candidate genes for sleep, and measured five repeatable sleep behaviors in free-living great tits (Parus major), partly replicating a previous study in blue tits (Cyanistes caeruleus). Microsatellites in the CLOCK and NPAS2 clock genes exhibited an association with sleep duration relative to night length, and morning latency to exit the nest box, respectively. Furthermore, microsatellites in the NPSR1 and PCSK2 genes associated with relative sleep duration and proportion of time spent awake at night, respectively. Given the detection rate of associations in the same models run with random markers instead of candidate genes, we expected two associations to arise by chance. The detection of four associations between candidate genes and sleep, however, suggests that clock genes, a clock-related gene, or a gene involved in the melanocortin system, could play key roles in maintaining phenotypic variation in sleep behavior in avian populations. Knowledge of the genetic architecture underlying sleep behavior in the wild is important because it will enable ecologists to assess the evolution of sleep in response to selection. 
26738972	There is controversy about the anti- or pro-oxidative effects of the nitric oxide (NO)-donor sodium nitroprusside (SNP). Hence, the activity of the antioxidant enzyme catalase (CAT) and the status of malondialdehyde (MDA) were investigated after a 2.5 mg/kg dose of SNP had been i.p. administered to different and comparable groups of mice (n = 48). The drug was administered at two different circadian times (1 and 13 h after light onset [HALO]). There were, irrespectively of sampling time, no significant differences in the means of CAT activity and MDA status between control and SNP-treated groups, no matter the treatment time. However, CAT activity was significantly (Student's t-test, p < 0.001) increased 1 h following SNP administration at 1 HALO, whereas the significant (p < 0.001) increase in the enzyme activity was found only 3 h after injection at 13 HALO. The drug dosing either at 1 or 13 HALO resulted in no significant differences of MDA status between control and treated groups regardless to the sampling time. Two-way analysis of variance (ANOVA) detected a significant (F0.05(7,88)= 5.3; p < 0.0006) interaction between sampling time and treatment in mice injected at 1 HALO, suggesting the influence of treatment on sampling-time-related changes in CAT activity. However, ANOVA validated no interaction between the two factors in mice treated at 13 HALO, illustrating that the sampling-time differences in enzyme activity were greater. Furthermore, two-way ANOVA revealed no interaction in the variation of MDA status in animals treated either at 1 or 13 HALO. This study indicates that SNP significantly affected the anti-oxidant system.
26738310	The purpose was to calculate thresholds of diurnal blood pressure parameters (BP) in men with isolated clinical hypertension (ICH) living beyond the Arctic circle, and selection of those parameters that will be particularly informative for differential diagnostics of ICH and essential hypertension (EH) in this contingent. Fifty male subjects were distributed in the ICH group (n = 25) and normotensive group with one and more cardiovascular risk factors (n = 25). No drug therapy was provided during diurnal BP monitoring (DBPM). ICH was diagnosed in the event of increased office BP, normal DBPM values and self-monitoring of BP (BPSM). ROC-analysis was applied to calculate thresholds of the BP diurnal profile for men with ICH and identify the most useful ones. Specifically, these include the following thresholds: average daily systolic BP (SBP) (> 122 mm Hg), average daytime SBP (> 127 mm Hg) and average nighttime SBP (> 108 mmHg), and SBP time indices over 24 hrs. (> 16.7%) and daytime (> 14.4 %). The range of scatter of these values allows differential diagnostics of both ICH and EH which is important for health expertise of male dwellers in the region. Early ICH detection in men with high cardiovascular risks and prescription of anti-hypertension therapy will reduce the probability of ICH progression to stable hypertension, prevent damage to target-organs and mitigate the total cardiovascular risk.
26738267	Light pollution is defined as the abnormal and disturbing nocturnal presence of light, its adverse consequences on flora, fauna, and, ecosystems, and its suspected or proven effects on human health. Light pollution is a quite recent and increasing phenomenon within our society; it leads to a major environmental damage not only on wildlife, but also on human health (cancers, obesity, fatigue, depression...). The solutions to this problem are however simple, efficient and, de facto, inexpensive because they involve a substantial energy saving.
26737266	Sleeping is a crucial part of our circadian rhythm and the quality of sleep has substantial impact on the quality of life in general and the overall well-being of a person. That is why sleep related physiological measurements have been in the focus of many scientific studies along the years, and why a large number of different measurement methods have been developed for this purpose. The ability to monitor heart rate respiration without any sensors or electrodes being directly attached to the body is extremely useful especially in long-term monitoring and it allows automated daily measurements without any medical staff present. This is the reason why ballistocardiographic force sensors and accelerometers have been introduced alongside electrocardiography (ECG) and thermistors or respiration belts as a means to monitor the heart rate and respiration during sleep. While ECG remains as the most reliable and accurate method for heart rate monitoring, the development of unobtrusive monitoring methods has improved to the point where the commercialization of such sleep monitoring systems has been possible. In this paper, the signals of five sensors and sensor placement combinations for measuring physiological parameters from a sleeping person are evaluated and compared in terms of their measurement sensitivities and waveform quality. The sensors are accelerometer and film type force sensors made of PVDF and EMFi material placed under the mattress topper and PVDF and EMFi sensors placed under the bed posts. 
26737009	R-R interval signals that come from different subjects are regularly aligned and averaged according to the horological starting time of the recordings. We argue that the horological time is a faulty alignment criterion and provide evidence in the form of a new alignment method. Our main motivation is that the human heart rate (HR) rhythm follows a circadian cycle, whose pattern can vary among different classes of people. We propose two novel alignment algorithms that consider the HR circadian rhythm, the Puzzle Piece Alignment Algorithm (PPA) and the Event Based Alignment Algorithm (EBA). First, we convert the R-R interval signal into a series of time windows and compute the mean HR per window. Then our algorithms search for matching circadian patterns to align the signals. We conduct experiments using R-R interval signals extracted from two databases in the Physionet Data Bank. Both algorithms are able to align the signals with respect to the circadian rhythmicity of HR. Furthermore, our findings confirm the presence of more than one pattern in the circadian HR rhythm. We suggest an automatic classification of signals according to the three most prominent patterns. 
26736994	This paper is presenting a software development for simulating and processing thermometry data. The motivation of this research is the miniaturization of actuators attached to human body which allow frequent temperature measurements and improve the medical diagnosis procedures related to circadian dynamics. 
26736954	LTMS-S is a new wearable system for the monitoring of several physiological signals--including a two-lead electrocardiogram (ECG)--and parameters, such as the heart rate, the breathing rate, the peripheral oxygen saturation (SpO2), the core body temperature (CBT), and the physical activity. All signals are measured using only three sensors embedded within a vest. The sensors are standalone with their own rechargeable battery, memory, wireless communication and with an autonomy exceeding 24 hours. This paper presents the results of the clinical validation of the LTMS-S system.
26736258	This study was designed to characterize in time, frequency and information domains heart period (HP) and QT interval variabilities in asymptomatic (ASYMP) long QT syndrome type 2 (LQT2) subjects. HP, approximated as the temporal distance between two consecutive R-wave peaks, and QT, approximated as the temporal distance between the R-wave peak and the T-wave offset, were automatically derived from 24h Holter recordings in 10 ASYMP LQT2 patients and 13 healthy non mutation carriers (NMC) subjects. All analyses were carried out during DAY (from 2 to 6 PM) and NIGHT (from 12 to 4 AM). Mean, variance, spectral power and complexity indices at short, medium and long time scales were assessed over HP and QT beat-to-beat series. Circadian rhythmicity was evident in both NMC and ASYMP LQT2 but ASYMP LQT2 subjects were characterized by higher HP, QT interval and HP variability during both DAY and NIGHT. In addition, multiscale complexity analysis was able to differentiate the groups by showing a higher HP complexity and a lower QT complexity at long time scales in ASYMP LQT2 during DAY. ASYMP LQT2 exhibited a different autonomic control compared to NMC and such a differentiation could be protective and assure them a lower risk profile. 

26735517	The paradigm of chronobiology is based almost wholly upon the daily biological clock, or circadian rhythm, which has been the focus of intense molecular, cellular, pharmacological, and behavioral, research. However, the circadian rhythm does not explain biological timings related to fundamental aspects of life history such as rates of tissue/organ/body size development and control of the timing of life stages such as gestation length, age at maturity, and lifespan. This suggests that another biological timing mechanism is at work. Here we focus on a "many days" (multidien) chronobiological period first observed as enigmatic recurring growth lines in developing mammalian tooth enamel that is strongly associate with all adult tissue, organ, and body masses as well as life history attributes such as gestation length, age at maturity, weaning, and lifespan, particularly among the well studied primates. Yet, knowledge of the biological factors regulating the patterning of mammalian life, such as the development of body size and life history structure, does not exist. To identify underlying molecular mechanisms we performed metabolome and genome analyses from blood plasma in domestic pigs. We show that blood plasma metabolites and small non-coding RNA (sncRNA) drawn from 33 domestic pigs over a two-week period strongly oscillate on a 5-day multidien rhythm, as does the pig enamel rhythm. Metabolomics and genomics pathway analyses actually reveal two 5-day rhythms, one related to growth in which biological functions include cell proliferation, apoptosis, and transcription regulation/protein synthesis, and another 5-day rhythm related to degradative pathways that follows three days later. Our results provide experimental confirmation of a 5-day multidien rhythm in the domestic pig linking the periodic growth of enamel with oscillations of the metabolome and genome. This association reveals a new class of chronobiological rhythm and a snapshot of the biological bases that regulate mammalian growth, body size, and life history. 
26734985	This study represents a first controlled comparison of restricted versus unrestricted sleep in both day and night sleep categories. A repeated measures study of a homogenous group of young women without sleep disorders (n=14) found that stage 1, 2, 3 and REM sleep, as well as sleep latency were not statistically different between day ad libitum sleep (DAL) and day interrupted (DI) sleep categories, while night interrupted (NI) and ad libitum (NAL) sleep showed strikingly different architecture.
26734724	Morphology of the cell nucleus has been used as a key indicator of disease state and prognosis, but typically without quantitative rigor. It is also not well understood how nuclear morphology varies with time across different genetic backgrounds in healthy cells. To help answer these questions we measured the size and shape of nuclei in cell-cycle-synchronized primary human fibroblasts from 6 different individuals at 32 time points over a 75 hour period.The nucleus was modeled as an ellipsoid and its dynamics analyzed. Shape and volume changed significantly over this time. Two prominent frequencies were found in the 6 individuals: a 17 hour period consistent with the cell cycle and a 26 hour period. Our findings suggest that the shape of the nucleus changes over time and thus any time-invariant shape property may provide a misleading characterization of cellular populations at different phases of the cell cycle. The proposed methodology provides a general method to analyze morphological change using multiple time points even for non-live-cell experiments.	
26732455	Body temperature (BT) monitoring in cattle could be used to early detect fever from infectious disease or physiological events. Various ways to measure BT have been applied at different locations on cattle including rectum, reticulum, milk, subcutis and ear canal. In other to evaluate the temperature stability and reliability of subcutaneous temperature (ST) in highly fluctuating field conditions for continuous BT monitoring, long term ST profiles were collected and analyzed from cattle in autumn/winter and summer season by surgically implanted thermo-logger devices. Purposes of this study were to assess ST in the field condition as a reference BT and to determine any location effect of implantation on ST profile. In results, ST profile in cattle showed a clear circadian rhythm with daily lowest at 05:00 to 07:00 AM and highest around midnight and rather stable temperature readings (mean±standard deviation [SD], 37.1°C to 37.36°C±0.91°C to 1.02°C). STs are 1.39°C to 1.65°C lower than the rectal temperature and sometimes showed an irregular temperature drop below the normal physiologic one: 19.4% or 36.4% of 54,192 readings were below 36.5°C or 37°C, respectively. Thus, for BT monitoring purposes in a fever-alarming-system, a correction algorithm is necessary to remove the influences of ambient temperature and animal resting behavior especially in winter time. One way to do this is simply discard outlier readings below 36.5°C or 37°C resulting in a much improved mean±SD of 37.6°C±0.64°C or 37.8°C±0.55°C, respectively. For location the upper scapula region seems the most reliable and convenient site for implantation of a thermo-sensor tag in terms of relatively low influence by ambient temperature and easy insertion compared to lower scapula or lateral neck. 
26732296	Physiology of living beings show circadian rhythms entrained by a central timekeeper present in the hypothalamic suprachiasmatic nuclei. Nevertheless, virtually all peripheral tissues hold autonomous molecular oscillators constituted essentially by circuits of gene expression that are organized in negative and positive feed-back loops. Accumulating evidence reveals that cell metabolism is rhythmically controlled by cell-intrinsic molecular clocks and the specific pathways involved are being elucidated. Here, we show that in vitro-synchronized cultured cells exhibit BMAL1-dependent oscillation in mitochondrial respiratory activity, which occurs irrespective of the cell type tested, the protocol of synchronization used and the carbon source in the medium. We demonstrate that the rhythmic respiratory activity is associated to oscillation in cellular NAD content and clock-genes-dependent expression of NAMPT and Sirtuins 1/3 and is traceable back to the reversible acetylation of a single subunit of the mitochondrial respiratory chain Complex I. Our findings provide evidence for a new interlocked transcriptional-enzymatic feedback loop controlling the molecular interplay between cellular bioenergetics and the molecular clockwork. 

26731717	It is widely known that there is an increase in the inflammatory responses and oxidative stress in temporal lobe epilepsy (TLE). Further, the seizures follow a circadian rhythmicity. Retinoic acid receptor-related orphan receptor alpha (RORα) is related to anti-inflammatory and antioxidant enzyme expression and is part of the machinery of the biological clock and circadian rhythms. However, the participation of RORα in this neurological disorder has not been studied. The aim of this study was to evaluate the RORα mRNA and protein content profiles in the hippocampus of rats submitted to a pilocarpine-induced epilepsy model at different time points throughout the 24-h light-dark cycle analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases of the experimental model. Real-time PCR and immunohistochemistry results showed that RORα mRNA and protein expressions were globally reduced in both acute and silent phases of the pilocarpine model. However, 60days after the pilocarpine-induced status epilepticus (chronic phase), the mRNA expression was similar to the control except for the time point 3h after the lights were turned off, and no differences were found in immunohistochemistry. Our results indicate that the status epilepticus induced by pilocarpine is able to change the expression and daily variation of RORα in the rat hippocampal area during the acute and silent phases. These findings enhance our understanding of the circadian pattern present in seizures as well as facilitate strategies for the treatment of seizures. 
26731697	Night work has been suggested as a risk factor for diabetes. Individuals with high triglyceride levels, high LDL cholesterol, low HDL cholesterol and obesity, especially abdominal obesity, have a greater chance of developing diabetes. The aim of this study was to analyze glycemic levels, total cholesterol, HDL-C, LDL-C, triglycerides and the anthropometric alterations that precede diabetes, considering their possible association with nigh work among a non-diabetic population. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) comprises of 15,105 civil servants (35-74 years old) at baseline (2008-2010). The following parameters were analyzed: serum cholesterol (total cholesterol, HDL-C, LDL-C), triglycerides and glucose drawn from 12-hour fasting blood sample, glycated hemoglobin and 2-hour plasma glucose obtained after a 75 g oral glucose tolerance test, BMI, hip and waist measurements using standard equipment and techniques. Participants with diabetes, retired workers and day workers with previous experience of night work were excluded. Generalized linear models, a gamma regression model with an identity link function, were performed to test the association of night work with metabolic and anthropometric variables. The study sample consisted of 3918 men and 4935 women; 305 (7.8%) and 379 (7.7%) of the participants were men and women who worked at night, respectively. Among the men, the exposure to night work was associated with an increase in BMI (b-value = 0.542; p = 0.032) and waist circumference (b-value = 1.66; p = 0.014). For women, increased fasting plasma glucose (b-value = 2.278; p < 0.001), glycated hemoglobin (b-value = 0.099, p < 0.001) and 2 hour plasma glucose (b-value = 5.479, p = 0.001) were associated with night work after adjustments. No significant associations between night work and triglycerides, LDL-C, HDL-C, total cholesterol levels or waist-hip ratio were found. The influences of night work on metabolic and anthropometric factors suggest night work as a potential risk factor for type 2 diabetes. Further studies are needed to investigate the inconclusive data on gender differences in the associations.
26731571	Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 ± 3.7 (mean ± SD) years, participated. Blood (hourly) and urine (4-hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 ± 104 (mean ± SEM) vs. 642 ± 47 pg/ml.h; AUC cortisol: 13581 ± 1313 vs. 7340 ± 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 ± 5.8 vs. 29.9 ± 2.3 pg/ml; cortisol: 241.7 ± 23.1 vs. 161.8 ± 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 ± 63.8 vs. 349.2 ± 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users.
26731556	Sleep disorders in individuals with developmental difficulties continue to be a significant challenge for families, carers, and therapists with a major impact on individuals and carers alike. This review is designed to update the reader on recent developments in this area.A systematic search identified a variety of studies illustrating advances in the regulation of circadian rhythm and sleep disturbance in neurodevelopmental disorders. Specific advances are likely to lead in some disorders to targeted therapies. There is strong evidence that behavioural and sleep hygiene measures should be first line therapy; however, studies are still limited in this area. Nonpharmacological measures such as exercise, sensory interventions, and behavioural are reported. Behavioural regulation and sleep hygiene demonstrate the best evidence for improved sleep parameters in individuals with neurodisability.	Although the mainstay of management of children with sleep problems and neurodevelopmental disability is similar to that of typically developing children, there is emerging evidence of behavioural strategies being successful in large-scale trials and the promise of more targeted therapies for more specific resistant disorders.	
26731279	El jet lag es un trastorno exógeno del sueño y el ritmo circadiano que ocurre frecuentemente en viajeros que cruzan múltiples zonas horarias en un tiempo reducido. La administración de melatonina oral, neurohormona epifisiaria relacionada con la regulación de ritmos circadianos, se ha utilizado con el fin de disminuir los síntomas que caracterizan esta condición. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, encontramos cuatro revisiones sistemáticas que en conjunto incluyen 11 estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que la administración de melatonina oral probablemente disminuye los síntomas asociados al jet lag, y que no está claro si se asocia a efectos adversos, aunque estos serían leves.Jet lag syndrome is an exogenous circadian rhythm sleep disorder, frequently reported in travelers who cross multiple time zones in a short period of time. Oral melatonin -a pineal neurohormone normally produced during darkness and responsible for regulating the body's circadian rhythms- has been used as treatment for this condition. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including 11 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of oral melatonin probably reduces symptoms associated with jet lag syndrome. It is not clear whether its use produces adverse effects; however, these would be probably mild. 	
26731185	Increased short-term blood pressure (BP) variability on 24-hour ambulatory BP monitoring (ABPM) is known to be a risk factor for cardiovascular events. However, very few studies have evaluated the effect of salt restriction on BP variability particularly in hypertensive patients with type 2 diabetes. This study aimed to investigate the effect of salt restriction on systolic BP (SBP) variability.10 hypertensive patients with type 2 diabetes and not receiving antihypertensive agents were enrolled in the study. After admission, all patients received a salt-restricted diet and appropriate anti-diabetic treatments and were followed up for 7 consecutive days using ABPM. After the 7-day treatment, the median [interquartile range (IQR)] coefficient of variation (CV) for diurnal SBP variability changed from day 1 to day 7-13.0 [10.8 to 16.8] % to 13.3 [9.1 to 18.9] % (P = 0.959)--and the median [IQR] change between days 1 and 7 was -0.3 [-3.2 to 2.9] %. In addition, CV for BP variability and circadian rhythm of BP varied greatly on a day-by-day basis for 7 days, compared to mean BP values. Interestingly, increased SBP variability was associated with greater day-by-day changes in circadian rhythm of BP.	Salt restriction during 7-day hospitalization led to a -0.3 [-3.2 to 2.9] (median [IQR]) % change from baseline in CV for diurnal SBP variability in 10 hypertensive patients with type 2 diabetes not receiving antihypertensive agents.	UMIN Clinical Trials Registry UMIN000016243.	
26731021	This study aimed to determine the prevalence of Night Eating Syndrome (NES) among overweight or obese patients with serious mental illness and its relationship with insomnia and quality of life.This study included 158 overweight or obese patients diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder (according to DSM-IV criteria) that were not in the active disease period. A clinical interview and Night Eating Questionnaire (NEQ) were used to assess the prevalence of NES among those in the study group. Body mass index (BMI), sleep quality, and quality of life measures were also evaluated for each patient.	Twelve patients (7.6%) were diagnosed with NES via clinical interview while 26 (16.5%) were diagnosed by having ≥25 points in the NEQ. There were no statistically significant differences between the NES and non-NES groups with respect to age, gender, education and body mass index. However, quality of life scores were lower while the severity of insomnia scores were higher in patients with NES.	The prevalence of NES is higher among overweight or obese patients with serious mental illness when compared to prevalence data in a general population, as demonstrated by previously published studies. Night eating behavior may be related to insomnia and poor quality of life measures. The recognition of NES among patients with severe mental disease is essential to promote prevention of obesity and insomnia as related to night eating behavior.	
26730983	We investigated sleep quality and melatonin in 12 adults who wore blue-light shield or control eyewear 2 hours before sleep while using a self-luminous portable device, and assessed visual quality for the two eyewear types. Overnight melatonin secretion was significantly higher after using the blue-light shield (P < 0.05) than with the control eyewear. Sleep efficacy and sleep latency were significantly superior for wearers of the blue-light shield (P < 0.05 for both), and this group reported greater sleepiness during portable device use compared to those using the control eyewear. Participants rated the blue-light shield as providing acceptable visual quality.
26730807	Emotional intelligence (EI) and morningness-eveningness (M-E) preference have been shown to influence mood states. The present article investigates the way in which these two constructs may interact, influencing morning and evening mood levels. A sample of 172 participants completed a multidimensional mood scale measuring energetic arousal (EA), tense arousal (TA), and hedonic tone at 7:00 and at 22:00. As expected, morning and evening types experienced higher EA at their preferred time of day; effects of M-E on other mood dimensions were weaker. EI was found to correlate with lower TA, but the association was stronger at 22:00, perhaps reflecting the role of EI in managing the social events characteristic for the evening hours. An interactive effect of EI and M-E was found for both diurnal changes and morning levels of EA. Namely, in individuals higher in EI, there appeared a more marked synchrony effect between chronotype and EA, which was absent in those low in EI; individuals higher in EI showed more pronounced diurnal changes in EA characteristic for their chronotype (i.e., higher EA at morning hours in morning chronotypes; higher EA at evening hours in evening chronotypes), while in participants low in EI, diurnal changes in EA were smaller. Moreover, the characteristic positive association between morningness and EA during morning hours was apparent only in those high in EI. These findings suggest that individual differences in circadian variation in mood reflect several factors, including an endogenous rhythm in energy, the distribution of social activities throughout the day, and the person's awareness of their own energy level.
26730643	Recovery is essential for high athletic performance, and therefore especially sleep has been identified as a crucial source for physical and psychological well-being. However, due to early-morning trainings, which are general practice in many sports, athletes are likely to experience sleep restrictions. Therefore, this study investigated the sleep-wake patterns of 55 junior national rowers (17.7 ± 0.6 years) via sleep logs and actigraphy during a four-week training camp. Recovery and stress ratings were obtained every morning with the Short Recovery and Stress Scale on a 7-point Likert-type scale ranging from 0 (does not apply at all) to 6 (fully applies). The first training session was scheduled for 6:30 h every day. With two to four training sessions per day, the training load was considerably increased from athletes' home training. Objective sleep measures (n = 14) revealed less total sleep time (TST) in the first two weeks (409.6 ± 19.1 and 416.0 ± 16.3 min), while training volume and intensity were higher. In the second half of the camp, less training sessions were implemented, more afternoons were training free and TSTs were longer (436.3 ± 15.8 and 456.9 ± 25.7 min). A single occasion of 1.5-h delayed bedtime and usual early morning training (6:30 h) resulted in reduced ratings of Overall Recovery (OR) (M = 3.3 ± 1.3) and greater Negative Emotional State (NES) (M = 1.3 ± 1.2, p < .05), which returned to baseline on the next day. Following an extended night due to the only training-free day, sleep-offset times were shifted from ~5:30 to ~8:00 h, and each recovery and stress score improved (p < .01). Moreover, subjective ratings of the first six days were summarised as a baseline score to generate reference data as well as to explore the association between sleep and recovery. Intercorrelations of these sleep parameters emphasised the relationship between restful sleep and falling asleep quickly (r = .34, p < .05) as well as few awakenings (r = .35, p < .05). Overall, the findings highlight the impact of sleep on subjective recovery measures in the setting of a training camp. Providing the opportunity of extended sleep (and a day off) seems the most simple and effective strategy to enhance recovery and stress-related ratings.
26730506	General anaesthesia administered during the day has previously been shown to phase shift the honey bee clock. We describe a phase response curve for honey bees (n=105) to six hour isoflurane anaesthesia. The honey bee isoflurane PRC is "weak" with a delay portion (maximum shift of -1.88 hours, circadian time 0 - 3) but no advance zone. The isoflurane-induced shifts observed here are in direct opposition to those of light. Furthermore, concurrent administration of light and isoflurane abolishes the shifts that occur with isoflurane alone. Light may thus provide a means of reducing isoflurane-induced phase shifts.
26729506	Fertilizers are often potential environmental pollutants, therefore increasing productivity and the efficiency of nutrient uptake to boost crop yields without the risk of environmental pollution is a desirable goal. Here, we show that the transcription factor encoding gene RDD1 plays a role in improving the uptake and accumulation of various nutrient ions in rice. RDD1 was found to be targeted by the microRNA miR166. An RDD1 transgene driven by a strong constitutive promoter exhibited a diurnally oscillating expression similar to that of the endogenous RDD1, and nucleotide substitution within the miR166 recognition site to prevent miR166-RDD1 mRNA pairing resulted in constitutive RDD1 expression. The RDD1 protein was localized to vascular tissue because miR166 repressed RDD1 expression in the mesophyll. The overexpression of RDD1 induced the expression of genes associated with the transport of several nutrients such as NH4(+), Na(+), SO4(2-), Cl(-), PO4(3-) and sucrose, and the uptake and accumulation of various nutrient ions under low-nutrient conditions. Moreover, the overexpression of RDD1 increased nitrogen responsiveness and grain productivity. Our results suggest that RDD1 can contribute to the increased grain productivity of rice via inducing the efficient uptake and accumulation of various nutrient ions.


26728391	An emerging cavefish model, the cyprinid genus Sinocyclocheilus, is endemic to the massive southwestern karst area adjacent to the Qinghai-Tibetan Plateau of China. In order to understand whether orogeny influenced the evolution of these species, and how genomes change under isolation, especially in subterranean habitats, we performed whole-genome sequencing and comparative analyses of three species in this genus, S. grahami, S. rhinocerous and S. anshuiensis. These species are surface-dwelling, semi-cave-dwelling and cave-restricted, respectively.The assembled genome sizes of S. grahami, S. rhinocerous and S. anshuiensis are 1.75 Gb, 1.73 Gb and 1.68 Gb, respectively. Divergence time and population history analyses of these species reveal that their speciation and population dynamics are correlated with the different stages of uplifting of the Qinghai-Tibetan Plateau. We carried out comparative analyses of these genomes and found that many genetic changes, such as gene loss (e.g. opsin genes), pseudogenes (e.g. crystallin genes), mutations (e.g. melanogenesis-related genes), deletions (e.g. scale-related genes) and down-regulation (e.g. circadian rhythm pathway genes), are possibly associated with the regressive features (such as eye degeneration, albinism, rudimentary scales and lack of circadian rhythms), and that some gene expansion (e.g. taste-related transcription factor gene) may point to the constructive features (such as enhanced taste buds) which evolved in these cave fishes.	As the first report on cavefish genomes among distinct species in Sinocyclocheilus, our work provides not only insights into genetic mechanisms of cave adaptation, but also represents a fundamental resource for a better understanding of cavefish biology.	
26728169	The environment in which individuals develop and mature is critical for their physiological and psychological outcome; in particular, the intrauterine environment has reached far more clinical relevance given its potential influence on shaping brain function and thus mental health. Gestational stress and/or maternal infection during pregnancy has been related with an increased incidence of neuropsychiatric disorders, including depression and schizophrenia. In this framework, the use of animal models has allowed a formal and deep investigation of causal determinants. Despite disruption of circadian clocks often represents a hallmark of several neuropsychiatric disorders, the relationship between disruption of brain development and the circadian system has been scarcely investigated. Nowadays, there is an increasing amount of studies suggesting a link between circadian system malfunction, early-life insults and the appearance of neuropsychiatric diseases at adulthood. Here, we briefly review evidence from clinical literature and animal models suggesting that the exposure to prenatal insults, i.e. severe gestational stress or maternal immune activation, changes the foetal hormonal milieu increasing the circulating levels of both glucocorticoids and pro-inflammatory cytokines. These two biological events have been reported to affect genes expression in experimental models and critically interfere with brain development triggering and/or exacerbating behavioural anomalies in the offspring. Herein, we highlight the importance to unravel the individual components of the body circadian system that might also be altered by prenatal insults and that may be causally associated with the disruption of neural and endocrine developmental programming. 
26727487	This study aimed to evaluate the association of night-time blood pressure (BP) assessed by home blood pressure (HBP) or ambulatory blood pressure (ABP) monitoring with preclinical target organ damage in untreated hypertension.Untreated hypertensive study participants were evaluated with ABP monitoring (24-h) and HBP monitoring during daytime (6 days, duplicate morning and evening measurements) and night-time (automated asleep measurements, three nights, 3-hourly measurements/night). Target organ damage was assessed by echocardiographic left ventricular mass index (LVMI), common carotid intima-media thickness (cIMT), urine albumin excretion (UAE), and ankle-brachial index (ABI).	A total of 131 study participants were analysed [mean age 52.1 ± 11.9 (SD) years, BMI 29.9 ± 5.3  kg/m2, men 58%, cardiovascular disease history 6.1%]. Daytime and night-time HBP were slightly higher than the respective ABP values (mean difference for systolic daytime/night-time 3.5 ± 10.6/2.6 ± 9.8  mmHg, P < 0.01 for both comparisons and diastolic -0.3 ± 6.8/1.2 ± 6.2  mmHg, P = NS/0.02, respectively). There was a strong correlation between daytime ABP and HBP (r = 0.71/0.72, systolic/diastolic), as well as between the respective night-time values (r = 0.80/0.79; all P < 0.01). Night-time ABP and HBP presented strong and comparable correlations with all the indices of preclinical target organ damage. In multivariate analyses, both LVMI (R2 = 0.26) and cIMT (R2 = 0.25) were determined by night-time systolic HBP, age and male sex; UAE (R2 = 0.28) by night-time systolic HBP and male sex; ABI (R2 = 0.20) by male sex and night-time home pulse pressure.	In untreated hypertensives, night-time BP assessed by home monitoring appears to be as good as night-time ambulatory monitoring in determining preclinical target organ damage.	
26727258	Alzheimer's disease (AD) is a neurodegenerative disease often accompanied with disruption of sleep-wake cycle. The sleep-wake cycle is controlled by mechanisms involving internal timekeeping (circadian) regulation. The aim of our present pilot study was to assess the circadian system in patients with mild form of AD in their home environment. In the study, 13 elderly AD patients and 13 age-matched healthy control subjects (the patient's spouses) were enrolled. Sleep was recorded for 21 days by sleep diaries in all participants and checked by actigraphy in 4 of the AD patient/control couples. The samples of saliva and buccal mucosa were collected every 4 hours during the same 24 h-interval to detect melatonin and clock gene (PER1 and BMAL1) mRNA levels, respectively. The AD patients exhibited significantly longer inactivity interval during the 24 h and significantly higher number of daytime naps than controls. Daily profiles of melatonin levels exhibited circadian rhythms in both groups. Compared with controls, decline in amplitude of the melatonin rhythm in AD patients was not significant, however, in AD patients more melatonin profiles were dampened or had atypical waveforms. The clock genes PER1 and BMAL1 were expressed rhythmically with high amplitudes in both groups and no significant differences in phases between both groups were detected. Our results suggest moderate differences in functional state of the circadian system in patients with mild form of AD compared with healthy controls which are present in conditions of their home dwelling. 
26726810	Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs' minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk. 
26725752	Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematically assess HR and HRV in two common diabetic mouse models.ECG radiotelemetry devices were implanted into db/db (type-2 diabetic), STZ-treated db/+ (type-1 diabetic), and control db/+ mice (n=4 per group). HR and HRV were analyzed over 24 h and during treadmill testing.	24 h analysis revealed that db/db mice had an altered pattern of circadian HR changes, and STZ-treated mice had reduced HR throughout. HRV measures linked to sympathetic control were reduced in db/db mice in the early morning and early afternoon, and partially reduced in STZ-treated mice. HR response to treadmill testing was blunted in both models.	It is important to consider both time of day and level of stress when assessing HR and HRV in diabetic mice. db/db mice may have altered circadian rhythm of sympathetic control of HR, whereas STZ-treated mice have a relative reduction. This study provides baseline data and a framework for HR analysis that may guide future investigations.	
26725725	Circadian clocks regulate the rhythms of biological activities with a period of approximately 24-hours and synchronize plant metabolism and physiology with the environmental cycles. The clock also gates responses to environmental stresses to maximize fitness advantages. Here we report that the MYB96 transcription factor is connected with the clock oscillator to shape the circadian gating of abscisic acid (ABA) responses. MYB96 directly binds to the TIMING OF CAB EXPRESSION 1 (TOC1) promoter to positively regulate its expression. The use of myb96 mutant plants shows that this regulation is essential for the gated induction of TOC1 by ABA. In turn, MYB96 induction by ABA is also altered in toc1-3 mutant plants. The increased tolerance to drought of MYB96 over-expressing plants is decreased in the toc1-3 mutant background, suggesting that MYB96 and TOC1 intersect the circadian clock and ABA signaling. The MYB96-TOC1 function might be also regulated by the clock component CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1), which binds to the MYB96 promoter and alters its circadian expression. Thus, a complex circuitry of CCA1-MYB96-TOC1 regulatory interactions provides the mechanistic basis underlying the connection between circadian and stress signaling to optimize plant fitness to ambient stresses. 
26725393	To investigate the relationship of the circadian rhythm of the urine volume and urine electrolytes excretion rate and the daily expression pattern of the clock genes and clock-controlled genes with the water electrolyte transportation circadian pattern in rat kidneys.Male adult SD rats were exposed to in a light:dark (12:12) cycles. We collected two period urine from zeitgeber time (ZT)00:00-ZT12:00 (light time,rest period) and ZT12:00-24:00 (dark time,activity period) and then compared the urinary excretion rates of volume, sodium, potassium, and chloride at light time with those at dark time. Rats were sacrificed every 4 hours throughout a 24-hour day-night cycle. Circadian clock gene CLOCK, BMAL1,Per1,Per2,Cry1,Cry2 and kidney specific clock-controlled gene NHE3,αENaC、NCC,Ptges,V1aR,V2R expression were profiled by real-time quantitative polymerase chain reaction. Data were analysed by a partial Fourier analysis and a stepwise regression technique.	Urine volume and urine potassium excretion rate displayed high level at dark time and low at light time in SD rats (P<0.05),and urine sodium and chloride excretion rate also showed the trend(P>0.05).Clock gene CLOCK,BMAL1,Per1,Per2,Cry1,Cry2(P<0.05)and kidney specific clock-controlled gene NHE3, αENaC, NCC, Ptges, V1aR, V2R (P<0.05)mRNA expression showed circadian pattern,and the peak times of the genes were in the dark time.	Urine volume and urine electrolyte excretion rate which displayed circadian pattern were temporally coupled with the rhythm of expression of clock and clock-controlled genes associated with water electrolyte transportation in rats kidney.	

26724713	In marmosets, a phase advance was observed in activity onset in pubertal animals living in captivity under semi-natural conditions which had stronger correlation with the times of sunrise over the course of the year than the age of the animal. In order to evaluate the effect of puberty on the circadian activity rhythm in male and female marmosets living in family groups in controlled lighting conditions, the activity of 5 dyads of twins (4 ♀/♂ and 1 ♂/♂) and their respective parents was continuously monitored by actiwatches between the 4th and 12th months of age. The families were kept under LD 12:12 h with constant humidity and temperature. The onset of puberty was identified by monitoring fecal steroids. Juveniles showed higher totals of daily activity and differences in the daily distribution of activity in relation to parents, in which the bimodal profile was characterized by higher levels in evening activity in relation to morning activity. Regarding the phase, the activity onset and offset, occurred later in relation to parents. After entering puberty, the activity onset and offset occurred later and there was an increase in total daily activity. On the other hand, when assessing the effect of sex, only females showed a delay in the activity offset and an increase in total daily activity. Therefore, the circadian activity rhythm in marmosets has peculiar characteristics in the juvenile stage in relation to the total of daily activity, the onset and offset of the active phase, and the distribution of activity during this phase. Besides, the entering puberty was associated with a phase delay and increase on total daily activity, with differences between sexes, possibly due to hormonal influences and/or social modulation on rhythm.
26724401	This study was undertaken to describe seizure phenotypes, natural progression, sleep-wake patterns, as well as periodicity of seizures in Kcna-1 null mutant mice. These mice were implanted with epidural electroencephalography (EEG) and electromyography (EMG) electrodes, and simultaneous video-EEG recordings were obtained while animals were individually housed under either diurnal (LD) condition or constant darkness (DD) over ten days of recording. The video-EEG data were analyzed to identify electrographic and behavioral phenotypes and natural progression and to examine the periodicity of seizures. Sleep-wake patterns were analyzed to understand the distribution and onset of seizures across the sleep-wake cycle. Four electrographically and behaviorally distinct seizure types were observed. Regardless of lighting condition that animals were housed in, Kcna-1 null mice initially expressed only a few of the most severe seizure types that progressively increased in frequency and decreased in seizure severity. In addition, a circadian periodicity was noted, with seizures peaking in the first 12h of the Zeitgeber time (ZT) cycle, regardless of lighting conditions. Interestingly, seizure onset differed between lighting conditions where more seizures arose out of sleep in LD conditions, whereas under DD conditions, the majority occurred out of the wakeful state. We suggest that this model be used to understand the circadian pattern of seizures as well as the pathophysiological implications of sleep and circadian disturbances in limbic epilepsies. 
26721740	There is emerging evidence of a relationship between the cortisol awakening response (CAR) and the neural mechanisms underlying learning and memory. The aim of this study was to determine whether the CAR is associated with acquisition, retention and overnight consolidation or improvement of a serial sequence reaction time task. Salivary samples were collected at 0, 15, 30 and 45 min after awakening in 39 healthy adults on 2 consecutive days. The serial sequence reaction time task was repeated each afternoon. Participants completed the perceived stress scale and provided salivary samples prior to testing for cortisol assessment. While the magnitude of the CAR (Z score) was not associated with either baseline performance or the timed improvement during task acquisition of the serial sequence task, a positive correlation was observed with reaction times during the stable performance phase on day 1 (r=0.373, p=0.019). Residuals derived from the relationship between baseline and stable phase reaction times on day 1 were used as a surrogate for the degree of learning: these residuals were also correlated with the CAR mean increase on day 1 (r=0.357, p=0.048). Task performance on day 2 was not associated with the CAR obtained on this same day. No association was observed between the perceived stress score, cortisol at testing or task performance. These data indicate that a smaller CAR in healthy adults is associated with a greater degree of learning and faster performance of a serial sequence reaction time task. These results support recognition of the CAR as an important factor contributing to cognitive performance throughout the day.
26721736	The neuropeptide Y system is known to play an important role in the regulation of bone homeostasis and while the functions of its major receptors, Y1R and Y2R, in this process have become clearer, the contributions of other Y-receptors, like the y6 receptor (y6R), are unknown. Y6R expression is restricted to the suprachiasmatic nucleus (SCN) of the hypothalamus, an area known to regulate circadian rhythms, and the testis. Here we show that lack of y6R signalling, results in significant reduction in bone mass, but no changes in bone length. Male and female y6R knockout (KO) mice display reduced cortical and cancellous bone volume in axial and appendicular bones. Mechanistically, the reduction in cancellous bone is the result of an uncoupling of bone remodelling, leading to an increase in osteoclast surface and number, and a reduction in osteoblast number, osteoid surface, mineralizing surface and bone formation rate. y6R KO mice displayed increased numbers of osteoclast precursors and produced greater numbers of osteoclasts in RANKL-treated cultures. They also produced fewer CFU-ALP osteoblast precursors in the marrow and showed reduced mineralization in primary osteoblastic cultures, as well as reduced expression for the osteoblast lineage marker, alkaline phosphatase, in bone isolates. The almost exclusive location of y6Rs in the hypothalamus suggests a critical role of central neuronal pathways controlling this uncoupling of bone remodelling which is in line with known actions or other Y-receptors in the brain. In conclusion, y6R signalling is required for maintenance of bone mass, with loss of y6R uncoupling bone remodelling and resulting in a negative bone balance. This study expands the scope of hypothalamic regulation of bone, highlighting the importance for neural/endocrine coordination and their marked effect upon skeletal homeostasis. 
26719365	Do your kidneys know what time it is? Mounting evidence from human studies and animal models strongly suggests that the answer to this question is yes. The time has come to start reporting the time of day at which renal physiology studies are performed. 
26718555	Cobelli's glucose-insulin model is the only computer simulator of glucose-insulin interactions accepted by Food Drug Administration as a substitute to animal trials. However, it consists of multiple differential equations that make it hard to be implemented on a hardware platform. In this investigation, the Cobelli's model is simplified by Padé approximant method and implemented on a field-programmable gate array-based platform as a hardware model for predicting glucose changes in subjects with type 1 diabetes mellitus. Compared with the original Cobelli's model, the implemented hardware model provides a nearly perfect approximation in predicting glucose changes with rather small root-mean-square errors and maximum errors. The RMSE results for 30 subjects show that the method for simplifying and implementing Cobelli's model has good robustness and applicability. The successful hardware implementation of Cobelli's model will promote a wider adoption of this model that can substitute animal trials, provide fast and reliable glucose and insulin estimation, and ultimately assist the further development of an artificial pancreas system. 
26718202	Aging leads to several anatomical and functional deficits in circadian timing system. In previous works, we observed morphological alterations with age in hypothalamic suprachiasmatic nuclei, one central component of this system. However, there are few data regarding aging effects on other central components of this system, such as thalamic intergeniculate leaflet (IGL). In this context, we studied possible age-related alterations in neurochemical components and retinal projections of rat IGL. For this goal, young (3 months), adult (13 months), and aged (23 months) Wistar rats were submitted to an intraocular injection of neural tracer, cholera toxin subunit b (CTb), 5 days before a tissue fixation process by paraformaldehyde perfusion. Optical density measurements and cell count were performed at digital pictures of brain tissue slices processed by immunostaining for glutamic acid decarboxylase (GAD), enkephalin (ENK), neuropeptide Y (NPY) and CTb, characteristic markers of IGL and its retinal terminals. We found a significant age-related loss in NPY immunoreactive neurons, but not in immunoreactivity to GAD and ENK. We also found a decline of retinal projections to IGL with age. We conclude aging impairs both a photic environmental clue afferent to IGL and a neurochemical expression which has an important modulatory circadian function, providing strong anatomical correlates to functional deficits of the aged biological clock. 
26717863	Salivary cortisol may be used as a biomarker of stress and anxiety in children with an Autism Spectrum Disorder (ASD) and is particularly valuable in studies of the association between stress-related cortisol concentrations and other factors such as comorbid disorders or aspects of the ASD phenotype. Although protocols for the collection of cortisol shortly after waking are often based on the assumption of the presence of a diurnal rhythm in cortisol, that rhythm may not be as reliable in children with an ASD as in non-ASD children. Alternatively, collecting cortisol during the afternoon may represent a more reliable procedure with less inter-participant variability. 
28525688	Суточные колебания присущи практически всем процессам в живых организмах. Нарушения циркадианных ритмов могут являться как причиной, так и следствием различных заболеваний. В статье рассмотрены литературные данные о роли изменения суточных ритмов и экспрессии часовых генов в развитии нейродегенеративных и сердечно-сосудистых заболеваний, метаболического синдрома и сахарного диабета 2-го типа у людей и животных.Almost all the functions of a living organism have circadian oscillations. Disturbance of circadian rhythms can be either a reason or a consequence of a number of diseases. The article describes data on relationship of circadian rhythm and clock genes disturbances with type 2 diabetes mellitus, cardiovascular and neurodegenerative disease development in humans and animals.	
28509476	Во 2-й части обзора подробно рассмотрены механизмы ослабления координации циркадианной системы по отношению к внешним и внутренним датчикам времени. Проанализированы основные направления стратегии противодействия проявлениям возрастного десинхроноза с учетом роли ведущего фактора — фотопериодизма и вторичных факторов синхронизации. Светотерапия, применение мелатонина и других хронобиотиков, поддержание ритма температуры тела, режим физической активности и питания рассмотрены через призму возможностей совершенствования эффективности каждого из методов на основе персонифицированного подхода и новых преимуществ сочетания этих методов.Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.	
28423243	В функционировании практически всех систем организма обнаруживаются околосуточные ритмы, поддержание которых на уровне клетки обеспечивается системой часовых генов и белков. Нарушение синхронизации этих ритмов или их утрату наблюдают при старении и ассоциированы с повышением риска онкологических заболеваний. В статье рассмотрены литературные данные о механизмах регуляции циркадианных ритмов на уровне организма и клетки, их изменениях при старении и связи нарушений этих ритмов человека и животных сразвитием опухолей различных локализаций.Almost all the body's functions exhibit circadian rhythm maintained in a cell by a system of Clock genes and proteins. Failure to synchronize or loss of these rhythms are found in aged organism and are associated with risk of cancer development. The article describes data on mechanisms of circadian rhythms regulation in whole organism and cell, rhythm change during aging and relationship between rhythm disturbances and tumorigenesis of different localisations in humans and animals.	
28278873	The circadian clock involves co-operative transcription of circadian genes including Clock and regulates circadian rhythms in mammals such as the rhythm of sleep and wakefulness. In reproductive physiologies in mammals, there are several time-dependent events such as progression of the oestrous cycle and embryonic development, and we therefore checked the reproductive characters of mice homozygous for Clock delta-19 mutation (CL) having a diminished circadian clock to elucidate the effect of the circadian clock on reproductive physiologies. Profiles of the oestrous cycle were the same in female (f) wild-type mice (WT) and fCL: oestrous cycles of both fWT and fCL consisted of the same 3 stages, proestrous, oestrous, and metestrous/diestrous stages, and the average lengths of each stage and one oestrous cycle were the same in 10 fWT and 14 fCL. We therefore compared outcomes from the 4 possible mating groups between WT and CL. Average numbers of newborn pups obtained from mating pairs of 14 male (m) WT×fWT, 10 mCL×fWT, 14 mWT×fCL, and 15 mCL×fCL were 13.4±0.8, 12.6±0.4, 12.3±0.7, and 8.6±1.5, respectively, and gradually decreased depending on the number of mutated Clock alleles in mothers and embryos. Since increases in body weights of the mothers during the gestation period were not different in the 4 mating groups and since there were no signs of spontaneous abortion from mid to late gestation, we reasoned that some embryos were lost before or at the time of implantation. Immediately before implantation (88h after fertilization), neither the number of embryos collected from uteri nor the percentage of embryos that reached the pre-implantation stage (blastocyst stage) differed significantly among mating groups. In contrast, immediately after implantation (160h after fertilization), the average numbers of implantation sites in mating pairs of 12 mWT×fWT, 11 mCL×fWT, 13 mWT×fCL, and 13 fCL×fCL were 13.0±1.5, 13.1±1.2, 11.7±0.8, and 7.0±1.3, respectively, and also gradually decreased with increase in the number of mutated Clock alleles in mothers and embryos. This decrease was accompanied by a significant lowering of the positions of implantation sites in uteri, a possible cause of the decrease of the number of newborns and implantation sites, and average percentages of embryos implanted in a lower part of the uterus were 48.8, 59.3, 69.7, and 77.7% in mWT×fWT, mCL×fWT, mWT×fCL, and mCL×fCL, respectively. The difference between the mCL×fWT and mWT×fWT groups was statistically significant (P<0.05), and this difference was thought to be due to the difference in embryonic genotype, specifically between WT and heterozygous embryos. However, the distribution of implantation sites in the mWT×fCL group was significantly smaller than that in the mCL×fWT group (P<0.05), presumably due to the difference in maternal genotype, specifically between WT and homozygous mutant dams. This study showed involvement of the circadian clock, possibly the maternal and embryonic circadian clock, in implantation among events that occur from fertilization to parturition.
26717147	Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots' physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3-9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural disorders and stress in this bird species, and could also help in their captive management. 
26715971	Sleep hygiene is important for sleep quality and optimal performance during the day. However, it is not always possible to follow sleep hygiene requirements. In multiday relay events, athletes have to sleep immediately after physical exertion and sometimes against their biological clock.In this pilot study we investigated the effect of having to sleep at an abnormal circadian time on sleep duration.	Eight runners and two cyclists performing a 500 km relay race were followed. They were divided into two groups that took turns in running and resting. Each group ran four times for approximately five hours while the other group slept. As a result, sleep times varied between normal and abnormal times. All athletes wore actigraphs to record the duration and onset of sleep.	Linear mixed model analyses showed that athletes slept on average 43 minutes longer when they slept during usual (night) times than during abnormal (day) times. In general, sleep duration decreased during the race with on average 18 minutes per period.	This pilot study shows that, even under extreme violation of sleep hygiene rules, there still is an apparent effect of circadian rhythm on sleep duration in relay race athletes.	
26715747	Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness. 
26715746	Vertebrate retinas are generally composed of rod (dim-light) and cone (bright-light) photoreceptors with distinct morphologies that evolved as adaptations to nocturnal/crepuscular and diurnal light environments. Over 70 years ago, the "transmutation" theory was proposed to explain some of the rare exceptions in which a photoreceptor type is missing, suggesting that photoreceptors could evolutionarily transition between cell types. Although studies have shown support for this theory in nocturnal geckos, the origins of all-cone retinas, such as those found in diurnal colubrid snakes, remain a mystery. Here we investigate the evolutionary fate of the rods in a diurnal garter snake and test two competing hypotheses: (i) that the rods, and their corresponding molecular machinery, were lost or (ii) that the rods were evolutionarily modified to resemble, and function, as cones. Using multiple approaches, we find evidence for a functional and unusually blue-shifted rhodopsin that is expressed in small single "cones." Moreover, these cones express rod transducin and have rod ultrastructural features, providing strong support for the hypothesis that they are not true cones, as previously thought, but rather are modified rods. Several intriguing features of garter snake rhodopsin are suggestive of a more cone-like function. We propose that these cone-like rods may have evolved to regain spectral sensitivity and chromatic discrimination as a result of ancestral losses of middle-wavelength cone opsins in early snake evolution. This study illustrates how sensory evolution can be shaped not only by environmental constraints but also by historical contingency in forming new cell types with convergent functionality. 
26715136	Twenty Dorper × Pelibuey primiparous ewes were used to evaluate effects of seasonal ambient heat stress (i.e., spring vs. summer) on physiological and metabolic responses under production conditions in an arid region. Ten ewes experiencing summer heat stress (i.e., temperature = 34.8 ± 4.6 °C; THI = 81.6 ± 3.2 units) and 10 under spring thermoneutral conditions (temperature = 24.2 ± 5.4 °C; THI = 68.0 ± 4.8 units) were corralled together to measure rectal temperature, respiratory frequency, and skin temperatures at 0600, 1200, 1800, and 2400 h on four occasions over 40 days. Blood metabolite and electrolyte concentrations were also measured at 0600 and 1800 hours. Data were analyzed with a completely randomized design using repeated measurements in time. Rectal and skin temperatures, as well as respiratory frequency, were higher (P < 0.01) in summer than spring at all measured days. Blood serum glucose, cholesterol, triglycerides, and chlorine concentrations were lower (P < 0.01) in summer than spring at 0800 and 1800 hours. In contrast, summer heat stress increased (P < 0.01) blood urea and potassium concentrations at 0800 and 1800 hours. Compared with spring thermoneutral conditions, summer heat stress affected the physiological and metabolic status of hair breed ewes in an arid region, which included blood metabolite and electrolyte adjustments to efficiently cope with summer heat stress. 
26714872	The cockroach, Leucophaea maderae, can be trained in an associative olfactory memory task by either classical or operant conditioning. When trained by classical conditioning, memory formation is regulated by a circadian clock, but once the memory is formed, it can be recalled at any circadian time. In contrast, when trained via operant conditioning, animals can learn the task at any circadian phase, but the ability to recall the long-term memory is tied to the phase of training. The optic lobes of the cockroach contain a circadian clock that drives circadian rhythms of locomotor activity, mating behavior, sensitivity of the compound eye to light, and the sensitivity of olfactory receptors in the antennae. To evaluate the role of the optic lobes in regulating learning and memory processes, the authors examined the effects of surgical ablation of the optic lobes on memory formation in classical conditioning and memory recall following operant conditioning. The effect of optic lobe ablation was to "rescue" the deficit in memory acquisition at a time the animals normally cannot learn and "rescue" the animal's ability to recall a memory formed by operant conditioning at a phase where memory was not normally expressed. The results suggested that the optic lobe pacemaker regulates these processes through inhibition at "inappropriate" times of day. As a pharmacological test of this hypothesis, the authors showed that injections of fipronil, an antagonist of GABA and glutamate-activated chloride channels, had the same effects as optic lobe ablation on memory formation and recall. The data suggest that the optic lobes contain the circadian clock(s) that regulate learning and memory processes via inhibition of neural processes in the brain. 
26714273	Cardiac and vascular autonomic neuropathy contributes to increased morbidity and mortality in patients with chronic kidney disease. The aim of this study was to analyze the effects of a decline in glomerular filtration rate (GFR) on heart rate variability (HRV) and nocturnal blood pressure dipping.This cross-sectional study comprises 124 patients (46 women, 78 men; age 66 ± 14 years) with chronic kidney disease (CKD) 3-5, not on renal replacement therapy. GFR was measured with iohexol clearance, HRV with 24 h Holter electrocardiogram (ECG) and nocturnal dipping with 24 hour ambulatory blood pressure.	The GFR was 22.5 ± 8.5 mL/min per 1.73 m2 . The main finding was a significant curvilinear association between the 24 h standard deviation of NN interval (24SDNN) in the HRV analysis and GFR (P = 0.01), logGFR (P = 0.006), diabetes mellitus (P = 0.05) and beta blocker treatment (0.03), respectively. The effect of diabetes mellitus on 24SDNN corresponded to a decline in GFR from 30 to 12 mL/min per 1.73 m2 . There were significant curvilinear associations between systolic nocturnal dipping (P = 0.02) and diastolic nocturnal dipping (P = 0.05), respectively, and diabetes mellitus but not with GFR or logGFR.	In conclusion, cardiac sympathetic overdrive and decreased vagal control appear during CKD 4 and 5. The association with GFR is curvilinear. Diabetes mellitus was significantly associated with both cardiac and vascular autonomic neuropathy, as measured by heart rate variability and nocturnal blood pressure dipping, respectively. Knowing that arrhythmias, often due to sympathetic hyperactivity, are an important cause of sudden death in the dialysis population, this study contributes important knowledge on possible intervention thresholds.	
26714244	Memory is among the most important and neglected forces that shapes animal movement patterns. Research on the movement-memory interface is crucial to understand how animals use spatial learning to navigate across space because memory-based navigation is directly linked to animals' space use and home range behaviour; however, because memory cannot be measured directly, it is difficult to account for. Here, we incorporated spatial memory into step selection functions (SSF) to understand how resource selection and spatial memory affect space use of feral hogs (Sus scrofa). We used Biased Random Bridge kernel estimates linked to residence time as a surrogate for memory and tested four conceptually different dynamic maps of spatial memory. We applied this memory-based SSF to a data set of hog relocations to evaluate the importance of land cover type, time of day and spatial memory on the animals' space use. Our approach has shown how the incorporation of spatial memory into animal movement models can improve estimates of habitat selection. Memory-based SSF provided a feasible way to gain insight into how animals use spatial learning to guide their movement decisions. We found that while hogs selected forested areas and water bodies and avoided grasslands during the day (primarily at noon), they had a strong tendency to select previously visited areas, mainly those held in recent memory. Beyond actively updating their memory with recent experiences, hogs were able to discriminate among spatial memories encoded at different circadian phases of their activity. Even though hogs are thought to have long memory retention, they likely relied on recent experiences because the local food resources are quickly depleted and slowly renewed, yielding an uncertain spatial distribution of resources. 
26712167	The first German Charité Jet Lag Scale (CJS), based on the only validated English questionnaire, was introduced in a former study. In addition to providing further jet lag investigations, this second method-comparison study aims to evaluate the CJS. Consistent interviewing methods are essential for future research in identifying possible cross-cultural tendencies, advancing jet lag definition, and establishing potential alleviation methods. Jet lag in 17 German chorus members (5 male, 12 female, mean age 42.35 ± 13.06 years) was monitored on their 2½-week trip from Germany to Argentina and back by use of actigraphy, sleep diaries, and the CJS. Cronbach's alpha, Pearson and Lin correlations, and Bland-Altman diagrams were applied to assess CJS reliability and validity between all measurement methods. CJS study analysis results reconfirmed the prevalence of jet lag at approximately 60%. Moreover, the study assessed high Cronbach's alpha values and significant positive correlations for several corresponding and related sleep parameters and CJS items such as total sleep time (TST) and sleep onset latency (SOL). The confidence limits in the Bland-Altman diagrams remained within the limits of earlier studies (TST ± 1 h, SOL ± 30 min). Overall, jet lag measures in this study confirmed previous jet lag studies. Evidence indicates positive reliability and validity of the CJS, with lower specificity in some parameters. We conclude that the CJS is applicable for complex jet lag studies. The findings provide support for further development of the scale and its capability as a consistent jet lag interviewing method. 
26712166	The suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behavior. Previous studies suggest a critical role for neurons expressing vasoactive intestinal peptide (VIP) in coordinating rhythmicity and synchronization in the SCN. Here we examined the firing properties of VIP-expressing SCN neurons in acute brain slices. Active and passive membrane properties were measured in VIP and in non-VIP neurons during the day and at night. Current-clamp recordings revealed that both VIP and non-VIP neurons were spontaneously active, with higher firing rates during the day than at night. Average firing frequencies, however, were higher in VIP neurons (3.1 ± 0.2 Hz, day and 2.4 ± 0.2 Hz, night) than in non-VIP neurons (1.8 ± 0.2 Hz, day and 0.9 ± 0.2 Hz, night), both day and night. The waveforms of individual action potentials in VIP and non-VIP neurons were also distinct. Action potential durations (APD50) were shorter in VIP neurons (3.6 ± 0.1 ms, day and 2.9 ± 0.1 ms, night) than in non-VIP neurons (4.4 ± 0.3 ms, day and 3.5 ± 0.2 ms, night) throughout the light-dark cycle. In addition, afterhyperpolarization (AHP) amplitudes were larger in VIP neurons (21 ± 0.8 mV, day and 24.9 ± 0.9 mV, night) than in non-VIP neurons (17.2 ± 1.1 mV, day and 20.5 ± 1.2 mV, night) during the day and at night. Furthermore, significant day/night differences were observed in APD50 and AHP amplitudes in both VIP and non-VIP SCN neurons, consistent with rhythmic changes in ionic conductances that contribute to shaping the firing properties of both cell types. The higher day and night firing rates of VIP neurons likely contribute to synchronizing electrical activity in the SCN. 

26712028	Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes. 
26711258	In the Neurospora circadian system, the White Collar complex (WCC) of WC-1 and WC-2 drives transcription of the circadian pacemaker gene frequency (frq), whose gene product, FRQ, as a part of the FRQ-FRH complex (FFC), inhibits its own expression. The WCC is also the principal Neurospora photoreceptor; WCC-mediated light induction of frq resets the clock, and all acute light induction is triggered by WCC binding to promoters of light-induced genes. However, not all acutely light-induced genes are also clock regulated, and conversely, not all clock-regulated direct targets of WCC are light induced; the structural determinants governing the shift from WCC's dark circadian role to its light activation role are poorly described. We report that the DBD region (named for being defective in binding DNA), a basic region in WC-1 proximal to the DNA-binding zinc finger (ZnF) whose function was previously ascribed to nuclear localization, instead plays multiple essential roles assisting in DNA binding and mediating interactions with the FFC. DNA binding for light induction by the WCC requires only WC-2, whereas DNA binding for circadian functions requires WC-2 as well as the ZnF and DBD motif of WC-1. The data suggest a means by which alterations in the tertiary and quaternary structures of the WCC can lead to its distinct functions in the dark and in the light. 
26711257	The main components regulating the pace of circadian (≅24 h) clocks in animals are PERIOD (PER) proteins, transcriptional regulators that undergo daily changes in levels and nuclear accumulation by means of complex multisite phosphorylation programs. In the present study, we investigated the function of two phosphorylation sites, at Ser826 and Ser828, located in a putative nuclear localization signal (NLS) on the Drosophila melanogaster PER protein. These sites are phosphorylated by DOUBLETIME (DBT; Drosophila homolog of CK1δ/ε), the key circadian kinase regulating the daily changes in PER stability and phosphorylation. Mutant flies in which phosphorylation at Ser826/Ser828 is blocked manifest behavioral rhythms with periods slightly longer than 1 h and with altered temperature compensation properties. Intriguingly, although phosphorylation at these sites does not influence PER stability, timing of nuclear entry, or transcriptional autoinhibition, the phospho-occupancy at Ser826/Ser828 is rapidly stimulated by light and blocked by TIMELESS (TIM), the major photosensitive clock component in Drosophila and a crucial binding partner of PER. Our findings identify the first phosphorylation sites on core clock proteins that are acutely regulated by photic cues and suggest that some phosphosites on PER proteins can modulate the pace of downstream behavioral rhythms without altering central aspects of the clock mechanism. 
26710124	Patients with rheumatoid arthritis (RA) have altered circadian rhythm of circulating serum cortisol, melatonin and IL-6, as well as disturbance in the expression of clock genes ARNTL2 and NPAS2. In humans, TNFα increases the expression ARNTL2 and NPAS2 but paradoxically suppresses clock output genes DPB and PER3. Our objective was to investigate the expression of direct clock suppressors DEC1 and DEC2 (BHLHE 40 and 41 proteins) in response to TNFα and investigate their role during inflammation.Cultured primary fibroblasts were stimulated with TNFα. Effects on DEC2 were studied using RT-qPCR and immunofluorescence staining. The role of NF-κB in DEC2 increase was analyzed using IKK-2 specific inhibitor IMD-0354. Cloned DEC2 was transfected into HEK293 cells to study its effects on gene expression. Transfections into primary human fibroblasts were used to confirm the results. The presence of DEC2 was analyzed in (RA) and osteoarthritis (OA) synovial membranes by immunohistochemistry.	TNFα increased DEC2 mRNA and DEC2 was mainly detected at nuclei after the stimulus. The effects of TNFα on DEC2 expression were mediated via NF-κB. Overexpression, siRNA and promoter activity studies disclosed that DEC2 directly regulates IL-1β, in both HEK293 cells and primary human fibroblasts. DEC2 was increased in synovial membrane in RA compared to OA.	Not only ARNTL2 and NPAS2 but also DEC2 is regulated by TNFα in human fibroblasts. NF-κB mediates the effect on DEC2, which upregulates IL-1β. Circadian clock has a direct effect on inflammation in human fibroblasts.	
26709878	Although mounting evidence suggests that sleep and epilepsy are reciprocal and seizures influence circadian rhythms, sleep-wake pattern and seizure control have not been widely researched. This study aimed to investigate the association of sleep-wake pattern, sleep quality, and chronotype with seizures in patients with epilepsy (PWE).160 consecutive PWE (aged 20-49 years, focal epilepsy, FE: generalized epilepsy, GE=127:33) and 130 age-gender matched healthy controls (HC) were enrolled. All subjects completed a sleep diary for more than 2 weeks, Pittsburgh Sleep Quality Index (PSQI), Epworth sleepiness scale (ESS), and the Morningness-Eveningness questionnaire (MEQ). Detailed seizure history was reviewed for the last 1 year.	Sleep-wake patterns on workdays were different between PWE and HC (p<0.001), although PSQI, ESS, and MEQ did not differ. Social jetlag (difference of mid-sleep time between workdays and free days) was more evident in PWE (1.4h) than HC (0.7h, p<0.001). GE showed lower MEQ, later mid-sleep time on both workdays and free days, and larger social jetlag than FE. Higher seizure frequency was positively correlated with higher PSQI and ESS after adjusting for age, gender, and number of antiepileptic drugs (p<0.05). PWE with lower MEQ presented worse sleep quality.	Contrary to HC, PWE maintained sleep-wake patterns more regularly during workdays and free days. GE patients reported more eveningness-preference; however, their sleep quality was not worse than FE. Although sleep quality may affect seizure frequency, sleep-wake patterns and chronotype were not related to seizures in PWE.	
26708682	The intestinal microbiota is well-known for a long time, but due to newly recognized functions, clinician's attention has turned to it again in the last decade. About 100 000 billion bacteria are present in the human intestines. The composition of bacteriota living in diverse parts of the intestinal tract is variable according to age, body weight, geological site, and diet as well. Normal bacteriota defend the organism against the penetration of harmful microorganisms, and has many other functions in the gut wall integrity, innate immunity, insulin sensitivity, metabolism, and it is in cross-talk with the brain functions as well. It's a recent recognition, that intestinal microbiota has a direct effect on the brain, and the brain also influences the microbiota. This two-way gut-brain axis consists of microbiota, immune and neuroendocrine system, as well as of the autonomic and central nervous system. Emerging from fermentation of carbohydrates, short-chain fatty acids develop into the intestines, which produce butyrates, acetates and propionates, having favorable effects on different metabolic processes. Composition of the intestinal microbiota is affected by the circadian rhythm, such as in shift workers. Dysruption of circadian rhythm may influence intestinal microbiota. The imbalance between the microbiota and host organism leads to dysbacteriosis. From the membrane of Gram-negative bacteria lipopolysacharides penetrate into the blood stream, via impaired permeability of the intestinal mucosa. These processes induce metabolic endotoxaemia, inflammation, impaired glucose metabolism, insulin resistance, obesity, and contribute to the development of metabolic syndrome, type 2 diabetes, inflammarory bowel diseases, autoimmunity and carcinogenesis. Encouraging therapeutic possibility is to restore the normal microbiota either using pro- or prebiotics, fecal transplantation or bariatric surgery. Human investigations seem to prove that fecal transplant from lean healthy individuals into obese diabetic patients improved all the pathological parameters. Wide spread use of bariatric surgery altered gut microbiota and improved metabolic parameters apart from surgery itself. Pathomechanism is not yet completely clarified. Clinicians hope, that deeper understanding of complex functions of intestinal microbiota will contribute to develop more effective therapeutic proceedings against diabetes, metabolic syndrome, and obesity.
26707659	The aim of this study was to investigate interchangeability of two tests to diagnose Cushing's syndrome. We compared 10:00-11:00 PM urinary free cortisol/creatinine ratio (UFC/Cr) with late night 11:00 PM salivary cortisol (LNSC) in normal and obese controls vs. patients with Cushing's syndrome. Mean UFC/Cr did not differ between 69 normal and 62 obese controls (9.9 ± 7.9 vs. 9.7 ± 9.3) whereas 116 Cushing's patients had significantly higher values (277.0 ± 318.0; z: -11.1 and -10.2, respectively; p < 0.001). LNSC was 1.9 ± 1.2 nmol/l in 44 normal and 2.5 ± 1.6 in 45 obese subjects with no differences between them, but was significantly higher in 47 Cushing's patients (24.8 ± 23.3; z: -7.22 and -6.96, respectively, p < 0.001). Comparison of UFC/Cr and LNSC in samples obtained simultaneously showed that UFC/Cr was 12.0 ± 8.7 ng cortisol/mg creatinine in 34 normal, 12.3 ± 8.9 in 40 obese and 319.5 ± 333.4 in 35 CS subjects (p < 0.001 vs. normal and obese), whereas LNSC was 1.8 ± 1.2 nmol/l in normal, 2.6 ± 1.7 in obese and 24.6 ± 17.4 in CS patients (p < 0.001 vs. normal and obese); ROC curves showed comparable high sensitivity and specificity figures for the diagnosis of CS. We concluded that UFC/Cr test is easy to perform, readily available in routine laboratories, has high sensitivity and specificity, and offers a valuable alternative to LNSC in the study of Cushing's syndrome. 
26706567	Cyclical expression of cell-autonomous circadian clock components and key metabolic regulators coordinate often discordant and distant cellular processes for efficient metabolism. Perturbation of these cycles, either by genetic manipulation, disruption of light/dark cycles, or, most relevant to the human population, via eating patterns, contributes to obesity and dysmetabolism. Time-restricted feeding (TRF), during which time of access to food is restricted to a few hours, without caloric restriction, supports robust metabolic cycles and protects against nutritional challenges that predispose to obesity and dysmetabolism. The mechanism by which TRF imparts its benefits is not fully understood but likely involves entrainment of metabolically active organs through gut signaling. Understanding the relationship of feeding pattern and metabolism could yield novel therapies for the obesity pandemic. 
26706287	Recently, investigators have shown that ubiquitin-proteasome-mediated protein degradation is critical in regulating the balance between bone formation and bone resorption. The major signal transduction pathways regulating bone formation are the RANK/NF-κB pathway and the Wnt/β-catenin pathway. These signal transduction pathways regulate the activity of mature osteoblasts and osteoclasts. In addition, the Wnt/β-catenin pathway is one of the major signaling pathways in the differentiation of osteoblasts. The ubiquitin ligases that are reported to be of major significance in regulating these pathways are the ubiquitin SCF(B-TrCP) ligase (which regulates activation of NF-κB via degradation of IkBα in osteoclasts, and regulates bone transcription factors via degradation of β-catenin), the Keap-Cul3-Rbx1 ligase (which regulates degradation of IkB kinase, Nrf2, and the antiapoptotic factor Bcl-2), and Smurf1. Also of significance in regulating osteoclastogenesis is the deubiquitinase, CYLD (cylindramatosis protein), which facilitates the separation of NF-κB from IkBα. The degradation of CYLD is also under the regulation of SCF(B-TrCP). Proteasome inhibitors influence the activity of mature osteoblasts and osteoclasts, but also modulate the differentiation of precursor cells into osteoblasts. Preclinical studies show that melatonin also influences bone metabolism by stimulating bone growth and inhibiting osteoclast activity. These actions of melatonin could be interpreted as being mediated by the ubiquitin ligases SCF(B-TrCP) and Keap-Cul3-Rbx, or as an inhibitory effect on proteasomes. Clinical trials of the use of melatonin in the treatment of bone disease, including multiple myeloma, using both continuous and intermittent modes of administration, are warranted. 
26705556	The aim of the study was to assess a possible circadian variation of premature atrial contractions (PACs) in a community-based population and to determine if the daily variation could be used to assess a more vulnerable period of PACs in predicting later incidence of atrial fibrillation (AF).We studied 638 subjects between the ages of 55 and 75 years from the Copenhagen Holter Study who underwent up to 48 h electrocardiogram recording. Follow-up on cardiovascular endpoints was performed in 2013 with a median follow-up time of 14.4 years. According to previous studies, two subgroups were studied based on a cut-off point of ≥720 PACs/day termed frequent PACs (n = 66) and not frequent PACs with <720 PACs/day (n = 572). Based on median values, a circadian rhythm could not be demonstrated in the population as a whole and the group without frequent PACs. However, a circadian variation was observed in the group with frequent PACs, who had the fewest PACs/h during the night with a nadir at 6 am and then reaching a peak value in the afternoon at 3 pm. Runs of PACs in all subjects showed a similar circadian variation. Both PACs/h and runs of PACs seemed to follow the daily variation in heart rate. After adjusting for relevant risk factors, the risk of AF was equal in all time intervals throughout the day.	Premature atrial contractions showed a circadian variation in subjects with frequent PACs. No specific time interval of the day was more predictive of AF than others.	
26705310	The accumulation of epicuticular waxes over stomata in Quercus coccifera L. contributes to a severe reduction in maximum stomatal conductance (g s,max) under Mediterranean (MED) conditions. However, this phenomenon was not observed in this species under temperate (TEM) conditions, which could lead to differences in the ability to assimilate CO2 between the sites. We hypothesise that the overall importance of such a reduction in gs,max on photosynthesis is modulated by other factors affecting carbon gain, mainly mesophyll conductance to CO2 (g m), through a plastic response to changes in environmental conditions (i.e., vapour pressure deficit, VPD, and mean daily quantum flux density, Q int). The results reveal that leaves grown at the TEM site did not show an increased ability for net CO2 assimilation (A N), mainly due to an equal gm at both sites. This fact is explained by a trade-off between an increased conductance of the gas phase (g ias) and a reduced conductance of the liquid phase (g liq) at the TEM site compared with the MED site. In spite of the reduction in gs,max at the MED site, transpiration (E) did not diminish during midsummer to the levels of the TEM site due to a higher VPD found at the MED site, yielding a higher water use efficiency (AN/E) at the TEM site. Moreover, photosynthetic nitrogen use efficiency was also higher at the TEM site, indicating these leaves can reach similar values of AN with lower nitrogen investment that those at the MED site. These results suggest that Q. coccifera does not always use the main resources (water and nutrients) at leaf level as efficiently as possible. Moreover, the different patterns of resource use (in particular N), together with the functional plasticity, cannot overcome the morpho-functional constraints that limit photosynthetic activity, even under potentially favourable conditions.
26705201	We describe a very rare case of nonfunctional pituitary adenoma (NFPA) that exhibited corticotrophic activity after resection and radiotherapy. The possible mechanisms of the transformation from NFPA to Cushing disease (CD) are discussed.A 43-year-old man presented with impaired vision, bilateral frontal headaches, and hyposexuality. He had no symptoms suggestive of hypercortisolism, and 8 am plasma cortisol concentration was 67.88 ng/mL. Brain imaging revealed a 15 × 15 × 21-mm sellar mass suggestive of a macroadenoma. The tumor was resected by transsphenoidal surgery and identified by immunohistochemical analysis as a chromophobic adenoma that did not stain for pituitary hormones. The patient was treated with prednisone and levothyroxine replacement therapy. After a third recurrence, the patient presented with clinical features and physical signs of Cushing syndrome. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were elevated, and there was a loss of circadian rhythms. Inferior petrosal sinus sampling after desmopressin showed the central-peripheral ACTH ratio was greater than 3:1. A repeat transsphenoidal resection was undertaken. Immunohistochemistry revealed ACTH positivity. Three months following surgery, imaging showed little residual tumor, but plasma ACTH remained elevated. He was referred for postoperative Gamma Knife radiotherapy.The immunological activity and biological features of the hormones secreted from a pituitary adenoma vary with time. Because long-term outcomes are unpredictable, postoperative follow-up is essential to detect postoperative transformation from NFPA to CD.
26704081	The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN. 
26703233	Recent studies have shown that animals are affected by night-time light exposure. Light is a continuous variable, but our knowledge on how individuals react to different light intensities during the night is limited. We therefore determined the relationship between night light intensity and the behaviour and physiology of great tits (Parus major). We measured daily activity patterns and melatonin levels in 35 males exposed to five different light intensities and found strong, dose-dependent effects. Activity onset was increasingly advanced, and activity offset delayed with higher light intensities. Furthermore, night-time activity increased and melatonin levels measured at midnight decreased with higher intensities. In this experimental study, we demonstrate for the first time dose-dependent effects of artificial light at night on birds' daily activity patterns and melatonin levels. Our results imply that these effects are not limited to a certain threshold, but emerge even when nocturnal light levels are slightly increased. However, in a natural area, these effects may be limited as artificial light levels are commonly low; light intensities drop rapidly with distance from a light source and birds can avoid exposure to light at night. Future studies should thus focus on examining the impact of different intensities of light at night in the wild. 
26702363	Achieving successful early mobilization for the intubated, critically ill child is dependent on optimizing sedation and analgesia. Finding the fine balance between oversedation and undersedation can be challenging. The ideal is for a child to be lucid and interactive during the daytime and demonstrate normal circadian rhythm for sleep with rest at night. Being alert during the day facilitates active participation in therapy including potential ambulation, while decreasing the risk of delirium during mechanical ventilation. An active state during the day with frequent mobilization promotes restorative sleep at night, which brings with it multiple benefits for healing and recovery. Indeed, this ideal may not be physiologically feasible given a child's critical illness and trajectory, but defining it as the "gold standard" for early mobilization provides a consistent goal for the pediatric intensive care unit (PICU) hospitalization. As such, goal-directed, patient-specific sedation plans are integral to creating a culture of mobility in the PICU. We review currently available sedation strategies for mechanically ventilated children for successful implementation of early mobilization in the PICU, as well as pharmacologic considerations for specific classes of sedative-analgesics.
26701294	Circadian rhythms in mammals are regulated by a system of circadian oscillators that includes a light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) and food-entrainable oscillators (FEOs) elsewhere in the brain and body. In nocturnal rodents, the SCN promotes sleep in the day and wake at night, while FEOs promote an active state in anticipation of a predictable daily meal. For nocturnal animals to anticipate a daytime meal, wake-promoting signals from FEOs must compete with sleep-promoting signals from the SCN pacemaker. One hypothesis is that FEOs impose a daily rhythm of inhibition on SCN output that is timed to permit the expression of activity prior to a daytime meal. This hypothesis predicts that SCN activity should decrease prior to the onset of anticipatory activity and remain suppressed through the scheduled mealtime. To assess the hypothesis, neural activity in the SCN of mice anticipating a 4-5-h daily meal in the light period was measured using FOS immunohistochemistry and in vivo multiple unit electrophysiology. SCN FOS, quantified by optical density, was significantly reduced at the expected mealtime in food-anticipating mice with access to a running disk, compared to ad libitum-fed and acutely fasted controls. Group differences were not significant when FOS was quantified by other methods, or in mice without running disks. SCN electrical activity was markedly decreased during locomotion in some mice but increased in others. Changes in either direction were concurrent with locomotion, were not specific to food anticipation, and were not sustained during longer pauses. Reduced FOS indicates a net suppression of SCN activity that may depend on the intensity or duration of locomotion. The timing of changes in SCN activity relative to locomotion suggests that any effect of FEOs on SCN output is mediated indirectly, by feedback from neural or systemic correlates of locomotion. 
26700754	It was economically feasible to screen strains adaptive to wide temperature fluctuation for outdoor cultivation without temperature control. In this research, three Chlorella strains from arctic glacier, desert soil and temperate native lake were isolated and identified. The growth, biochemical composition, lipid content and fatty acid composition of each strain cultured under the mode of diurnal temperature fluctuations were compared. All the three Chlorella strains showed desirable abilities of accumulating lipid under diurnal temperature fluctuations and their fatty acid profiles were suitable for biodiesel production, although the growth and biochemical composition were seemed to be region-specific. The highest lipid content was at 51.83±2.49% DW, 42.80±2.97% DW and 36.13±2.27% DW under different temperature fluctuation of 11 °C, 25 °C, 7 °C, respectively. The results indicated that the three Chlorella strains could be promising biodiesel feedstock for outdoor cultivation by the cultural mode of diurnal temperature fluctuations.
26699809	Arabidopsis thaliana plants are less resistant to attack by the generalist lepidopteran herbivore Trichoplusia ni when plants and herbivores are entrained to opposite, versus identical diurnal cycles and tested under constant conditions. This effect is associated with circadian fluctuations in levels of jasmonic acid, the transcription factor MYC2, and glucosinolate contents in leaves. We tested whether a similar effect could be observed in a different plant-herbivore system: the wild tobacco Nicotiana attenuata and its co-evolved specialist herbivore, Manduca sexta. We measured larval growth on plants under both constant and diurnal conditions following identical or opposite entrainment, profiled the metabolome of attacked leaf tissue, quantified specific metabolites known to reduce M. sexta growth, and monitored M. sexta feeding activity under all experimental conditions. Entrainment did not consistently affect M. sexta growth or plant defense induction. However, both were reduced under constant dark conditions, as was M. sexta feeding activity. Our data indicate that the response induced by M. sexta in N. attenuata is robust to diurnal cues and independent of plant or herbivore entrainment. We propose that while the patterns of constitutive or general damage-induced defense may undergo circadian fluctuation, the orchestration of specific induced responses is more complex. 
26699539	Low haemoglobin oxygen saturation (SpO2) predicts complications in children with sickle cell anaemia (SCA) in the North but there are few data from Africa, where the majority of the patients reside. We measured daytime and overnight SpO2 in children with SCA in routine follow-up clinic, and controls without symptoms of SCA, comparing rural (Kilifi, Kenya) and urban (Dar-es-Salaam, Tanzania) cohorts. Daytime SpO2 was lower in 65 Tanzanian children with SCA (TS; median 97 (IQR 94-100)%); p<0.0001) than in 113 Kenyan children with SCA (KS; 99 (98-100)%) and 20 Tanzanian controls (TC; 100 (98-100)%). Compared with 95 Kenyan children with SCA, in 54 Tanzanian children with SCA and 19 TC who returned for overnight oximetry, mean (KS 99.0 (96.7-99.8)%; TS 97.9 (95.4-99.3)%; TC 98.4 (97.5-99.1)%; p=0.01) and minimum nocturnal SpO2 (92 (86-95)%; 87 (78.5-91)%; 90 (83.5-93)% p=0.0001) were lower. The difference between children with SCA persisted after adjustment for haemoglobin (p=0.004). Urban Tanzanian children, with and without SCA, experience greater exposure to low daytime and night-time SpO2 compared with rural Kenyan children with SCA. Possible explanations include differences in the prevalence of obstructive sleep apnoea or asthma, alterations in the oxyhaemoglobin desaturation curve or cardiovascular compromise, for example, to shunting at atrial or pulmonary level secondary to increased pulmonary artery pressure. The fact that non-SCA siblings in the urban area are also affected suggests that environmental exposures, for example, air pollution, nutrition or physical exercise, may play a role. Further studies should determine aetiology and clinical relevance for the SCA phenotype in children resident in Africa. 
26699485	With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼ 10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.
26699470	Night-shift workers are at high risk of drowsiness-related motor vehicle crashes as a result of circadian disruption and sleep restriction. However, the impact of actual night-shift work on measures of drowsiness and driving performance while operating a real motor vehicle remains unknown. Sixteen night-shift workers completed two 2-h daytime driving sessions on a closed driving track at the Liberty Mutual Research Institute for Safety: (i) a postsleep baseline driving session after an average of 7.6 ± 2.4 h sleep the previous night with no night-shift work, and (ii) a postnight-shift driving session following night-shift work. Physiological measures of drowsiness were collected, including infrared reflectance oculography, electroencephalography, and electrooculography. Driving performance measures included lane excursions, near-crash events, and drives terminated because of failure to maintain control of the vehicle. Eleven near-crashes occurred in 6 of 16 postnight-shift drives (37.5%), and 7 of 16 postnight-shift drives (43.8%) were terminated early for safety reasons, compared with zero near-crashes or early drive terminations during 16 postsleep drives (Fishers exact: P = 0.0088 and P = 0.0034, respectively). Participants had a significantly higher rate of lane excursions, average Johns Drowsiness Scale, blink duration, and number of slow eye movements during postnight-shift drives compared with postsleep drives (3.09/min vs. 1.49/min; 1.71 vs. 0.97; 125 ms vs. 100 ms; 35.8 vs. 19.1; respectively, P < 0.05 for all). Night-shift work increases driver drowsiness, degrading driving performance and increasing the risk of near-crash drive events. With more than 9.5 million Americans working overnight or rotating shifts and one-third of United States commutes exceeding 30 min, these results have implications for traffic and occupational safety. 
26699280	To examine if there were circadian variations in surgeons' ability to diagnose acute appendicitis.Retrospective database study of all patients admitted to an acute surgical procedure under the potential diagnosis of acute appendicitis in a 4-year period. The day was divided into 2 time intervals, day to evening hours (08:00-23:59) and night hours (00:00-07:59). Relevant data regarding the admission and surgical procedures were categorized into these 2 time intervals.	Department of Surgery at a Danish university hospital in Copenhagen.	A total of 2366 patients were included. There were no age limitations or selection in sex.	There was no significant difference in the ability to diagnose appendicitis in day-evening hours vs night hours (p = 0.391), nor was any significant difference found on weekdays (Monday-Thursday) vs weekends (Friday-Sunday) (p = 0.278). There were no differences in duration of the procedures, rate of conversion, or severity of postoperative surgical complications between the 2 groups. More patients underwent diagnostic imaging during day to evening hours compared with night hours (308 vs 46; p = 0.014). The use of imaging had no effect on the ability to diagnose appendicitis. Male sex showed a higher probability of the diagnosis being appendicitis compared with other or no pathology (odds ratio: 3.094; p < 0.001). Age between 40 and 80 years was significantly associated with a higher probability of the diagnosis being appendicitis compared with other or no pathology. The negative appendectomy rate was 10.5%.	We found no difference in the surgeons' ability to diagnose acute appendicitis during night hours compared with day to evening hours.	
26699132	MicroRNAs are a class of small non-coding RNA that regulate gene expression at a post-transcriptional level. MicroRNAs have been identified in various body fluids under normal conditions and their stability as well as their dysregulation in disease opens up a new field for biomarker study. However, diurnal and day-to-day variation in plasma microRNA levels, and differential regulation between males and females, may affect biomarker stability. A QuantStudio 12K Flex Real-Time PCR System was used to profile plasma microRNA levels using OpenArray in male and female healthy volunteers, in the morning and afternoon, and at four time points over a one month period. Using this system we were able to run four OpenArray plates in a single run, the equivalent of 32 traditional 384-well qPCR plates or 12,000 data points. Up to 754 microRNAs can be identified in a single plasma sample in under two hours. 108 individual microRNAs were identified in at least 80% of all our samples which compares favourably with other reports of microRNA profiles in serum or plasma in healthy adults. Many of these microRNAs, including miR-16-5p, miR-17-5p, miR-19a-3p, miR-24-3p, miR-30c-5p, miR-191-5p, miR-223-3p and miR-451a are highly expressed and consistent with previous studies using other platforms. Overall, microRNA levels were very consistent between individuals, males and females, and time points and we did not detect significant differences in levels of microRNAs. These results suggest the suitability of this platform for microRNA profiling and biomarker discovery and suggest minimal confounding influence of sex or sample timing. However, the platform has not been subjected to rigorous validation which must be demonstrated in future biomarker studies where large differences may exist between disease and control samples. 
26698673	Beta-cypermethrin (BCYP), a synthetic pyrethriod (PYR) pesticide which is a mixture of the alpha- and theta- cypermethrin, have been reported various toxicological profiles to non-target organisms. But little is known about assimilation, accumulation and toxic effects of BCYP in reptiles. The present study firstly elucidated absorption, tissue distribution, excretion of BCYP in Eremias argus . Treated group were administered orally with BCYP 20mg/kg body weight (bw) dissolved in corn oil. Neurotoxicity was observed at 24h after gavage, and the poisoning symptom ameliorated at 72h. The changes of BCYP concentration depended on degradation time and tissues. Lizards had a strong capacity to eliminate BCYP with different tissue distribution. The tissues concentration of BCYP from high to low were intestine, stomach, heart, kidney, blood, lung, liver and brain. Bimodal phenomena were observed in lung, liver and kidney. These results may be due to the activities of enzymes, circadian rhythm, and enterohepatic circulation in lizards. Based on the results of organ coefficient and histopathology analysis in liver, the liver was confirmed as the main target organ. 
26696807	The circadian activity of the hypothalamo-pituitary-adrenal/interrenal (HPA/I) axis is crucial for maintaining vertebrate homeostasis. In mammals, both the principle regulator, corticotropin-releasing hormone (crh) in the hypothalamic paraventricular nucleus (PVN) and the final effector, the glucocorticoids show daily rhythmic patterns. While glucocorticoids are the main negative regulator of PVN crh under stress, whether they modulate the PVN crh rhythm under basal condition is unclear in diurnal animals. Using zebrafish larvae, a recently-established diurnal model organism suited for the HPA/I axis and homeostasis research, we ask if glucocorticoid changes are required to maintain the daily variation of PVN crh. We first characterized the development of the HPI axis overtime and showed that the basal activity of the HPI axis is robust and tightly regulated by circadian cue in 6-day old larvae. We demonstrated a negative correlation between the basal cortisol and neurosecretory preoptic area (NPO) crh variations. To test if cortisol drives NPO crh variation, we analyzed the NPO crh levels in glucorcorticoid antagonist-treated larvae and mutants lacking circadian cortisol variations. We showed that NPO crh basal fluctuation is sustained although the level was decreased without proper cortisol signaling in zebrafish. Our data indicates that glucocorticoids do not modulate the basal NPO crh variations but may be required for maintaining overall NPO crh levels. This further suggests that under basal and stress conditions the HPA/I axis activity is modulated differently by glucocorticoids. 
26696094	The inhalation anesthetic sevoflurane suppresses Per2 expression in the suprachiasmatic nucleus (SCN) in rodents. Here, we investigated the intra-SCN regional specificity, time-dependency, and pharmacological basis of sevoflurane-effects. Bioluminescence image was taken from the SCN explants of mPer2 promoter-destabilized luciferase transgenic rats, and each small regions of interest (ROI) of the image was analyzed. Sevoflurane suppressed bioluminescence in all ROIs, suggesting that all regions in the SCN are sensitive to sevoflurane. Clear time-dependency in sevoflurane effects were also observed; application during the trough phase of the bioluminescence cycle suppressed the subsequent increase in bioluminescence and resulted in a phase delay of the cycle; sevoflurane applied during the middle of the ascending phase induced a phase advance; sevoflurane on the descending phase showed no effect. These results indicate that the sevoflurane effect may depend on the intrinsic state of circadian machinery. Finally, we examined the involvement of GABAergic signal transduction in the sevoflurane effect. Co-application of both GABAA and GABAB receptor antagonists completely blocked the effect of sevoflurane on the bioluminescence rhythm, suggesting that sevoflurane inhibits Per2 expression via GABAergic signal transduction. Current study elucidated the anesthetic effects on the molecular mechanisms of circadian rhythm. 
26693661	Although obesity is considered to result from an imbalance between energy uptake and energy expenditure, the strategy of dietary changes and physical exercise has failed to tackle the global obesity epidemic. In search of alternative and more adequate treatment options, research has aimed at further unravelling the mechanisms underlying this excessive weight gain. While numerous studies are focusing on the neuroendocrine alterations that occur after bariatric Roux-en-Y gastric bypass surgery, an increasing amount of chronobiological studies have started to raise awareness concerning the pivotal role of the circadian system in the development and exacerbation of obesity. This internal timekeeping mechanism rhythmically regulates metabolic and physiological processes in order to meet the fluctuating demands in energy use and supply throughout the 24-h day. This review elaborates on the extensive bidirectional interaction between the circadian system and metabolism and explains how disruption of body clocks by means of shift work, frequent time zone travelling or non-stop consumption of calorie-dense foods can evoke detrimental metabolic alterations that contribute to obesity. Altering the body's circadian rhythms by means of time-related dietary approaches (chrononutrition) or pharmacological substances (chronobiotics) may therefore represent a novel and interesting way to prevent or treat obesity and associated comorbidities. 
26692477	Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. Therefore, we aimed to identify a novel small molecule modulator that regulates Bmal1 gene expression in RORE-dependency, thereby influencing the molecular feedback loop of the circadian clock. For this purpose, we carried out a cell-based screen of more than 1000 drug-like compounds, using a luciferase reporter driven by the proximal region of the mouse Bmal1 promoter. One compound, designated KK-S6, repressed the RORE-dependent transcriptional activity of the mBmal1 promoter and reduced endogenous BMAL1 protein expression. More importantly, KK-S6 significantly altered the amplitude of circadian oscillations of Bmal1 and Per2 promoter activities in a dose-dependent manner, but barely affected the period length. KK-S6 effectively decreased mRNA expression of metabolic genes acting downstream of REV-ERBα, Pai-1 and Citrate synthase, that contain RORE cis-element in their promoter. KK-S6 likely acts in a RORE-dependent manner by reinforcing the REV-ERBα activity, though not by the same mechanism as known REV-ERB agonists. In conclusion, the present study demonstrates that KK-S6 functions as a novel modulator of the amplitude of molecular circadian rhythms by influencing RORE-mediated BMAL1 expression. 
26691765	The principle clock of mammals, named suprachiasmatic nucleus (SCN), coordinates the circadian rhythms of behavioral and physiological activity to the external 24 h light-dark cycle. In the absence of the daily cycle, the SCN acts as an endogenous clock that regulates the ~24 h rhythm of activity. Experimental and theoretical studies usually take the light-dark cycle as a main external influence, and often ignore light pollution as an external influence. However, in modern society, the light pollution such as induced by electrical lighting influences the circadian clock. In the present study, we examined the effect of external noise (light pollution) on the collective behavior of coupled circadian oscillators under constant darkness using a Goodwin model. We found that the external noise plays distinct roles in the network behavior of neurons for weak or strong coupling between the neurons. In the case of strong coupling, the noise reduces the synchronization and the period of the SCN network. Interestingly, in the case of weak coupling, the noise induces a circadian rhythm in the SCN network which is absent in noise-free condition. In addition, the noise increases the synchronization and decreases the period of the SCN network. Our findings may shed new light on the impact of the external noise on the collective behavior of SCN neurons.
26691298	The Timeless (Tim) gene, originally identified in Drosophila melanogaster and subsequently in mammals, is involved in the molecular clockwork that drives 24h periodicity in physiology and behavior. The Tim protein is involved not only in circadian rhythmicity but also in embryonic development, cell cycle progression, DNA replication, and the DNA damage response (DDR). It is thus a multifaceted factor implicated in the maintenance of many cellular processes, tissue functions, and ultimately homeostasis of various organisms, from insects to humans. This review highlights the current knowledge of Tim functions, especially the most recent achievements, and illustrates the possible roles that this factor plays in the physiological preservation of health, as well as in the pathogenic mechanisms of related diseases. 
26691014	To operate Navy ships 24h per day, watchstanding is needed around the clock, with watch periods reflecting a variety of rotating or fixed shift schedules. The 5/15 watch schedule cycles through watch periods with 5h on, 15h off watch, such that watches occur 4h earlier on the clock each day - that is, the watches rotate backward. The timing of sleep varies over 4-day cycles, and sleep is split on some days to accommodate nighttime watchstanding. The 3/9 watch schedule cycles through watch periods with 3h on, 9h off watch, allowing for consistent sleep timing over days. In some sections of the 3/9 watch schedule, sleep may need to be split to accommodate nighttime watchstanding. In both the 5/15 and 3/9 watch schedules, four watch sections alternate to cover the 24h of the day. Here we compared sleep duration, psychomotor vigilance and subjective sleepiness in simulated sections of the 5/15 and 3/9 watch schedules. Fifteen healthy male subjects spent 6 consecutive days (5 nights) in the laboratory. Sleep opportunities were restricted to an average of 6.5h daily. Actigraphically estimated sleep duration was 5.6h per watch day on average, with no significant difference between watch sections. Sleep duration was not reduced when sleep opportunities were split. Psychomotor vigilance degraded over watch days, and tended to be more variable in the 5/15 than in the 3/9 watch sections. These laboratory-based findings suggest that Navy watch schedules are associated with cumulative sleep loss and a build-up of fatigue across days. The fixed watch periods of the 3/9 watch schedule appear to yield more stable performance than the backward rotating watch periods of the 5/15 watch schedule. Optimal performance may require longer and more consistent daily opportunities for sleep than are typically obtained in Navy operations.
26690871	Chronic psychological stress is associated with enhanced abdominal pain and altered intestinal barrier function that may result from a perturbation in the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) exploits diverse mechanisms to activate or suppress congeneric gene expression, with regulatory variation associated with stress-related disorders in psychiatry and gastroenterology.During acute and chronic stress, corticotropin-releasing hormone drives secretion of adrenocorticotropic hormone from the pituitary, ultimately leading to the release of cortisol (human) and corticosterone (rodent) from the adrenal glands. Cortisol binds with the GR in the cytosol, translocates to the nucleus, and activates the NR3C1 (nuclear receptor subfamily 3, group C, member 1 [GR]) gene. This review focuses on the rapidly developing observations that cortisol is responsible for driving circadian and ultradian bursts of transcriptional activity in the CLOCK (clock circadian regulator) and PER (period circadian clock 1) gene families, and this rhythm is disrupted in major depressive disorder, bipolar disorder, and stress-related gastrointestinal and immune disorders. Glucocorticoid receptor regulates different sets of transcripts in a tissue-specific manner, through pulsatile waves of gene expression that includes occupancy of glucocorticoid response elements located within constitutively open spatial domains in chromatin. Emerging evidence supports a potentially pivotal role for epigenetic regulation of how GR interacts with other chromatin regulators to control the expression of its target genes. Dysregulation of the central and peripheral GR regulome has potentially significant consequences for stress-related disorders affecting the brain-gut axis.	
26689749	Changes in sleep patterns negatively influence some emotional responses, but their effects on facial expressiveness identification are unclear. To investigate these effects, 21 young, healthy, male volunteers of intermediate chronotype evaluated emotional expressiveness of faces depicting 6 basic emotions in 5 emotional gradients every 4 h over 36 h of continuous wakefulness. To measure attention and mood we used the Psychomotor Vigilance test and the Positive and Negative Affect Schedule Expanded, respectively. We found effects of emotional gradient for all types of emotions (100% > 80% > 60% > 40% > 20%) during all tested periods, with no indications of circadian effects. The only emotional rating to be affected was disgust, which was progressively blunted throughout the experiment. This effect did not parallel homeostatic and circadian changes in mood, alertness or attention. We conclude that identifying disgust on facial photographs is particularly sensitive to lack of sleep irrespective of sleep-induced changes in mood and attention in males.
26688947	This study investigates the circadian variation rules of the clock gene Per2 and clock-controlled genes of vascular endothelial growth factor (VEGF), Ki67, c-Myc, and P53 in different stages of carcinogenesis in buccal mucosa carcinoma and their roles in the development of buccal mucosa carcinoma.Ninety Syrian golden hamsters were housed under. 12 h light/12 h dark cycles. Dimethylbenzanthracene (DMBA) was used to establish the carcinoma model by smearing the golden hamster buccal mucosa. Before DMBA painting and after 6 and 14 weeks, the hamsters were sacrificed at six time points within a period of 24 h (i.e., 4, 8, 12, 16, 20, and 24 h after light onset), and the normal buccal mucosa, precancerous lesions, and cancer tissues were simultaneously obtained. Hematoxylin and eosin stained sections were prepared to observe the canceration of each tissue. Real time polymerase chain reaction was used to detect the mRNA expression of Per2, VEGF, Ki67, c-Myc, and P53. Cosine analysis was employed to determine the circadian-rhythm variations of Per2, VEGF, Ki67, c-Myc, and P53 mRNA expression in terms of median, amplitude, and acrophase.	The expression of Per2, VEGF, P53, and c-Myc mRNA in three different stages appeared with circadian rhythms (P<0.05), whereas the Ki67 mRNA was expressed with circadian rhythm only in normal and precancerous lesion stages (P<0.05). The midline-estimating statistic of rhythms (MESORs) of Per2 and P53 mRNA were significantly down-regulated with the development of cancer (P<0.05), whereas the MESORs of VEGF, c-Myc, and Ki67 mRNA were up-regulated (P<0.05). The amplitude of P53 mRNA significantly decreased with the development of cancer (P<0.05). Moreover, compared with the normal group, the amplitudes of Per2, VEGF, Ki67, and c-Myc mRNA significantly increased in precancerous lesions and cancer tissue (P<0.05). In precancerous stage, the acrophases of Per2, VEGF, and c-Myc mRNA were earlier than that in the normal group, whereas that of Ki67 and P53 mRNA were delayed.	The circadian-rhythm characteristics of the clock gene Per2 and clock-controlled gene expression of VEGF, Ki67, c-Myc, and P53 mRNA have changed with the occurrence and development of carcinoma.	
26688731	Shift work is closely related with workers' health. In particular, sleep is thought to be affected by shift work. In addition, shift work has been reported to be associated with the type or direction of shift rotation, number of consecutive night shifts, and number of off-duty days. We aimed to analyze the association between the night shift rotation interval and the quality of sleep reported by Korean female shift workers.In total, 2,818 female shift workers from the manufacturing industry who received an employee physical examination at a single university hospital from January to August in 2014 were included. Subjects were classified into three groups (A, B, and C) by their night shift rotation interval. The quality of sleep was measured using the Korean version of the Pittsburgh Sleep Quality Index (PSQI). Descriptive analysis, univariate logistic regression, and multivariate logistic regression were performed.	With group A as the reference, the odds ratio (OR) for having a seriously low quality of sleep was 1.456 (95% CI 1.171-1.811) and 2.348 (95% CI 1.852-2.977) for groups B and C, respectively. Thus, group C with the shortest night shift rotation interval was most likely to have a low quality of sleep. After adjustment for age, obesity, smoking status, alcohol consumption, exercise, being allowed to sleep during night shifts, work experience, and shift work experience, groups B and C had ORs of 1.419 (95% CI 1.134-1.777) and 2.238 (95% CI 1.737-2.882), respectively, compared to group A.	Our data suggest that a shorter night shift rotation interval does not provide enough recovery time to adjust the circadian rhythm, resulting in a low quality of sleep. Because shift work is influenced by many different factors, future studies should aim to determine the most optimal shift work model and collect accurate, prospective data.	
26687120	Hypertension is the most important potentially reversible risk factor for stroke in all age groups; high blood pressure (BP) is also associated with increased risk of recurrent stroke in patients who have already had an ischemic or hemorrhagic event. Twenty-four hour ambulatory BP monitoring (ABPM) has become an important tool for improving the diagnosis and management of hypertension, and is increasingly used to assess patients with hypertension. Nevertheless, although ABPM devices are increasingly used for assessment of hypertension, their value in the chronic management of hypertension in patients with stroke has not been systematically studied. In fact, among large-scale randomized trials for secondary stroke prevention, only the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention trial included 24-hour ABPM. ABPM has demonstrated chronic disruption of the circadian rhythm of BP after acute phase of stroke and has shown higher sensitivity compared to office BP in evaluating the effectiveness of antihypertensive treatment among stroke survivors. High 24-hour BP is an independent predictor for cerebrovascular events, brain microbleeds, and subsequent development of dementia. Nevertheless, although stroke care guidelines endorse the importance of hypertension management, the specific role of ABPM among stroke survivors after the acute phase of disease has not been established. Further studies are needed to clarify whether routine application of ABPM among these patients should be recommended. 
26686899	There has been a lot of effort by scientists to elucidate the multi functions of the naturally occurring hormone, dehydroepiandrosterone (DHEA). However, to plan research experiments optimally, it is important first to characterize the diurnal rhythm in healthy individuals. The aim of this research was to investigate the daily circadian rhythms of DHEA among the 2 genders, and the effect of age and exercise on salivary DHEA circadian rhythms. Volunteers (20-39 and 40-60 years) were recruited for 2 studies investigating the salivary DHEA circadian rhythm. The first study looked at the effect of gender and age on DHEA levels on 2 non-consecutive days, and the second study explored the effect of exercise on DHEA circadian rhythm in males. DHEA levels were estimated by a sensitive and specific ELISA method. The results showed a clear daily circadian rhythm in salivary DHEA in all participants groups, however the profile was flatter in the older female group. There was a significant difference between age and gender groups particularly at 8.00 h. In young males DHEA reduced from 541.1 ± 101.3 (mean ± sd) at 8.00 h to 198.9 ± 90.7 pg/mL at 18.00 h; p<0.0001, and young females from 401.6 ± 149.5 to 215.4 ± 95.3 pg/mL; p<0.001. In older males DHEA reduced from 267.5 ± 32.4 to 132.5 ± 46.7 pg/mL; p<0.001, and older females from 147.7 ± 78.1 to 89.5 ± 29.1 pg/mL; p=0.05. DHEA levels on 2 non-consecutive days showed some variations but this was not significant. Aerobic exercise has significantly increased DHEA levels at 2 time points of the day (p=0.05) in male subjects. In conclusion, our study showed a clear daily circadian rhythm in salivary DHEA in all participants was observed, but the profile was flatter in the older groups.
26686628	Circadian rhythms offer temporal control of anticipatory physiologic adaptations in animals. In the mammalian cardiovascular system, the importance of these rhythms is underscored by increased cardiovascular disease in shift workers, findings recapitulated in experimental animal models. However, a nodal regulator that allows integration of central and peripheral information and coordinates cardiac rhythmic output has been elusive. Here, we show that kruppel-like factor 15 (KLF15) governs a biphasic transcriptomic oscillation in the heart with a maximum ATP production phase and a remodeling and repair phase corresponding to the active and resting phase of a rodent. Depletion of KLF15 in cardiomyocytes leads to a disorganized oscillatory behavior without phasic partition despite an intact core clock. Thus, KLF15 is a nodal connection between the clock and meaningful rhythmicity in the heart. 
26686390	Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time.
26685594	To evaluate the ecological adaptation mechanism of Haloxylon ammodendron and H. persicum from Ningxia, the host of Cistanche deserticola, the chlorophyll fluorescence under dehydration and diurnal variation was determined by IMAGING-PAM method. The results showed that H. ammodendron had higher photosynthetic electron transport activity (Fv/Fm), photosynthetic efficiency (qP), and PS II electron transport activity (ETR) than H. persicum. After 48 h dehydration, the chlorophyll fluorescence and water-retaining property of H. ammodendron were significantly higher than those of H. persicum. The significant difference in diurnal variation between H. ammo- dendron and H. persicum was observed and a 'V' trend was exhibited. It suggested that H. ammodendron had a stronger ability to adapt to the environment and had wider distribution, while H. persicum was limited by water and light and had narrow distribution.
26684510	The impact of ambient light on mood and anxiety is best exemplified in seasonal affective disorder, in which patients experience depression and anxiety in winter when there is less light in the environment. However, the brain mechanisms underlying light-dependent changes in affective state remain unclear. Our previous work revealed increased depression-like behaviors in the diurnal Nile grass rat (Arvicanthis niloticus) housed in a dim light-dark (dim-LD) cycle as compared to the controls housed in a bright light-dark (bright-LD) condition. As depression is often comorbid with anxiety and is associated with dysregulation of the body's stress response system, the present study examined the anxiety-like behaviors as well as indicators of the hypothalamic-pituitary-adrenal (HPA) axis functioning in the grass rats. Animals housed in dim-LD showed increased anxiety-like behaviors compared to bright-LD controls, as revealed by fewer entries and less time spent at the center in the open field test and more marbles buried during the marble-burying test. Following the marble-burying test, dim-LD animals showed higher plasma corticosterone (CORT) levels and hippocampal Fos expression. Although the daily CORT rhythm was comparable between bright-LD and dim-LD groups, the day/night variation of corticotropin-releasing hormone mRNA expression in the paraventricular nucleus was diminished in dim-LD animals. In addition, glucocorticoid receptor and mineralocorticoid receptor mRNA expression were higher in the hippocampus of dim-LD animals. The results suggest that in diurnal species, reduced daytime illumination can lead to increased anxiety-like behaviors and altered HPA axis functioning, providing insights into the link between decreased environmental illumination and negative emotion. 
26684430	Diurnal disc height changes, due to fluid in- and outflow, are in equilibrium while daytime spinal loading is twice as long as night time rest. A direction-dependent permeability of the endplates, favouring inflow over outflow, reportedly explains this; however, fluid flow through the annulus fibrosus should be considered. This study investigates the fluid flow of entire intervertebral discs. Caprine discs were preloaded in saline for 24h under four levels of static load. Under sustained load, we modulated the disc׳s swelling pressure by exchanging saline for demineralised water (inflow) and back to saline (outflow), both for 24h. We measured disc height creep and used stretched exponential models to determine time-constants. During inflow disc height increased in relation to applied load, and during outflow disc height decreased to preload levels. When comparing in- and outflow phases, there was no difference in creep, and time-constants were similar indicating no direction-dependent resistance to fluid flow in the entire intervertebral disc. Results provoked a new hypothesis for diurnal fluid flow: in vitro time-constants for loading are shorter than for unloading and in vivo daytime loading is twice as long as night time unloading, i.e. in diurnal loading the intervertebral disc is closer to loading equilibrium than to unloading equilibrium. Per definition, fluid flow is slower close to equilibrium than far from equilibrium; therefore, as diurnal loading occurs closer to loading equilibrium, fluid inflow during night time unloading can balance fluid outflow during daytime loading, despite a longer time-constant.
26683607	The aim of this preliminary study was to evaluate if Sleep Restriction Therapy for insomnia is associated with modifications to physiological arousal, indexed through overnight measures of plasma cortisol concentrations and core body temperature.In a pre-to-post open label study design, eleven patients with chronic and severe Psychophysiological Insomnia underwent 5 weeks of Sleep Restriction Therapy.	Eight (73%) patients out of 11 consented completed therapy and showed a decrease in insomnia severity pre-to-post treatment (mean (SD): 18.1 (2.8) versus 8.4 (4.8); p = .001). Six patients were analyzed with pre-to-post overnight measures of temperature and cortisol. Contrary to our hypothesis, significantly higher levels of plasma cortisol concentrations were found during the early morning at post-treatment compared to baseline (p < .01), while no change was observed in the pre-sleep phase or early part of the night. Core body temperature during sleep was however reduced significantly (overall mean [95% CI]: 36.54 (°C) [36.3, 36.8] versus 36.45 [36.2, 36.7]; p < .05).	Sleep Restriction Therapy therefore was associated with increased early morning cortisol concentrations and decreased core body temperature, supporting the premise of physiological changes in functioning after effective therapy. Future work should evaluate change in physiological variables associated with clinical treatment response.	Australian New Zealand Clinical Trials Registry ANZCTR 12612000049875.	
26683511	The clinical relevance of ambulatory blood pressure monitoring (ABPM) for risk stratification in renal transplant patients still remains poorly defined.We investigated the association between clinic and ABPM with an established biomarker of atherosclerosis (intima-media thickness [IMT] by echo-color Doppler) in a large, inclusive survey (n = 172) in renal transplant patients at a single institution.	Forty-two patients (24%) were classified as hypertensive by ABPM criteria and 29 (17%) by clinic blood pressure (BP) criteria. Average daytime and nighttime BP was 126 ± 12/78 ± 9 mm Hg and 123 ± 13/74 ± 10 mm Hg, respectively. Forty-five patients (26%) were classified as hypertensive by the daytime criterion (>135/85 mm Hg) and a much higher proportion (n = 119, 69%) by the nighttime criterion (>120/70 mm Hg). Sixty-two patients (36%) had a night-day ratio of 1 or greater, indicating clear-cut nondipping. The average nighttime systolic BP (r = 0.24, P = 0.001) and the night-day systolic BP ratio (r = 0.23, P = 0.002) were directly related to IMT, and these associations were much more robust than the 24-hour systolic BP-IMT relationship (r = 0.16, P = 0.04). Average daytime BP and clinic B were unrelated to IMT. In a multiple regression analysis adjusting for confounders, the night-day systolic BP ratio maintained an independent association with IMT (β = 0.14, P = 0.04).	In renal transplant patients, the prevalence of nocturnal hypertension by far exceeds the prevalence of hypertension as assessed by clinic, daytime, and 24-hour ABPM. Nighttime systolic BP and the night-day ratio but no other BP metrics are independently associated with IMT. Blood pressure during nighttime may provide unique information for the assessment of cardiovascular risk attributable to BP burden in renal transplant patients.	
26683495	Since the first use of cortisone in patients around 65 years ago, the use of synthetic glucocorticoids has made a crucial impact on the treatment of several diseases in medicine. Although significant reductions in morbidity and mortality have occurred in patients suffering from cortisol deficiency, conventional hydrocortisone replacement treatment is still inadequate. A major limitation is that it fails to replace cortisol in a physiological manner. Cortisol has a distinct circadian rhythm and acts as a secondary messenger synchronizing the central to peripheral clocks, hence playing a key role in biological processes and the circadian timing system. Circadian misalignment has been associated with ill-health and so nonphysiological glucocorticoid treatment could explain the increased mortality rate, poor quality of life and metabolic complications in patients suffering from adrenal insufficiency. Attempts at replacing cortisol in a physiological manner have shown significant progress in the past decade with the development of modified-release formulations of hydrocortisone (Chronocort® and Plenadren®) and continuous subcutaneous hydrocortisone infusions. Initial studies investigating the use of these replacement regimens are promising, demonstrating both clinical and biochemical improvement. Larger studies are needed to determine whether this novel approach enhances long-term outcomes in both children and adults with cortisol deficiency. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel. 
26683380	Seventeen male patients with severe obstructive sleep apnea syndrome (OSAS; apnea-hypopnea index>30/h) were monitored by polysomnography in the sleep lab before and after about 8 weeks of continuous positive airway pressure (CPAP). Twelve of the patients were hypertensive, but treated by antihypertensive drugs. The circadian rhythms in blood pressure (BP) and heart rate were determined by ambulatory BP monitoring and motor activity was monitored by a motion logger. As the sympathetic tone is reported to be increased in sleep apnea, the circadian rhythm in plasma norepinephrine was studied in parallel and as a marker rhythm of the biological clock plasma melatonin was determined around the clock by radioimmunoassay.Level and rhythm in BP and heart rate were not significantly affected by CPAP in this group of patients, but the number of dippers increased after CPAP intervention. The high 24 h plasma values of norepinephrine were lowered by CPAP therapy. In contrast, melatonin values were disturbed in OSAS patients with a loss in nocturnal increase; this pattern was not corrected by CPAP. Sleep functions (deep sleep, slow wave sleep, rapid eye movement sleep, arousal index, apnea-hypopnea index, desaturation index) were disturbed in OSAS patients as monitored by polysomnography and were significantly improved by CPAP therapy.	The study indicates that BP-controlled hypertensive patients with OSAS can additionally benefit from CPAP therapy by increasing the number of dippers. This treatment significantly improved sleep functions and OSAS symptoms. In addition, arousal movements at night were also reduced and the high sympathetic tone during early morning hours was also decreased. However, there is still an indication of a disturbed function of the biological clock as the loss in the rhythm in plasma melatonin was not corrected by CPAP.	
26683231	In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs. 
26682609	It was hypothesized that an individual's chronotype might influence the response to physical activity at a given time of day. This study aimed to analyze the psychophysiological responses during a walking task at different times of day in individuals with different chronotypes. 46 students (M age=24.8 yr., SD=7.2) filled in the Morningness-Eveningness Questionnaire to determine chronotypes. Heart rate, walking time, and the rating of perceived exertion (RPE) were measured during two self-paced walking sessions: one in the morning (08:30) and one in the afternoon (15:30). A multivariate analysis of variance found a significant interaction between chronotype and time of day. The post hoc analysis showed a significant difference for RPE in the morning session, with evening types reporing a higher RPE compared with the morning types. The chronotype and the time of day when a physical task is undertaken can influence the RPE response, although it might not influence physiological or performance parameters. This has to be taken into account, because it can affect test reliability as well as possibly have a negative influence on the affective responses to a given task.
26682214	Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. 
26681432	The aims of this study were to determine the within-patient variation in the duration of morning stiffness (MS) over 1 year and the corresponding monetary equivalents assigned to its changes using the willingness-to-pay (WTP) methodology.A sample of 100 patients with rheumatoid arthritis (RA) was drawn from the register of the Hospital District of Southwest Finland. Subjects were interviewed by telephone on recruitment and 1 year later, using the same structured questionnaire. The subjects were asked to estimate in minutes the typical duration of their MS during the previous week. Sociodemographic background data and subjects' WTP for a 25, 50, 75, and 100% reduction in MS duration were requested, and years with RA diagnosis and serological data were obtained from hospital records.	After 1 year, there was a reduction in average MS duration from 44.7 min to 39.0 min (ns); duration was reduced in 35% of patients, unchanged in 35%, and prolonged in 30%. Changes in MS duration were reflected by within-patient variation in WTP estimates. In linear regression models, change in duration of MS significantly (p < 0.03) explained the variation in change of WTP for symptom reduction.	WTP methodology produces consistent monetary values to assess the relative values patients with RA place on reduction in duration of MS.	
26680765	A significant number of chronic diseases are linked to perinatal nutrition, and prevention may be associated to naturally occurring components of breast milk. One key hormone in breast milk is leptin, related with the protection from obesity in the adulthood, thus knowing its changes through the day or lactation is crucial. We aimed to investigate the daily rhythms in the milk levels of leptin, together with other two related hormones, ghrelin and adiponectin, during lactation (days 5, 10 and 15) in rat dams, and the relation with morphometric parameters (dams and pups). Summarizing the main results, the existence of biological rhythms, but not daily and maybe circasemidian, was confirmed for the three hormones at the earliest period of lactation. The correlations performed generally showed a possible dependence of milk hormone levels on plasma levels at the early phase of lactation, while with the progression of lactation this dependence may fade and the hormone levels are suggested to be more dependent on mammary gland production/maturation. There was also a correlation between milk leptin and adiponectin levels, especially in the first half of lactation, suggesting a possible parallel regulation. Interestingly, we describe a milk leptin surge around the mid of lactation (at day 10) which may be related with pup's growth (males and females) and with the well-known (in the literature) plasma leptin surge in pups. All this knowledge may be crucial for future applications in the development of formula milk and in relation with the role of leptin surge during lactation.
26680580	The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated. 
26680483	The aim of this study was to look for changes in the daily profile of steroid hormones after standardized food intake. Eight young women not taking contraceptives were followed from 5:30 a.m. till 9:30 p.m. before and 1 and 2 h after eating breakfast, snack, lunch, the second snack and dinner. The differences in steroid levels before and after meals were evaluated. As expected, glucose, C-peptide and ghrelin levels changed postprandially. The steroid hormones cortisol, progesterone, pregnenolone and dehydroepiandrosterone showed a decrease after main meals, whereas testosterone and dihydrotestosterone showed no significant dependence on food intake. Estrogen levels did not exhibit a significant nycthemeral rhythm, but estradiol decreased after main meals. In our study the known nycthemeral rhythm of LH, FSH, cortisol, progesterone and pregnenolone after food intake were confirmed, but significant changes after meals were also observed in the levels of cortisol, dehydroepiandrosterone, estradiol and SHBG. 
26679264	Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated.The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB).	The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment.	The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.	
26679065	Circadian rhythm disturbance increases cardiovascular risk but the effects of daylight saving time (DST) transitions on the risk of myocardial infarction (MI) are unclear.We studied association of DST transitions in 2001-2009 with incidence and in-hospital mortality of MI admissions nationwide in Finland. Incidence rations (IR) of observed incidences on seven days following DST transition were compared to expected incidences.	Incidence of MI increased on Wednesday (IR 1.16; CI 1.01-1.34) after spring transition (6298 patients' cohort). After autumn transition (8161 patients' cohort), MI incidence decreased on Monday (IR 0.85; CI 0.74-0.97) but increased on Thursday (IR 1.15; CI 1.02-1.30). The overall incidence of MI during the week after each DST transition did not differ from control weeks. Patient age or gender, type of MI or in-hospital mortality were not associated with transitions. Renal insufficiency was more common among MI patients after spring transition (OR 1.81; CI 1.06-3.09; p < 0.05). Diabetes was less common after spring transition (OR 0.71; CI 0.55-0.91; p = 0.007), but more common after autumn transition (OR 1.21; 1.00-1.46; p < 0.05).	DST transitions are followed by changes in the temporal pattern but not the overall rate of MI incidence. Comorbidities may modulate the effects DST transitions.	
26678364	Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities. 
26678051	Diurnal preference is an individual's preference for daily activities and sleep timing and is strongly correlated with the underlying circadian clock and the sleep-wake cycle validating its use as an indirect circadian measure in humans. Recent research has implicated DNA methylation as a mechanism involved in the regulation of the circadian clock system in humans and other mammals. In order to evaluate the extent of epigenetic differences associated with diurnal preference, we examined genome-wide patterns of DNA methylation in DNA from monozygotic (MZ) twin-pairs discordant for diurnal preference. MZ twins were selected from a longitudinal twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. Fifteen pairs of MZ twins were identified in which one member scored considerably higher on the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) than the other. Genome-wide DNA methylation patterns were assessed in twins' buccal cell DNA using the Illumina Infinium HumanMethylation450 BeadChips. Quality control and data pre-processing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. Our data indicate that DNA methylation differences are detectable in MZ twins discordant for diurnal preference. Moreover, downstream gene ontology (GO) enrichment analysis on the top-ranked diurnal preference associated DMPs revealed significant enrichment of pathways that have been previously associated with circadian rhythm regulation, including cell adhesion processes and calcium ion binding. 
26677460	Normal blood pressure (BP) follows a circadian rhythm, with dipping of BP at night. However, knowledge is limited in how the nocturnal dipping in hypertensive patients changes with the seasons. The study aims to examine the pattern of seasonal changes of nocturnal dip in an Irish population and furthermore, to compare it to the pattern observed near the equator where such seasonal variations are minimal, by also studying a Singaporean population.Ambulatory Blood Pressure Monitor recordings were obtained from 220 patients, half were from Mercy University Hospital, Cork, Ireland and half from the National Heart Centre, Singapore during the summer period from May to June and the winter period from October to December.	Irish seasonal changes resulted in an increase in nocturnal dipping in the hypertensive patients, especially for diastolic pressure (95% CI, 0.72 to 6.03, 3.37mmHg; p<0.05) and a change in the duration of dipping at night (95% CI, 0.045 to 1.01, 0.53h; p < 0.05). In Singapore, slight differences in dipping in systolic pressure were apparent despite the presence of only minor alterations in temperature (95% CI, 0.38 to 4.83, 2.61mmHg; P<0.05) or duration of daylight.	Seasonal changes not only affected the daily blood pressure but also the night time dipping status in hypertensive patients by mean value of 1.99mmHg and 3.38mmHg for systolic and diastolic pressure dip respectively. This has implications on how hypertensive patients should be treated during different seasons and when they are traveling to countries of different climatic environment.	
26677027	The detection of testosterone abuse in sports is routinely achieved through the 'steroidal module' of the Athlete Biological Passport by GC-MS(/MS) quantification of selected endogenous anabolic androgenic steroids (EAAS) from athletes' urines. To overcome some limitations of the "urinary steroid profile" such as the presence of confounding factors (ethnicity, enzyme polymorphism, bacterial contamination, and ethanol), ultrahigh performance liquid chromatography (UHPLC) measurements of blood concentrations of testosterone, its major metabolites, and precursors could represent an interesting and complementary strategy. In this work, two UHPLC-MS/MS methods were developed for the quantification of testosterone and related compounds in human serum, including major progestogens, corticoids, and estrogens. The validated methods were then used for the analyses of serum samples collected from 19 healthy male volunteers after oral and transdermal testosterone administration. Results from unsupervised multiway analysis allowed variations of target analytes to be assessed simultaneously over a 96-h time period. Except for alteration of concentration values due to the circadian rhythm, which concerns mainly corticosteroids, DHEA, and progesterone, significant variations linked to the oral and transdermal testosterone administration were observed for testosterone, DHT, and androstenedione. As a second step of analysis, the longitudinal monitoring of these biomarkers using intra-individual thresholds showed, in comparison to urine, significant improvements in the detection of testosterone administration, especially for volunteers with del/del genotype for phase II UGT2B17 enzyme, not sensitive to the main urinary marker, T/E ratio. A substantial extension of the detection window after transdermal testosterone administration was also observed in serum matrix. The longitudinal follow-up proposed in this study represents a first example of 'blood steroid profile' in doping control analysis, which can be proposed in the future as a complement to the 'urinary module' for improving steroid abuse detection capabilities.
26676400	In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life.
26675649	Now that the 24-hour economy is putting an ever-increasing mark on social life, the effects of the disruption of natural biological rhythms are becoming clearer. In addition to its effects on sleep, this article discusses its long-term health effects. Potential measures to reduce and counteract the adverse effects of working night shifts on general well-being, sleep and health are summarized; the roles of light and rhythm are explored. Further research into the health effects of working nights and unsociable shift patterns is indicated.
26674859	Drosophila melanogaster's large lateral ventral neurons (lLNvs) are part of both the circadian and sleep-arousal neuronal circuits. In the past, electrophysiological analysis revealed that lLNvs fire action potentials (APs) in bursting or tonic modes and that the proportion of neurons firing in those specific patterns varies circadianly. Here, we provide evidence that lLNvs fire in bursts both during the day and at night and that the frequency of bursting is what is modulated in a circadian fashion. Moreover, we show that lLNvs AP firing is not only under cell autonomous control, but is also modulated by the network, and in the process we develop a novel preparation to assess this. We demonstrate that lLNv bursting mode relies on a cholinergic input because application of nicotinic acetylcholine receptor antagonists impairs this firing pattern. Finally, we found that bursting of lLNvs depends on an input from visual circuits that includes the cholinergic L2 monopolar neurons from the lamina. Our work sheds light on the physiological properties of lLNvs and on a neuronal circuit that may provide visual information to these important arousal neurons.Circadian rhythms are important for organisms to be able to anticipate daily changes in environmental conditions to adjust physiology and behavior accordingly. These rhythms depend on an endogenous mechanism that operates in dedicated neurons. In the fruit fly, the large lateral ventral neurons (lLNvs) are part of both the circadian and sleep-arousal neuronal circuits. Here, we provide new details about the firing properties of these neurons and demonstrate that they depend, not only on cell-autonomous mechanisms, but also on a specific neurotransmitter derived from visual circuits. Our work sheds light on the physiological properties of lLNvs and on a neuronal circuit that may provide visual information to these important arousal neurons.	
26672044	The deletion of thyroid hormone receptor-α (TRα) in atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice (ApoE(-/-)TRα(0/0)) accelerates the formation of atherosclerotic plaques without aggravation of hypercholesterolemia. To evaluate other predisposition risk factors to atherosclerosis in this model, we studied blood pressure (BP) and cardiac and vascular functions, as well as exercise tolerance in young adult ApoE(-/-)TRα(0/0) mice before the development of atherosclerotic plaques. Telemetric BP recorded for 4 consecutive days showed that the spontaneous systolic BP was slightly decreased in ApoE(-/-)TRα(0/0) compared with ApoE(-/-) mice associated with a reduced locomotor activity. The percentage of animals that completed endurance (57% vs. 89%) and maximal running (0% vs. 89% at 46 cm/s speed in ApoE(-/-)TRα(0/0) and ApoE(-/-) mice, respectively) tests was lower in ApoE(-/-)TRα(0/0) mice. Moreover, during the maximal running test, both maximal running speed and running distance were significantly reduced in ApoE(-/-)TRα(0/0) mice, associated with a blunted BP response to exercise. Transthoracic echocardiography revealed a decreased interventricular septum thickness and an increased end-systolic left ventricular volume in ApoE(-/-)TRα(0/0) mice. Accordingly, left ventricular fractional shortening, ejection fraction, and stroke volume were all significantly decreased in ApoE(-/-)TRα(0/0) mice with a concomitant blunted cardiac output. No interstrain difference was observed in vascular reactivity, except that ApoE(-/-)TRα(0/0) mice exhibited an enhanced acetylcholine-induced relaxation in mesenteric and distal femoral arteries. In conclusion, the deletion of TRα in ApoE(-/-) mice alters cardiac structure and contractility; both could contribute to blunted BP response to physical exercise and impaired exercise performance. 
26671182	Rhythmic events in female reproductive physiology, including ovulation, are tightly controlled by the circadian timing system. The molecular clock, a feedback loop oscillator of clock gene transcription factors, dictates rhythms of gene expression in the hypothalamo-pituitary-ovarian axis. Circadian disruption due to environmental factors (eg, shift work) or genetic manipulation of the clock has negative impacts on fertility. Although the central pacemaker in the suprachiasmatic nucleus classically regulates the timing of ovulation, we have shown that this rhythm also depends on phasic sensitivity to LH. We hypothesized that this rhythm relies on clock function in a specific cellular compartment of the ovarian follicle. To test this hypothesis we generated mice with deletion of the Bmal1 locus in ovarian granulosa cells (GCs) (Granulosa Cell Bmal1 KO; GCKO) or theca cells (TCs) (Theca Cell Bmal1 KO; TCKO). Reproductive cycles, preovulatory LH secretion, ovarian morphology and behavior were not grossly altered in GCKO or TCKO mice. We detected phasic sensitivity to LH in wild-type littermate control (LC) and GCKO mice but not TCKO mice. This decline in sensitivity to LH is coincident with impaired fertility and altered patterns of LH receptor (Lhcgr) mRNA abundance in the ovary of TCKO mice. These data suggest that the TC is a pacemaker that contributes to the timing and amplitude of ovulation by modulating phasic sensitivity to LH. The TC clock may play a critical role in circadian disruption-mediated reproductive pathology and could be a target for chronobiotic management of infertility due to environmental circadian disruption and/or hormone-dependent reprogramming in women. 
26671159	Cerebral white matter hyperintensity (WMH) is highly prevalent in the elderly population, and increases the risk of dementia and stroke. We investigated the relationship between ambulatory blood pressure monitoring levels and quantitatively measured WMH volumes among elderly hypertensive patients with well-controlled blood pressure (BP) to re-evaluated effective hypertension management methods to prevent the progression of WMH.Participants comprised 84 hypertensive patients aged between 65 and 75 years without symptomatic heart failure, ischemic heart disease, atrial fibrillation, stroke or cognitive dysfunction.	Linear regression analysis showed that office BP was not associated with WMH volume increases. Raised night-time systolic BP (P = 0.013) were associated with greater WMH volumes during ambulatory blood pressure monitoring. To clarify the effect of asleep systolic BP on WML volume, we then classified patients into two systolic BP groups as follows: <125 mmHg (n = 47) and ≥125 mmHg (n = 37). Baseline characteristics were almost similar in both groups, except the dipper type of circadian BP variation was significantly common in the group with night-time systolic BP <125 mmHg. However, WMH volume was greater in the group with night-time systolic BP ≥125 mmHg than that in the <125 mmHg group (9.0 ± 8.4 mL vs 4.1 ± 4.3 mL, P = 0.015).	Higher night-time systolic BP levels were observed to contribute greater WMH volumes in elderly hypertensive patients. To prevent the progression of WMH, controlling BP on the basis of ambulatory blood pressure monitoring is important.	
26670607	Rev-erbα and Rev-erbβ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erbα recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erbβ (FLRev-erbβ) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo- and heme-replete FLRev-erbβ·DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erbβ·NCoR1 complex. The interaction between FLRev-erbβ and NCoR1 as well as Rev-erbβ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erbβ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10(-6) s(-1)) of heme dissociation from Rev-erbβ rules out a prior proposal that Rev-erbβ acts as an intracellular heme sensor. 
26670249	Previous research has found an association between being overweight and short sleep duration. We hypothesized that this association could be modified by a high carbohydrate (HC) diet and that the timing and type (starch or sugar) of intake may be an important factor in this context. Participants in the prospective, eight-country European study IDEFICS were recruited from September 2007 to June 2008, when they were aged two to nine years. Data on lifestyle, dietary intake and anthropometry were collected on two occasions. This study included 5944 children at baseline and 4301 at two-year follow-up. For each meal occasion (morning, midday, and evening), starch in grams and sugar in grams were divided by total energy intake (EI), and quartiles calculated. HC-starch and HC-sugar intake categories were defined as the highest quartile for each meal occasion. In a mutually adjusted linear regression model, short sleep duration as well as HC-starch in the morning were positively associated with body mass index (BMI) z-scores at baseline. HC-starch at midday was positively associated with body mass index (BMI) z-scores in children with short sleep duration, and negatively associated with BMI z-scores in those with normal sleep. After adjustment for baseline BMI z-scores, associations between total HC from starch or sugar and high BMI z-scores at two-year follow-up did not persist. Our observations offer a perspective on optimal timing for macronutrient consumption, which is known to be influenced by circadian rhythms. Reduced carbohydrate intake, especially during morning and midday meals, and following nocturnal sleep duration recommendations are two modifiable factors that may protect children from being overweight in the future. 
26669694	Circadian variation of gene expression is often neglected when ionizing radiation-induced effects are studied, whether in animal models or in cell culture. This study characterized diurnal variation of genome-wide transcriptional regulation and responses of potential biomarkers and signature genes in normal mouse tissues at 24 h after i.v. administration of (131)I.Female BALB/c nude mice were i.v. injected with 90 kBq (131)I at 9:00 a.m., 12:00 p.m., or 3:00 p.m. and killed after 24 h (n = 4/group). Paired control groups were mock-treated (n = 3-4/group). The kidneys, liver, lungs, spleen, and thyroid were excised, snap-frozen, and stored at -80 °C until extraction of total RNA. RNA microarray technology was used for genome-wide expression analysis. Enriched biological processes were categorized after cellular function. Signature genes for ionizing radiation and thyroid hormone-induced responses were taken from the literature. Absorbed dose was estimated using the Medical Internal Radiation Dose (MIRD) formalism.	The thyroid received an absorbed dose of 5.9 Gy and non-thyroid tissues received 0.75-2.2 mGy over 24 h. A distinct peak in the total number of significantly regulated transcripts was observed at 9:00 a.m. in the thyroid, but 3 h later in the kidney cortex, kidney medulla, and liver. Transcriptional regulation in the lungs and spleen was marginal. Associated cellular functions generally varied in quality and response strength between morning, noon, and afternoon. In the thyroid, 25 genes were significantly regulated at all investigated times of day, and 24 thereof showed a distinct pattern of pronounced down-regulation at 9:00 a.m. and comparatively weak up-regulation at later times. Eleven of these genes belonged to the species-specific kallikrein subfamily Klk1b. Responses in signature genes for thyroid hormone-induced responses were more frequent than for ionizing radiation, and trends persisted irrespective of time of day.	Diurnal variation of genome-wide transcriptional responses to 90 kBq (131)I was demonstrated for the thyroid, kidney cortex and medulla, and liver, whereas variation was only marginal in the lungs and spleen. Overall, significant detection of potential biomarkers and signature genes was validated at each time of day, although direction of regulation and fold-change differed between morning, noon, and afternoon. These findings suggest that circadian rhythm should be considered in radiation research and that biological and analytical endpoints should be validated for circadian robustness.	
26667030	The prevalence of obesity and the female labor participation rate have been rapidly increasing in South Korea. To examine the relationship between these factors, we investigated the association between timing and type of work and obesity in the Korean female working population.Data collected by the 2008 Community Health Survey (CHS) were analyzed using a complex, stratified, multistage, probability cluster sampling method. Descriptive analysis of relevant variables was performed using the chi-square test, and work-related variables by work type were identified using multivariate logistic regression. The relationship between long working hours, night/shift work, and body-mass index in female workers and explanatory, stratifying, and dependent variables and covariates was analyzed using multiple logistic regression models.	A total of 42,234 CHS participants were eligible for study inclusion. Among both manual and nonmanual workers, working less than 40 (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI] 1.07-1.31 and aOR 1.29; 95% CI 1.09-0.52, respectively) or more than 60 (aOR 1.18, 95% CI 1.06-1.30 and aOR 1.28, 95% CI 1.04-1.57, respectively) hours per week was significantly associated with obesity after controlling for covariates. However, working type (day or night/shift) was significantly associated with obesity only in nonmanual workers (aOR 1.20, 95% CI 1.01-1.42). When we controlled working type in the model, manual workers who work more than 60 hours show higher likelihood of being obese (OR 1.10, 95% CI 1.02-1.18).	Working fewer (<40) or more than (>60) hours per week is significantly associated with obesity in the Korean female working population, regardless of the type of work. The type of work (day vs. night/shift work) was significantly associated with obesity only in only nonmanual workers.	
26666334	The objective of this study was to evaluate the contribution of personality traits in explaining the relationship between workplace stressors and variations in salivary cortisol concentrations.Multilevel regression analyses were performed on a sample of 401 employees from 34 Quebec firms. Saliva samples were collected five times a day (on awakening, 30 min after awakening, and at 2 p.m., 4 p.m., and bedtime). Sample collection was repeated on three days (1 rest day, 2 working days). Work-related variables comprised skill utilization, decision authority, psychological demands, physical demands, job insecurity, irregular schedule, number of working hours, and social support from coworkers and supervisors. Personality traits comprised self-esteem, locus of control, and the Big Five.	Cortisol levels at awakening and 30 min later were significantly higher for work days than for days off. Psychological demands and job insecurity were associated with lower cortisol levels at bedtime. Also, self-esteem moderated the relationship between physical demands and cortisol levels at awakening and 4 p.m. Agreeableness was associated with lower cortisol levels at awakening and at 2 p.m. and further moderated the relationship between number of hours worked and cortisol at 2 p.m. Neuroticism moderated the relationship between coworker support and cortisol at bedtime.	Specific working conditions and certain personality traits are associated with variations in salivary cortisol concentrations. In addition, certain personality traits moderate the relationship between stressors and salivary cortisol concentrations. In conclusion, salivary cortisol concentrations at work seem to be modulated in part by personality traits.	

26664064	The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study. 
26663673	Seasonal variation in blood pressure (BP) has been observed in different populations. However, only few studies have focused on BP seasonality in diabetic patients. This study examined the seasonal patterns in BP in 62,589 patients with type 1 diabetes mellitus (T1DM) and in 99,546 patients with type 2 diabetes mellitus (T2DM) from the German/Austrian Diabetes Follow-up Registry. Adjusted mean BP values revealed seasonal cycles of 12 months, with higher BP in colder months. Using harmonic regression models, the estimated systolic BP difference throughout the year was 2.28/2.48 mm Hg in T1DM/T2DM (both P<.001). Interestingly, seasonal variation in diastolic BP was larger in T1DM than in T2DM (1.24/0.64 mm Hg, P<.001). A sex difference was observed in T1DM only, while age differences occurred in both types of diabetes. Correlations between BP and potentially related factors such as outdoor temperature indicated that reasons underlying BP seasonality are likely to be complex and vary by subgroup. 
26663630	Synchronizing neural processes, mental activities, and social interactions is considered to be fundamental for the creation of temporal order on the personal and interpersonal level. Several different types of synchronization are distinguished, and for each of them examples are given: self-organized synchronizations on the neural level giving rise to pre-semantically defined time windows of some tens of milliseconds and of approximately 3 s; time windows that are created by synchronizing different neural representations, as for instance in aesthetic appreciations or moral judgments; and synchronization of biological rhythms with geophysical cycles, like the circadian clock with the 24-hr rhythm of day and night. For the latter type of synchronization, an experiment is described that shows the importance of social interactions for sharing or avoiding common time. In a group study with four subjects being completely isolated together for 3 weeks from the external world, social interactions resulted both in intra- and interindividual circadian synchronization and desynchronization. A unique phenomenon in circadian regulation is described, the "beat phenomenon," which has been made visible by the interaction of two circadian rhythms with different frequencies in one body. The separation of the two physiological rhythms was the consequence of social interactions, that is, by the desire of a subject to share and to escape common time during different phases of the long-term experiment. The theoretical arguments on synchronization are summarized with the general statement: "Nothing in cognitive science makes sense except in the light of time windows." The hypothesis is forwarded that time windows that express discrete timing mechanisms in behavioral control and on the level of conscious experiences are the necessary bases to create cognitive order, and it is suggested that time windows are implemented by neural oscillations in different frequency domains. 
26663435	Currently, adrenal venous sampling (AVS) is the only reliable method to distinguish unilateral from bilateral hyperaldosteronism in primary aldosteronism (PA). However, AVS is costly and time-consuming compared with simple blood tests. In this study, we conducted a retrospective study to determine whether circadian variation in plasma adrenocortical hormone levels (i.e. aldosterone, cortisol and ACTH) and a 24-h urinary aldosterone could contribute to the clinical differentiation between unilateral hyperaldosteronism (UHA) and bilateral hyperaldosteronism (BHA).In 64 patients who were diagnosed with PA and underwent AVS, 32 and 22 patients were diagnosed with UHA and BHA, respectively. Plasma adrenocortical hormone levels at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone under a condition of 6 g daily dietary sodium chloride intake were measured.	Baseline plasma aldosterone concentration (PAC) and 24-h urinary aldosterone level in patients with UHA were significantly higher than in patients with BHA, particularly at 6:00. The area under the ROC curve for PAC at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone to discriminate UHA and BHA was 0·839 [95% confidence interval (CI); 0·73-0·95], 0·922 (95% CI; 0·85-1·00), 0·875 (95% CI; 0·78-0·97), 0·811 (95% CI; 0·69-0·93), 0·898 (95% CI; 0·81-0·99), respectively.	PAC at different blood sampling times and 24-h urinary aldosterone level may be diagnostically helpful in discriminating between UHA and BHA. We believe that these tests could reduce the number of unnecessary AVS procedures.	
26663024	Diurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes are associated with aberrant cortisol patterns similar to sleep-deficient individuals.Cross-sectional.	A total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes.	Baseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (≤5·5, N = 103; >5·5-8·8, N = 103; >8·8, N = 100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates.	Women were 67% White and 24% African American, with 7·6 (SD 3·9) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 75·0 (SD 44·8) total, 8·6 (SD 5·6) wake, 10·0 (SD 7·5) wake +30 min, 3·7 (SD 3·3) early afternoon and 1·6 (SD 1·8) bedtime. Wake + 30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 11·4(SD 7·3), 10·3 (SD 6·5) and 8·6 (SD 7·8), respectively, P = 0·003. Beside the early afternoon value (P = 0·02), cortisol values did not vary by hot flash frequency.	Taken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance.	
26662479	Saliva in the mouth is a biofluid produced mainly by three pairs of major salivary glands--the submandibular, parotid and sublingual glands--along with secretions from many minor submucosal salivary glands. Salivary gland secretion is a nerve-mediated reflex and the volume of saliva secreted is dependent on the intensity and type of taste and on chemosensory, masticatory or tactile stimulation. Long periods of low (resting or unstimulated) flow are broken by short periods of high flow, which is stimulated by taste and mastication. The nerve-mediated salivary reflex is modulated by nerve signals from other centers in the central nervous system, which is most obvious as hyposalivation at times of anxiety. An example of other neurohormonal influences on the salivary reflex is the circadian rhythm, which affects salivary flow and ionic composition. Cholinergic parasympathetic and adrenergic sympathetic autonomic nerves evoke salivary secretion, signaling through muscarinic M3 and adrenoceptors on salivary acinar cells and leading to secretion of fluid and salivary proteins. Saliva gland acinar cells are chloride and sodium secreting, and the isotonic fluid produced is rendered hypotonic by salivary gland duct cells as it flows to the mouth. The major proteins present in saliva are secreted by salivary glands, creating viscoelasticity and enabling the coating of oral surfaces with saliva. Salivary films are essential for maintaining oral health and regulating the oral microbiome. Saliva in the mouth contains a range of validated and potential disease biomarkers derived from epithelial cells, neutrophils, the microbiome, gingival crevicular fluid and serum. For example, cortisol levels are used in the assessment of stress, matrix metalloproteinases-8 and -9 appear to be promising markers of caries and periodontal disease, and a panel of mRNA and proteins has been proposed as a marker of oral squamous cell carcinoma. Understanding the mechanisms by which components enter saliva is an important aspect of validating their use as biomarkers of health and disease.
26662267	We sought to investigate the relationship between blood pressure (BP) variability and left atrial (LA) phasic function assessed by volumetric and speckle tracking method in normal-weight, overweight and obese hypertensive patients. This cross-sectional study included 164 untreated hypertensive subjects who underwent a 24-h ambulatory BP monitoring and complete two-dimensional echocardiographic examination (2DE). All the patients were separated into three groups according to their body mass index (BMI): normal-weight patients (BMI < 25 kg/m(2)), overweight patients (25 ≤ BMI < 30 kg/m(2)), and obese patients (BMI ≥ 30 kg/m(2)). Daytime, nighttime and 24 h BP variability indices were higher in obese hypertensive subjects than in lean patients. Maximum and minimum LA volumes and volume indexes gradually and significantly increased, whereas pre-A LAV decreased, from normal-weight to obese subjects. Total and passive LA emptying fractions, representing LA reservoir and conduit function, gradually reduced from lean to obese individuals. Active LA EF, the parameter of LA booster pump function, increased in the same direction. Similar results were obtained by 2DE strain analysis. BP variability parameters were associated with structural, functional and mechanical parameters of LA remodeling in the whole study population. The parameters of LA reservoir function were negatively related with BP variability indices, whereas the parameters of LA pump function were positively related with BP variability indices. Obesity significantly impacts BP variability and LA phasic function in untreated hypertensive subjects. BP variability is associated with LA remodeling independent of BP, left ventricular systolic and diastolic function. 
26662127	Depression leads to disturbances in physiological rhythms, which result in disturbances in circadian sleep-wake cycles, hormonal secretion patterns and fluctuations in mood, all of which can be objectively measured. These disturbances, which are associated with depression, can be also used to define depression. Beyond these "transversal" time-related symptoms, there are the "longitudinal" time-related symptoms, since depression evolves over a long period of time, with a profound impact on a person's life and is often associated with long-term psychosocial consequences (Mendlewicz, 2010). The circadian rhythm reflects an approximate 24-hour cycle in the biochemical, physiological and behavioral processes of living entities, which crucially influences human well-being and health. Increasing evidence from clinical and neurobiological research suggests that disrupted temporal organization impairs behavior, cognition, mood, sleep and social activity and may be implicated in mental disorders. It has been proposed that circadian malfunction is a major core feature of mood disorders, depression in particular. In depressed patients, circadian rhythms and homeostatic processes are disrupted, thereby affecting mood, sleep, activity and a variety of biological functions such as hormone secretion and body temperature (Hajak & Landgrebe, 2010). Sleep difficulties are among the most current symptoms in depressed patients. Insomnia is often the reason why depressed patients seek help and relief of sleep disturbance may encourage compliance with antidepressant treatment. Apart from the discomfort that sleep problems produce, they may lead to exhaustion, poor functioning and they are associated with an increase in suicide risk (Wilson et al., 2013). 
26660638	It is not known whether individuals successful at long term weight loss maintenance differ in chronotype (i.e., being a "morning" or "evening" person) or sleep habits compared to those who are overweight and obese. We compared Morningness-Eveningness Questionnaire (MEQ) and Pittsburgh Sleep Quality Index scores of 690 National Weight Control Registry (NWCR) members (73 % female, 93 % white, age = 51.7 ± 12.5, BMI = 26.4 ± 5.1) to 75 enrollees in two behavioral weight loss interventions (INT; 77 % female, 88 % white, age = 55.7 ± 10.4, BMI = 36.2 ± 4.7). Controlling for age, MEQ scores were higher in NWCR than INT, p = .004, such that more NWCR than INT were morning-types and fewer were evening types, p = .014. Further, NWCR participants reported better sleep quality, longer sleep duration, and shorter latency to sleep onset compared to INT, ps < .05, and fewer NWCR participants reported <6 or <7 h of sleep, ps < .01. Future studies should examine if these factors change as a result of weight loss or are predictors of weight outcome.
26660098	Several lines of evidence suggest a regulatory role of histamine in circadian rhythms, but little is known about signaling pathways that would be involved in such a putative role. The aim of this study was to examine whether histamine mediates its effects on the circadian system through Hrh1 or Hrh3 receptors. We assessed both diurnal and free-running locomotor activity rhythms of Hrh1-/- and Hrh3-/- mice. We also determined the expression of Per1, Per2 and Bmal1 genes in the suprachiasmatic nuclei, several areas of the cerebral cortex and striatum under symmetric 24 h light-dark cycle at zeitgeber times 14 and 6 by using radioactive in situ hybridization. We found no differences between Hrh1-/- and wild type mice in the length, amplitude and mesor of diurnal and free-running activity rhythms as well as in expression of Per1, Per2 and Bmal1 genes in any of the examined brain structures. The amplitude of free-running activity rhythm of the Hrh3-/- mice was significantly flattened, whereas the expression of the clock genes in Hrh3-/- mice was similar to the wild type animals in all of the assessed brain structures. Therefore, the knockout of Hrh1 receptor had no effects on the circadian rhythm of spontaneous locomotion, and a knockout of Hrh3 receptor caused a substantial reduction of free-running activity rhythm amplitude, but none of these knockout models affected the expression patterns of the core clock genes in any of the studied brain structures. 
26657859	Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA. 
26657854	Circadian rhythms mediated by both central and tissue-specific peripheral clocks allow for the synchronization of biological processes with diurnal cycles such as activity and rest. Disruption of these rhythms can be caused by altered sleep-awake patterns or by pathological conditions and can initiate or exacerbate human disease through mechanisms that are only partially understood. In this issue, Dudek et al. identify a chondrocyte-autonomous cartilage clock and demonstrate that expression of an important circadian pacemaker, BMAL1, decreases during osteoarthritis progression. They show that chondrocyte-specific deletion of BMAL1 leads to cartilage degradation and disruption of key pathways, shifting cartilage homeostasis toward a catabolic state. These findings provide insight into the interplay between circadian rhythm and cartilage in osteoarthritis. 
26657846	The CLOCK-interacting protein, Circadian (CIPC), has been identified as an additional negative-feedback regulator of the circadian clock. However, recent study on CIPC knockout mice has shown that CIPC is not critically required for basic circadian clock function, suggesting other unknown biological roles for CIPC. In this study, we focused on the cell cycle dependent nuclear-cytoplasmic shuttling function of CIPC and on identifying its binding proteins. Lys186 and 187 were identified as the essential amino acid residues within the nuclear localization signal (NLS) of CIPC. We identified CIPC-binding proteins such as the multifunctional enzyme CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), which is a key enzyme for de novo pyrimidine synthesis. Compared to control cells, HEK293 cells overexpressing wild-type CIPC showed suppressed cell proliferation and retardation of cell cycle. We also found that PMA-induced Erk activation was inhibited with expression of wild-type CIPC. In contrast, the NLS mutant of CIPC, which reduced the ability of CIPC to translocate into the nucleus, did not exhibit these biological effects. Since CAD and Erk have significant roles in cell proliferation and cell cycle, CIPC may work as a cell cycle regulator by interacting with these binding proteins. 
26657326	The circadian clock is an endogenous biological timekeeping system that synchronizes physiology and behavior to day/night cycles. A wide variety of processes throughout the entire gastrointestinal tract and notably the liver appear to be under circadian control. These include various metabolic functions such as nutrient uptake, processing, and detoxification, which align organ function to cycle with nutrient supply and demand. Remarkably, genetic or environmental disruption of the circadian clock can cause metabolic diseases or exacerbate pathological states. In addition, modern lifestyles force more and more people worldwide into asynchrony between the external time and their circadian clock, resulting in a constant state of social jetlag. Recent evidence indicates that interactions between altered energy metabolism and disruptions in the circadian clock create a downward spiral that can lead to diabetes and other metabolic diseases. In this review, we provide an overview of rhythmic processes in the liver and highlight the functions of circadian clock genes under physiological and pathological conditions; we focus on their roles in regulation of hepatic glucose as well as lipid and bile acid metabolism and detoxification and their potential effects on the development of fatty liver and nonalcoholic steatohepatitis. 
26657008	Correlation between blood pressure (BP) and target organ damage, vascular risk and long-term patient prognosis is greater for measurements derived from around-the-clock ambulatory BP monitoring than in-clinic daytime ones. Numerous studies consistently substantiate the asleep BP mean is both an independent and a much better predictor of cardiovascular disease (CVD) risk than either the awake or 24 h means. Sleep-time hypertension is much more prevalent than suspected, not only in patients with sleep disorders, but also among those who are elderly or have type 2 diabetes, chronic kidney disease or resistant hypertension. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly affects BP control, particularly sleep-time BP, and adverse effects. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime vs. morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers better reduces the asleep BP mean, with additional benefit, independent of medication terminal half-life, of converting the 24 h BP profile into more normal dipper patterning. The MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares) study, first prospective randomized treatment-time investigation designed to test the worthiness of bedtime chronotherapy with ⩾1 conventional hypertension medications so as to specifically target attenuation of asleep BP, demonstrated, relative to conventional morning therapy, 61% reduction of total CVD events and 67% decrease of major CVD events, that is, CVD death, myocardial infarction, and ischemic and hemorrhagic stroke. The MAPEC study, along with other earlier conducted less refined trials, documents the asleep BP mean is the most significant prognostic marker of CVD morbidity and mortality; moreover, it substantiates attenuation of the asleep BP mean by a bedtime hypertension treatment strategy entailing the entire daily dose of ⩾1 hypertension medications significantly reduces CVD risk in both general and more vulnerable hypertensive patients, that is, those diagnosed with chronic kidney disease, diabetes and resistant hypertension. 
26656793	Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics. 
26656624	Measuring real-time gene activity in the brains of freely moving animals presents a challenging issue in neuroscience research. Circadian gene expression in neurons of the suprachiasmatic nucleus (SCN), a small nucleus in the hypothalamus, is reflected in behavioral rhythmicity. Cellular oscillatory gene expression is generated by a transcription-translation feedback loop of clock genes including 2 oscillatory genes, Per1 and Per2. Here we have succeeded in real-time monitoring of Per1 and Per2 transcription separately by detecting the bioluminescence of luciferase (luc) reporters using a plastic optical fiber inserted into the SCN of freely moving rats. Per1-luc and Per2-luc rhythms peaked in the middle and late subjective day, respectively, which was confirmed by quantitative PCR-based measurements of SCN tissue samples. Studies of in vivo transcriptional states of clock genes in freely moving animals should improve our understanding of how clock gene expression is reflected in behavior. 
26656623	The testis provides not just one but several models of temporal organization. The complexity of its rhythmic function arises in part from its compartmentalization and diversity of cell types: not only does the testis produce gametes, but it also serves as the major source of circulating androgens. Within the seminiferous tubules, the germ cells divide and differentiate while in intimate contact with Sertoli cells. The tubule is highly periodic: a spermatogenic wave travels along its length to determine the timing of the commitment of spermatogonia to differentiate, the phases of meiotic division, and the rate of differentiation of the postmeiotic germ cells. Recent evidence indicates that oscillations of retinoic acid play a major role in determining periodicity of the seminiferous epithelium. In the interstitial space, Leydig cells produce the steroid hormones required both for the completion of spermatogenesis and the development and maintenance of male sexual characteristics throughout the body. This endocrine output also oscillates; although the pulse generator lies outside the gonad, the steroidogenic function of Leydig cells is tuned to a regular episodic input. While the oscillations of the intratubular and interstitial cells have multihour (ultradian) and multiday (infradian) periodicities, respectively, the functions of both compartments also display dramatic seasonal rhythms. Furthermore, circadian rhythms are evident in some of the cell types, although their amplitude and pervasiveness are not as great as in many other tissues of the same organism, and their detection may require methods that recognize the heterogeneity of the testis. This review examines the periodicity of testicular function along multiple time scales. 
26655902	Genes expressing circadian RNA rhythms are enriched for metabolic pathways, but the adaptive significance of cyclic gene expression remains unclear. We estimated the genome-wide synthetic and degradative cost of transcription and translation in three organisms and found that the cost of cycling genes is strikingly higher compared to non-cycling genes. Cycling genes are expressed at high levels and constitute the most costly proteins to synthesize in the genome. We demonstrate that metabolic cycling is accelerated in yeast grown under higher nutrient flux and the number of cycling genes increases ∼40%, which are achieved by increasing the amplitude and not the mean level of gene expression. These results suggest that rhythmic gene expression optimizes the metabolic cost of global gene expression and that highly expressed genes have been selected to be downregulated in a cyclic manner for energy conservation. 
26655861	Theoretical models of Bipolar Disorder (BD) highlight that sleep disturbances may be a marker of underlying circadian dysregulation. However, few studies of sleep in BD have reported on the most prevalent circadian sleep abnormality, namely Delayed Sleep Phase (DSP).A cross-sectional study of 404 adults with BD who met published clinical criteria for insomnia, hypersomnia or DSP, and who had previously participated in a study of sleep in BD using a comprehensive structured interview assessment.	About 10% of BD cases with a sleep problem met criteria for a DSP profile. The DSP group was younger and had a higher mean Body Mass Index (BMI) than the other groups. Also, DSP cases were significantly more likely to be prescribed mood stabilizers and antidepressant than insomnia cases. An exploratory analysis of selected symptom item ratings indicated that DSP was significantly more likely to be associated with impaired energy and activity levels.	The cross-sectional design precludes examination of longitudinal changes. DSP is identified by sleep profile, not by diagnostic criteria or objective sleep records such as actigraphy. The study uses data from a previous study to identify and examine the DSP group.	The DSP group identified in this study can be differentiated from hypersomnia and insomnia groups on the basis of clinical and demographic features. The association of DSP with younger age, higher BMI and impaired energy and activity also suggest that this clinical profile may be a good proxy for underlying circadian dysregulation.	
26655789	The seasonality of depressive symptoms is prevalent in children and adolescents. However, the mechanisms that underlie such susceptibility to seasonal influences on mood disorders are unclear. We examined the effects of a short photoperiod condition on the susceptibility to subchronic unpredictable mild stress (SCUS) and rhythmic alterations of plasma corticosterone (CORT), melatonin, and neuropeptide Y (NPY) in adolescent male rats. Compared with the 12h/12h light/dark photoperiod control (CON) rats, the 8h/16h photoperiod SCUS rats exhibited significant anhedonia, a core symptom of human depression, together with a blunted diurnal rhythm and elevation of 24h CORT, melatonin, and NPY levels. The 8h/16h photoperiod condition also blunted the rhythmicity of CORT, caused a phase inversion of melatonin, and caused a phase delay of NPY compared with 12h/12h CON rats. Such abnormalities of plasma CORT, NPY, and melatonin might cause adolescent individuals to present higher stress reactivity and greater vulnerability to stress over their lifetimes. The present study provides evidence of the susceptibility to the seasonality of stress-related disorders in adolescence. 
26654995	The role of circadian clocks in timing daily behaviors is widely acknowledged, and while empirical evidence suggests that clock period is correlated with the preferred phase of a rhythmic behavior (chronotype), other clock properties have also been hypothesized to underlie chronotype variation. Here, we report that fruit fly Drosophila melanogaster populations exhibiting evening emergence chronotype (late) are characterized by higher incidence of behavioral arrhythmicity in constant dim light, wider range of entrainment, reduced rates of re-entrainment to simulated jet-lag and higher amplitude of both entrained and free-running rhythms as compared to those exhibiting morning emergence chronotype (early). Our results thus highlight the role of circadian clock properties such as zeitgeber sensitivity, amplitude and coupling in driving chronotype variation.
26654880	Exposure to artificial light at night (ALAN) has become increasing common, especially in developed countries. We investigated the effect of dALAN exposure during sleep in healthy young male subjects. A total of 30 healthy young male volunteers from 21 to 29 years old were recruited for the study. They were randomly divided into two groups depending on light intensity (Group A: 5 lux and Group B: 10 lux). After a quality control process, 23 healthy subjects were included in the study (Group A: 11 subjects, Group B: 12 subjects). Subjects underwent an NPSG session with no light (Night 1) followed by an NPSG session randomly assigned to two different dim light conditions (5 or 10 lux, dom λ: 501.4 nm) for a whole night (Night 2). We found significant sleep structural differences between Nights 1 and 2, but no difference between Groups A and B. Exposure to dALAN during sleep was significantly associated with increased wake time after sleep onset (WASO; F = 7.273, p = 0.014), increased Stage N1 (F = 4.524, p = 0.045), decreased Stage N2 (F = 9.49, p = 0.006), increased Stage R (F = 6.698, p = 0.017) and non-significantly decreased REM density (F = 4.102, p = 0.056). We found that dALAN during sleep affects sleep structure. Exposure to dALAN during sleep increases the frequency of arousals, amount of shallow sleep and amount of REM sleep. This suggests adverse effects of dALAN during sleep on sleep quality and suggests the need to avoid exposure to dALAN during sleep.
26654802	The influence of steroid hormones on food intake is well described. However, there are only a few studies on the effect of food intake on steroid levels. The study involved eight non-smoker women (average age 29.48±2.99 years; average BMI 21.3±1.3 kg/m2); they did not use any kind of medication affecting steroidogenesis. We analysed the influence of four various stimuli on the levels of steroid hormones and melatonin. During their follicular phase of menstrual cycle, each woman had an oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), a standard breakfast and psyllium (a non-caloric fibre). Cortisol declined during each test, which is a physiological decline in the morning hours. In all tests (except of the application of the non-caloric fibre, psyllium), however, this decline was modified. After the standard breakfast there was an increase in cortisol at 40th minute. The OGTT and IVGTT tests led to a plateau in cortisol levels. Testosterone levels and those of other steroid hormones showed no relationships to tested stimulations. Oral and intravenous glucose have influenced physiological decline of melatonin levels. During the IVGTT test, melatonin levels started to increase at 20th minute, reaching a maximum at 40th minute. The OGTT test led to a delayed increase in melatonin levels, compared to IVGTT. Despite the fact that we performed the tests in the morning hours, when steroid hormone levels physiologically start to change due to their diurnal rhythm, we still found that food intake influences some of the hormone levels.
26654772	Bipolar disorder (BD) is a long-recognized severe and common psychiatric disorder, with a complex and often diverse range of presentations. BD is a heterogenous disorder that has traditionally, if rather simply, been defined by the recurrences of manic and depressive episodes, and presents with numerous immune-inflammatory and circadian/sleep abnormalities. A number of different lines of research have investigated the biological underpinnings of BD and demonstrate a heritability of about 80-90%. This genetic contribution is thought to be mediated by a wide array of genetic factors, rather than being strongly influenced by a couple of genes. In this context, a clearer formulation of the biological underpinnings of BD is needed in order to encompass the diverse effects of multiple susceptibility genes. The biological underpinnings of BD includes work that has focussed on the role played by increased immune inflammatory activity, particularly changes in pro-inflammatory cytokines, as measured both centrally and systemically. Changes in immune- inflammatory activity are intimately associated with alterations in levels of oxidative and nitrosative stress (O&NS), which are increased in BD. Many of the neuroregulatory changes driven by O&NS and immune-inflammatory activity are mediated by the tryptophan catabolite (TRYCAT) pathways, with changes in TRYCATs being evident both centrally and peripherally. A consequence of increased pro-inflammatory cytokines, is their induction of indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin, Nacetylserotonin and melatonin synthesis, driving it to the synthesis of neuroregulatory TRYCATs. Most work exploring such changes has emphasized the role of TRYCATs in enhancing or decreasing neuronal activity. However, a relatively overlooked consequence of cytokine induced IDO and TRYCAT pathway activation is the impact that this has on aryl hydrocarbon receptor (AhR) activation and in decreasing melatonergic pathway activity. Melatonin is classically associated with night-time synthesis by the pineal gland, in turn regulating circadian rhythms. However, melatonin is produced by many, if not all mitochondria containing cells, with consequences for gut regulation, as well as glia and immune cell reactivity. The melatonergic pathways are genetic susceptibility factors for BD. Interactive changes in O&NS, immune-inflammatory activity, TRYCATs and the melatonergic pathways form an emerging biological perspective on the etiology, course and management of BD. Here, we review such changes in BD, and how this better integrates the diverse array of BD presentations and comorbidities, including addiction and cardiovascular disorders as well as decreased life-expectancy. We then look at the future directions such research may take. 
26654732	Studies have shown a relationship between circadian rhythm disruptions and type-2 diabetes. This investigation examined the effects of circadian disruption (6-h phase advances) on the progression of diabetes in a type-2 diabetic mouse model -TALLYHO/JngJ - and whether wheel-running can alleviate the effects of the phase advances. 6-h advances alter fasting glucose, glucose tolerance and insulin production. Wheel-running reduced body mass, improved glucose tolerance and reduced insulin in TALLYHO/JngJ and alleviated some of the changes in diabetic symptoms due to 6-h advances. These results indicate that individuals with type-2 diabetes can benefit from physical activity and exercise can be a countermeasure to offset the effects of an acute phase advance.
26654569	This cross-sectional population study examined associations of sleep duration and morning-evening type with sociodemographic and cardiometabolic disease in adults participating in the UK Biobank study (N = 439 933). Multivariable Poisson regression models of sleep duration and morning-evening type with a robust error variance were generated to estimate adjusted prevalence ratios and their 95% confidence intervals. All models were adjusted for sex, race, college attendance, employment status and age. Twenty five percent of the sample reported short sleep; 27% were morning, 64% intermediate and 9% evening type. Black ethnicity emerged as most strongly associated with sleep behavior. Short sleep was twice as prevalent, and morning versus intermediate type was 1.4 times more prevalent in Black than White participants. The greater prevalence of short sleep and morning type among Blacks suggests that sleep-based approaches to improving cardiometabolic outcomes may require a more multidimensional approach that encompasses adequate sleep and circadian alignment in this population.
26653934	A major challenge for biology is to extend our understanding of molecular regulation from the simplified conditions of the laboratory to ecologically relevant environments. Tractable examples are essential to make these connections for complex, pleiotropic regulators and, to go further, to link relevant genome sequences to field traits. Here, I review the case for the biological clock in higher plants. The gene network of the circadian clock drives pervasive, 24-hour rhythms in metabolism, behavior, and physiology across the eukaryotes and in some prokaryotes. In plants, the scope of chronobiology is now extending from the most tractable, intracellular readouts to the clock's many effects at the whole-organism level and across the life cycle, including biomass and flowering. I discuss five research areas where recent progress might be integrated in the future, to understand not only circadian functions in natural conditions but also the evolution of the clock's molecular mechanisms. 
26653333	Fasting blood glucose (FBG) and hepatic glucose production are regulated according to a circadian rhythm. An early morning increase in FBG levels, which is pronounced among diabetic patients, is known as the dawn phenomenon. Although the intracellular circadian clock generates various molecular rhythms, whether the hepatic clock is involved in FBG rhythm remains unclear. To address this issue, we investigated the effects of phase shift and disruption of the hepatic clock on the FBG rhythm. In both C57BL/6J and diabetic ob/ob mice, FBG exhibited significant daily rhythms with a peak at the beginning of the dark phase. Light-phase restricted feeding altered the phase of FBG rhythm mildly in C57BL/6J mice and greatly in ob/ob mice, in concert with the phase shifts of mRNA expression rhythms of the clock and glucose production-related genes in the liver. Moreover, the rhythmicity of FBG and Glut2 expression was not detected in liver-specific Bmal1-deficient mice. Furthermore, treatment with octreotide suppressed the plasma growth hormone concentration but did not affect the hepatic mRNA expression of the clock genes or the rise in FBG during the latter half of the resting phase in C57BL/6J mice. These results suggest that the hepatic circadian clock plays a critical role in regulating the daily FBG rhythm, including the dawn phenomenon. 
26653107	The circadian system induces rhythmic variation in a suite of biochemical and physiological processes that serve to optimise plant growth in diel cycles. To be of greatest utility, these rhythmic behaviors are coordinated with regular environmental changes such as the rising and setting of the sun. Photoreceptors, along with metabolites produced during photosynthesis, act to synchronise the internal timing mechanism with lighting cues. We have recently shown that phototropins help maintain robust rhythms of photosynthetic operating efficiency (ϕPSII or Fq'/Fm') under blue light, although rhythmic accumulation of morning-phased circadian transcripts in the nucleus was unaffected. Here we report that evening-phased nuclear clock transcripts were also unaffected. We also observe that rhythms of nuclear clock transcript accumulation are maintained in phototropin mutant plants under a fluctuating lighting regime that induced a loss of Fq'/Fm' rhythms. 
26652002	Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour. 
26651154	Previous findings have demonstrated that chronotype (morningness/intermediate/eveningness) is correlated with cognitive functions, that is, people show higher mental performance when they do a test at their preferred time of day. Empirical studies found a relationship between morningness and higher learning achievement at school and university. However, only a few of them controlled for other moderating and mediating variables. In this study, we included chronotype, gender, conscientiousness and test anxiety in a structural equation model (SEM) with grade point average (GPA) as academic achievement outcome. Participants were 158 high school students and results revealed that boys and girls differed in GPA and test anxiety significantly, with girls reporting better grades and higher test anxiety. Moreover, there was a positive correlation between conscientiousness and GPA (r = 0.17) and morningness (r = 0.29), respectively, and a negative correlation between conscientiousness and test anxiety (r = -0.22). The SEM demonstrated that gender was the strongest predictor of academic achievement. Lower test anxiety predicted higher GPA in girls but not in boys. Additionally, chronotype as moderator revealed a significant association between gender and GPA for evening types and intermediate types, while intermediate types showed a significant relationship between test anxiety and GPA. Our results suggest that gender is an essential predictor of academic achievement even stronger than low or absent test anxiety. Future studies are needed to explore how gender and chronotype act together in a longitudinal panel design and how chronotype is mediated by conscientiousness in the prediction of academic achievement.
26650243	Traditionally only a small proportion of the workforce was engaged in shift work. Changing economic pressures have resulted in increased engagement in shift work, with approximately 17 % of the workforce in Europe engaged in this work pattern. The present narrative review aimed to summarise the data on the effects of shift work on the diet, lifestyle and health of employees, while addressing the barriers to, and opportunities for, improving health among shift workers. Shift work can result in low-quality diet and irregular eating patterns. Adverse health behaviours are also reported; particularly increased smoking and poor sleep patterns. These altered lifestyle habits, in conjunction with disruption to circadian rhythms, can create an unfavourable metabolic phenotype which facilitates the development and progression of chronic disease. Although the data are inconclusive due to issues such as poor study design and inadequate control for confounding factors; shift workers appear to be at increased mental and physical health risk, particularly with regard to non-communicable diseases. Information is lacking on the obstacles to leading a healthier lifestyle while working shifts, and where opportunities lie for intervention and health promotion among this group. In order to provide an informed evidence base to assist shift workers in overcoming associated occupational hazards, this gap must be addressed. This review highlights the unique nutritional issues faced by shift workers, and the subsequent effect on health. In societies already burdened with increased incidence of non-communicable chronic diseases, there is a clear need for education and behaviour change interventions among this group.

26647714	Mammalian T-type Ca(2+) channels are encoded by three separate genes (Cav3.1, 3.2, 3.3). These channels are reported to be sleep stabilizers important in the generation of the delta rhythms of deep sleep, but controversy remains. The identification of precise physiological functions for the T-type channels has been hindered, at least in part, by the potential for compensation between the products of these three genes and a lack of specific pharmacological inhibitors. Invertebrates have only one T-type channel gene, but its functions are even less well-studied. We cloned Ca-α1T, the only Cav3 channel gene in Drosophila melanogaster, expressed it in Xenopus oocytes and HEK-293 cells, and confirmed it passes typical T-type currents. Voltage-clamp analysis revealed the biophysical properties of Ca-α1T show mixed similarity, sometimes falling closer to Cav3.1, sometimes to Cav3.2, and sometimes to Cav3.3. We found Ca-α1T is broadly expressed across the adult fly brain in a pattern vaguely reminiscent of mammalian T-type channels. In addition, flies lacking Ca-α1T show an abnormal increase in sleep duration most pronounced during subjective day under continuous dark conditions despite normal oscillations of the circadian clock. Thus, our study suggests invertebrate T-type Ca(2+) channels promote wakefulness rather than stabilizing sleep.
26647380	Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a regulatory, effect on standard measures of sleep. Study output is limited by small sample size and because only evening melatonin profiles were assessed. 
26647151	The hypothalamic pituitary-adrenal axis is thought to play a role in type 2 diabetes (T2D). However, evidence for an association between cortisol and future glucose disturbance is sparse.The aim was to examine the association of diurnal cortisol secretion with future T2D and impaired glucose metabolism in a community-dwelling population.	This is a prospective cohort study of salivary cortisol measured at the 2002-2004 clinical examination of the Whitehall II study, United Kingdom. We measured cortisol (nmol/l) from six saliva samples obtained over the course of a day: at waking, +30 minutes, +2.5 hours, +8 hours, +12 hours, and bedtime. Participants who were normoglycemic in 2002-2004 (phase 7) were reexamined in 2012-2013 (phase 11).	The occupational cohort was originally recruited in 1985-1988.	A total of 3270 men and women with an average age of 60.85 years at phase 7 (2002-2004).	Incident T2D and impaired fasting glucose in 2012-2013 were measured.	Raised evening cortisol at phase 7 was predictive of new-onset T2D at phase 11 (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01-1.37) with a trend for a flatter slope in participants with incident T2D (odds ratio, 1.15; 95% CI, 0.99-1.33). When expanding this analysis to a broader category of glucose disturbance we found that a flattened diurnal cortisol slope at phase 7 was predictive of future impaired fasting glucose or T2D at phase 11 (OR, 1.12; 95% CI, 1.02-1.22), as was high bedtime cortisol (OR, 1.10; 95% CI, 1.01-1.20).	In this nonclinical population, alterations in diurnal cortisol patterns were predictive of future glucose disturbance.	
26646204	Secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), by the intestinal L-cell is rhythmically regulated by an independent molecular clock. However, the impact of factors known to affect the activity of similar cell-autonomous clocks, such as circulating glucocorticoids and high-fat feeding, on GLP-1 secretory patterns remains to be elucidated. Herein the role of the endogenous corticosterone rhythm on the pattern of GLP-1 and insulin nutrient-induced responses was examined in corticosterone pellet-implanted rats. Moreover, the impact of nutrient excess on the time-dependent secretion of both hormones was assessed in rats fed a high-fat, high-sucrose diet. Finally, the effects of the saturated fatty acid, palmitate, on the L-cell molecular clock and GLP-1 secretion were investigated in vitro using murine GLUTag L-cells. Diurnal variations in GLP-1 and insulin nutrient-induced responses were maintained in animals lacking an endogenous corticosterone rhythm, suggesting that glucocorticoids are not the predominant entrainment factor for L-cell rhythmic activity. In addition to hyperglycemia, hyperinsulinemia, insulin resistance, and disorganization of feeding behavior, high-fat high-sucrose-fed rats showed a total abrogation of the diurnal variation in GLP-1 and insulin nutrient-induced responses, with comparable levels of both hormones at the normal peak (5:00 pm) and trough (5:00 am) of their daily pattern. Finally, palmitate incubation induced profound derangements in the rhythmic expression of circadian oscillators in GLUTag L-cells and severely impaired the secretory activity of these cells. Collectively our findings demonstrate that obesogenic diets disrupt the rhythmic activity of the L-cell, partially through a direct effect of specific nutritional components. 
26646203	The WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal. 
26645746	Arabidopsis thaliana has long been the model plant of choice for elucidating the mechanisms of the circadian clock. Recently, relevant results have accumulated in other species of green plant lineages, including green algae. This mini-review describes a comparison of the mechanism of the A. thaliana clock to those of the green alga Chlamydomonas reinhardtii and the moss Physcomitrella patens, focusing on commonalities and divergences of subsystems of the clock. The potential of such an approach from an evolutionary viewpoint is discussed. 
26645046	Bile acids are physiological detergents that also activate nuclear receptors to regulate glucose and lipid homeostasis. Cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme that converts cholesterol to bile acids, is transcriptionally regulated by bile acids and circadian rhythms. Fasting, nutrients and the circadian clock critically control hepatic bile acid and lipid homeostasis, while circadian misalignment is associated with metabolic syndrome in humans. To delineate these interactions, we employed a sleep disruption model to induce circadian disruption and examined hepatic metabolism with respect to bile acids, lipids and clock gene expression.B6xC57 mice were maintained on chow or Western diet and were sleep disrupted for 6 hr/day for 5 days. Mice were sacrificed at 4 hr intervals over 24 hr. Hepatic metabolic genes were examined, and bile acid pool and lipid profiles were measured over 24 hr.	Sleep disruption significantly suppressed circadian expression of core clock genes, genes involved in lipid metabolism, and key regulators of Cyp7a1 as well as Cyp7a1 expression itself. Sleep disruption abolished the peak in serum cholesterol and increased liver and serum free fatty acids. Bile acid pool size was increased while liver bile acids were decreased. ChIP assay revealed HNF4α and Dbp occupancies were suppressed at the Cyp7a1 promoter in sleep-disrupted mice. When coupled with Western diet, sleep disruption abolished liver clock rhythms and elevated free fatty acids.	This study suggests that even short-term circadian disruption dramatically alters hepatic clock gene expression, bile acid metabolism and lipid homeostasis to contribute to dyslipidemia.	
26644962	Bipolar disorder is affected by variables that modulate circadian rhythm, including seasonal variations. There is evidence of a seasonal pattern of admissions of mania in various geographical settings, though its timing varies by region and climate. Variables such as age and gender have been shown to affect seasonality in some studies.Data on monthly admission patterns for mania at a general hospital psychiatry unit in Pondicherry, India, were collected for 4 years (2010-2013) and analyzed for seasonality and seasonal peaks. The effects of age and gender were analyzed separately.	There was overall evidence of a seasonal pattern of admissions for mania (P < .01, Friedman test for seasonality), with a peak beginning during the rainy season and ending before summer (P < .0.1, Ratchet circular scan test). Male sex (P < .005, Ratchet circular scan test) and age > 25 years (P < .005, Ratchet circular scan test) were specifically associated with this seasonal peak.	The effect of seasons on mania is complex and is modulated by a variety of variables. Our study is consistent with earlier research findings: a greater degree of seasonality for mania in men. It is possible that climatic and individual variables interact to determine seasonal patterns in bipolar disorder in a given setting.	
26644470	Diagnosis and therapeutic interventions in pathological conditions rely upon clinical monitoring of key metabolites in the serum. Recent studies show that a wide range of metabolic pathways are controlled by circadian rhythms whose oscillation is affected by nutritional challenges, underscoring the importance of assessing a temporal window for clinical testing and thereby questioning the accuracy of the reading of critical pathological markers in circulation. We have been interested in studying the communication between peripheral tissues under metabolic homeostasis perturbation. Here we present a comparative circadian metabolomic analysis on serum and liver in mice under high fat diet. Our data reveal that the nutritional challenge induces a loss of serum metabolite rhythmicity compared with liver, indicating a circadian misalignment between the tissues analyzed. Importantly, our results show that the levels of serum metabolites do not reflect the circadian liver metabolic signature or the effect of nutritional challenge. This notion reveals the possibility that misleading reads of metabolites in circulation may result in misdiagnosis and improper treatments. Our findings also demonstrate a tissue-specific and time-dependent disruption of metabolic homeostasis in response to altered nutrition. 
26644408	Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms. 
26644369	ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis.A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening.	Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry.	Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake.	Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.	

26644017	Optimising the time of drug administration in alignment with circadian rhythms to enhance the clinical effect or minimise/avoid adverse effects is referred to as chronotherapy. Pharmacists have a key role in providing medicine related information, including counselling about the optimal time for medication administration. Where applicable, the principles of chronotherapy should underlie this aspect of medication counselling. Despite significant developments in the science of chronotherapy for specific pharmacological treatments, the perspective of pharmacists about their understanding and application of these principles in practice has not been explored.To explore community pharmacist's viewpoints about and experience with the application of chronotherapy principles in practice.	Community pharmacies within metropolitan Sydney in New South Wales, Australia.	Semi-structured, face to face interviews with a convenience sample of community pharmacists were conducted. All interviews were audio-recorded, transcribed verbatim and thematically analyzed using a 'grounded theory' approach, given the novelty of this area. Main outcome measure Community pharmacists' awareness, current practice and future practice support requirements about the principles of chronotherapy.	Twenty-five semi-structured interviews were conducted. Most participants reported encountering cases where clinical decision making about suggesting appropriate times of drug administration to patients was needed. Their approach was mainly pragmatic rather than based on theoretical principles of circadian variation in drug disposition or on current or emerging evidence; thus there was an evidence practice chasm in some cases. However, most participants believed they have an important role to play in counselling patients about optimal administration times and were willing to enact such roles or acquire skills/competence in this area.	Community pharmacists contribute to the safe and effective use of medications in providing the patients with information on optimal timing of drug administration during counselling. Further education, practical training and access to information may help pharmacists in translating principles of chronotherapy into the practice.	

26641268	Performance on different psychophysical tasks measuring the sense of time indicates a large amount of individual variation in the accuracy and precision of timing in the hundredths of milliseconds-to-minutes range. Quantifying factors with an influence on timing is essential to isolating a biological (genetic) contribution to the perception and estimation of time. In the largest timing study to date, 647 participants completed a duration-discrimination task in the sub-second range and a time-production task in the supra-second range. We confirm the stability of a participant's time sense across multiple sessions and substantiate a modest sex difference on time production. Moreover, we demonstrate a strong correlation between performance on a standardized cognitive battery and performance in both duration-discrimination and time-production tasks; we further show that performance is uncorrelated with age after controlling for general intelligence. Additionally, we find an effect of ethnicity on time sense, with African Americans and possibly Hispanics in our cohort differing in accuracy and precision from other ethnic groups. Finally, a preliminary genome-wide association and exome chip study was performed on 148 of the participants, ruling out the possibility for a single common variant or groups of low-frequency coding variants within a single gene to explain more than ~18% of the variation in the sense of time. 
26641263	The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG) axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL) alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP) accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis. 
26641075	Demands on concentrative and cognitive performance are high in sport shooting and vary in a circadian pattern, aroused by internal and external stimuli. The most prominent external stimulus is light. Bright light (BL) has been shown to have a certain impact on cognitive and physical performance.To evaluate the impact of a single half hour of BL exposure in the morning hours on physical and cognitive performance in 15 sport shooters. In addition, courses of sulfateoxymelatonin (aMT6s), tryptophan (TRP), and kynurenine (KYN) were monitored.	In a crossover design, 15 sport shooters were exposed to 30 min of BL and dim light (DL) in the early-morning hours. Shooting performance, balance, visuomotor performance, and courses of aMT6s, TRP, and KYN were evaluated.	Shooting performance was 365.4 (349.7-381.0) and 368.5 (353.9-383.1), identical in both light setups. Numbers of right reactions (sustained attention) and deviations from the horizontal plane (balance-related measure) were higher after BL. TRP concentrations decreased from 77.5 (73.5-81.4) to 66.9 (60.7-67.0) in the DL setup only.	The 2 light conditions generated heterogeneous visuomotor and physiological effects in sport shooters. The authors therefore suggest that a single half hour of BL exposure is effective in improving cognitive aspects of performance, but not physical performance. Further research is needed to evaluate BL's impact on biochemical parameters.	
26639917	Night follows day and as a consequence, organisms have evolved molecular machineries that allow them to anticipate and respond to the many changes that accompany these transitions. Circadian clocks are precise yet plastic pacemakers that allow the temporal organization of a plethora of biological process. Circadian clocks are widespread across the tree of life and while their exact molecular components differ among phyla, they tend to share common design principles. In this review, we discuss the circadian system of the filamentous fungus Neurospora crassa. Historically, this fungus has served a key role in the genetic and molecular dissection of circadian clocks, aiding in their detailed mechanistic understanding. Recent studies have provided new insights into the daily molecular dynamics that constitute the Neurospora circadian oscillator, some of which have questioned traditional paradigms describing timekeeping mechanisms in eukaryotes. In addition, recent reports support the idea of a dynamic network of transcription factors underlying the rhythmicity of thousands of genes in Neurospora, many of which oscillate only under specific conditions. Besides Neurospora, which harbors the best characterized circadian system among filamentous fungi, the recent characterization of the circadian system of the plant-pathogenic fungus Botrytis cinerea has provided additional insights into the physiological impact of the clock and potential additional functions of clock proteins in fungi. Finally, we speculate on the presence of FRQ or FRQ-like proteins in diverse fungal lineages. 
26639202	This investigation was conducted to examine circadian and seasonal rhythms of heart rate and heart rate variability (HRV) by means of hour-by-hour recordings over 24h in a large population of non-lactating Holstein-Friesian pregnant cows [N=56, summer (June-July); N=61, winter (November-December)]. Data were collected during a 5-day period from each animal. Besides parameters of cardiac autonomic function [the high-frequency (HF) component of HRV and the ratio between the low-frequency (LF) and the HF components (LF/HF ratio)], the RR triangular index and Lmax were calculated. A clear circadian profile was observed for every parameter in summer. Heart rate elevated gradually with the course of the day from 7:00 to 17:00 o'clock and then slightly decreased from 18:00 to 6:00. Sympathovagal balance shifted towards sympathetic dominance during the daytime (increased LF/HF ratio), whereas parasympathetic activity was predominant during the night (increased HF). Lmax reflected a chaotic behavior of heart rate fluctuations during the afternoon in summer. Decreased values of RR triangular index indicated a sensitive period for cows between 14:00 and 16:00 o'clock in summer. During winter, except for the RR triangular (RRtri) index reflecting a high overall variability in R-R intervals between 12:00 and 23:00 o'clock, heart rate and HRV showed no periodicity over the 24-h period. The results suggest an impaired cardiac autonomic function during daytime in summer. HF, Lmax and RRtri index showed seasonal differences for both daytime and nighttime. Heart rate was higher in summer than in winter during the daytime, whereas the LF/HF ratio was higher in winter during the nighttime. Circadian and seasonal rhythms of cardiovascular function are presumably related to the differing temperature, and animal activity associated with summer and winter. As all of the investigated parameters are commonly used in bovine HRV research, these findings have practical implications for behavioral, physiological and welfare studies on dairy cattle. 

26634682	Since the advent of modern molecular tools, researchers have extensively shown that essential cellular machineries have robust circadian (roughly 24 hours) variations in their pace. This molecular rhythmicity translates directly into time-of-day-dependent variation in physiology in most organ systems, which in turn provides the mechanistic rationale for why timing on a daily basis should matter in many aspects of human health. However, these basic science findings have been slow to move from bench to bedside because clinical studies are still lacking to demonstrate the importance of timing. Therefore, it has not been clear how physicians should incorporate knowledge of natural 24-hour rhythms into routine practice. This review is a brief summary of results from recently completed clinical studies on hypertension, myocardial infarction, diabetes mellitus, and adrenal dysfunction that highlights new evidence for the emerging importance of circadian rhythms in diagnosis, prognosis and treatment of disease. 
26634390	Background Chronotype and insomnia have been related to the development and to an unfavourable course of depression. However, the mutual relationship of both risk factors is as yet unclear, especially in acute, clinically manifest depressive disorders. Aims The present study was carried out to elucidate the separate direct and indirect influence of chronotype and poor sleep quality on depression severity in patients hospitalized for depression. Methods Depression severity (BDI-II), chronotype (Morningness-Eveningness Questionnaire), and subjective sleep quality (Pittsburgh Sleep Quality Index total score) were assessed concurrently in inpatients with a depressive syndrome and insomnia during routine treatment. Correlations, multiple regression and bootstrapping methods for testing mediation models were applied to assess the independent direct and indirect effects of chronotype and sleep quality on depression severity, after adjusting for effects of age and gender. Results Data from 57 consecutively admitted patients (88% with major depression) were analyzed (68% women, mean age 41 ± 13 years). Significant correlations between morningness-eveningness (p <0.05) or sleep quality (p <0.01) and depression severity were found; in a multiple regression model comprising chronotype, sleep quality, age and gender, only chronotype (p <0.05) and sleep disturbances (p <0.01) remained as independent significant concurrent predictors of depression severity (R(2) = 0.184, p <0.01). Two mediation models revealed no significant results. Conclusions Eveningness and poor subjective sleep quality were independently and directly associated with higher depression severity in inpatients with depressive syndromes. Chronotype and sleep quality should be taken into account not only in risk assessment and prevention but also in hospitalized patients to develop and improve treatment options. 
26634305	Faecal (f-) calprotectin is a biomarker of intestinal inflammation. Previous studies have described intra-individual day-to-day variability of this biomarker in patients with inflammatory bowel disease (IBD) and morning samples have been suggested for standardisation purposes. With this project, we investigated if day-to-day variability differed from diurnal variability. Additionally, we evaluated a new extraction method for f-calprotectin analysis.Fifty patients provided three faeces samples from morning - evening - morning on two consecutive days. Nineteen patients provided two faeces samples from the same bowel movement, one conventional spot sample, and one sample with a device for patient-administered sampling and extraction.	The two morning samples differentiated between mucosal inflammation and mucosal healing with same level of agreement as the two samples from the same day (kappa 0.76), using an f-calprotectin cut-off level of 259 μg/g. Although large intra-individual variation in f-calprotectin values, there were no significant day-to-day (p = 0.096) or diurnal variation (p = 0.78). Used by laboratory technicians, the new extraction device correlated significantly with the conventional extraction method (p < 0.001), Spearman's rank correlation coefficient 0.95. Of the 19 patients testing patient administered extraction, two patients provided samples leading to considerably higher f-calprotectin levels than conventional sampling procedure.	The reliability of f-calprotectin morning samples is equal to the reliability of samples from different bowel movements on the same day. The new extraction method is reliable when used by laboratory technicians, but larger studies are recommended to evaluate patient administered extraction.	
26633310	(1) To investigate the reference value of peak-trough difference in circadian rhythm of intraocular pressure (IOP) in habitual position and (2) to compare the IOP parameters among 3 age groups.Habitual IOP of healthy subjects sampled from the population in the Handan Eye Study was measured every 2 hours in the seated position during light-wake period (7:30 AM, 9:30 AM, 11:30 AM, 1:30 PM, 3:30 PM, 5:30 PM, 7:30 PM, 9:30 PM) and in the supine position during dark-sleep period (11:30 PM, 1:30 AM, 3:30 AM, 5:30 AM). Blood pressure and heart rate were obtained subsequently at each IOP measurement.	Two hundred six healthy subjects were included in the final analyses (n=20, 30 to 39 y old; n=95, 40 to 49 y old; n=91, 50 to 59 y old). For peak-trough difference (7.2±2.3 mm Hg; 6.8 to 7.5 mm Hg, 95% confidence interval) in habitual position, the reference value was described as median 7.0 mm Hg, 25th percentile 5.5 mm Hg, and 95th percentile 11.5 mm Hg. No significant differences in peak-trough difference, acrophase (cosine-fit analysis derived peak timing) and amplitude (half distance between the cosine-fit maximum and minimum) were found among the 3 age groups. In the cosine model, the nocturnal acrophase (3:49±0.53 AM; 3:42 to 3:55 AM, 95% confidence interval) was detected for the entire group. Furthermore, 106 subjects (52%) had a nocturnal peak pattern, 36 subjects (17%) had a diurnal peak pattern, and 64 subjects (31%) had no evident pattern.	In habitual position, 75% of healthy subjects from a population-based investigation had IOP variation >5.5 mm Hg and 95% subjects had <11.5 mm Hg variation. Aging may not influence the circadian habitual IOP rhythm.	
26632731	The aim of this study was to investigate the relationships between nocturnal variations in blood pressure (BP) and metabolic syndrome (MetS) in different gender.This cross-sectional study involved 509 hypertensive patients (254 males and 255 females, 45 to 75 years old) from September 2013 to March 2014. BP values were acquired from ambulatory BP monitoring (ABPM). The dipper pattern of BP was defined as 10% to 20% reduction of the mean systolic BP (SBP) values at night compared with the daytime values. The diagnosis of MetS was made according to NCEP ATP-III definition. Multivariate logistic regression analyses were used to explore the relationships between ABPM results and MetS.In our study, MetS were observed in 29.1% of male and 18.4% of female participants. The prevalence of MetS was higher in the patients with reverse-dipper pattern than in others. After multivariate logistic regression analysis, the reverse-dipper pattern of BP (odds ratio 2.298; P = 0.006) and 24-SBP (odds ratio 1.063; P = 0.021) were independently correlated with MetS in males. However, there was no association between MetS and BP reverse dipping in females.Our cross-sectional study showed that the reverse-dipper pattern of BP is associated with MetS in male, while the underlying mechanism deserves further investigation.
26632431	The aging process is often associated with more or less prominent shifts of the entrained phases of behavioral and physiological rhythms at earlier clock hours, but the oscillatory mechanisms underlying these shifts have to be determined. The analysis of self-reports on home sleep times and self-scorings of sleepiness provided by 130 participants of sleep deprivation experiments revealed the difference between intro-individual (age-related) and inter-individual (gender- and chronotype-related) variation in phase angle between sleep timing and timing of nocturnal rise of sleepiness. A heterochronity of age-related changes in phase characteristics of the circadian rhythms was suggested for explaining this difference. In particular, a rhythm's strength might determine the rate of age-related decline of its entrainment mechanism. In the case of a weak circadian rhythm, such as the homeostatic process underlying oscillations of slow wave activity in the sleep-wake cycle, a decline of the rhythm's strength might be already pronounced in middle aged adults. In contrast, a similar decline might occur much later in the cases of the homeostatic processes underlying stronger rhythms, such as the fluctuations of alertness-sleepiness, body temperature, melatonin secretion, etc. Moreover, the strength of a strong rhythm might become weaker earlier than that of the circadian pacemaker and, especially, earlier than decline of its ability to entrain to the light-dark cycle. Such sequence of changes in the circadian entrainment mechanisms might explain a general tendency to produce advance rather than delay shifts of entrained phases of circadian rhythms with progression of age from middle adulthood to elderly. 
26632430	Aging is associated with a marked increase in sleep complaints, and one factor causing sleep disruption is waking to void (nocturia). Urological surveys have found that few young adults report nocturia symptoms, but about half of those in their 60's and nearly 80% of older age groups are affected. Sleep surveys have found nocturia is a major cause of sleep disruption, with a majority of older adults with sleep disruption citing the need to void as the cause of their awakening. While much of the urological literature implies that nocturia causes sleep disruption, age-related changes in sleep depth and continuity may make it more likely that an older adult will wake in response to a filling bladder, or that an older adult will wake for another reason and then decide to void. There is also evidence that age-related changes in the amplitude of circadian rhythms contribute to nocturia. There is a well-described circadian rhythm in urine output, and evidence of circadian rhythmicity in some diuretic and anti-diuretic hormones. In this article, we describe how age-related changes in sleep depth and continuity and age-related changes in circadian rhythm amplitude may contribute to nocturia, and how nocturia in turn leads to sleep disruption. Better understanding of how changes in sleep and circadian rhythmicity impact nocturia may lead to improved treatments and better quality of life for older adults. 
26632429	In the article authors discuss the current data on sleep changes with aging focusing on the influence of age-related degenerative changes in orexin-containing and pacemaker brain areas. Pathophysiological mechanisms of sleep disturbances in Parkinson's and Alzheimer's diseases have much in common with normal age neurophysiological changes. Maintenance of the sleep-promoting systems function could positively modify the course of these diseases. 
26632428	Increased blood pressure and reduced robustness of circadian rhythms are frequently reported in elderly subjects. The present study was aimed to investigate whether such changes can be reversed by daily melatonin ingestion. 97 normotensive and hypertensive volunteers of both genders and 63 to 91 years old participated. They lived in the Tyumen Elderly Veteran House on a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted for three weeks. After one control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen(TM)) each day at 22:30 h for two weeks. The other 34 subjects were placebo-treated. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured using semi-automated devices at 03:00, 08:00, 11:00, 14:00, 17:00, 23:00 h each day of the first and the third week. Specially trained personnel made the measurements, taking care not to disturb subjects' sleep. Rhythm characteristics were estimated by means of single and population-mean cosinor analyses. Bingham test was used to compare rhythm parameters between groups and investigated physiologic variables. The 24-h HR rhythm was monophasic as described in other studies for young subjects though with a steeper increase in the morning. The daily SBP and DBP rhythms were bimodal. In reference to previously reported data of younger subjects, mean blood pressure of our cohort was elevated, particularly the nocturnal fall was less pronounced. Also, the overall SBP variability was higher as was the percentage of the 12-h component. Both values and also the SBP and DBP levels were reduced during melatonin treatment. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events, and in subjects with highest BP values before treatment. Moreover, the morning increase of HR was gentler what could have been of additional benefit. Melatonin has a direct hypotensive effect. Also, it stabilizes the internal temporal order enhancing the circadian component and the synchronization between rhythms of different physiological functions. This may further improve health and welfare of elderly subjects and particularly of those with hypertension. Taken together our data show the usefulness of melatonin for adjuvant medication.
26632427	This review summarizes current knowledge on deteriorations in temporal order with advanced age. Changes of the overt rhythms will be described but also their putative causes and possible treatments of the disturbances. In aging animals and humans, all rhythm characteristics change. The most prominent changes are a decrease of circadian amplitude, leading to an extra-circadian dissemination (ECD), and a diminished ability to synchronize with the periodic environment. ECD is a shift from circadian to ultradian and infradian frequencies, accompanied by the loss of day-to-day phase stability. Responsiveness to photic and non-photic cues is decreased. As a consequence, both internal and external temporal order are disturbed not only under steady-state conditions but and even more markedly after changes in the periodic environment or following stressful events. Many of the changes seem to occur within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, itself. The number of functioning neurons decreases with advancing age as does the coupling between them. Accordingly, the SCN generates a weaker and less stable circadian signal, insufficient to entrain peripheral oscillators properly or to regulate body functions rhythmically. However, age-dependent disturbances in peripheral organs must also be considered. These changes may occur at different ages, thus causing further internal desynchronization. Several possibilities exist with regard to treating circadian disruptions or at least minimizing their consequences for health and fitness and preventing sleep disturbances. Benefits of bright light, melatonin and other chronobiotics, physical activity, social contacts and regular feeding schedules in preserving the temporal order of aged organisms are discussed. 
26632340	The drive to eat is regulated by two compensatory brain pathways termed as homeostatic and hedonic. Hypothalamic orexinergic (ORX) neurons regulate metabolism, feeding and reward, thus controlling physiological and hedonic appetite. Circadian regulation of feeding, metabolism and rhythmic activity of ORX cells are driven by the brain suprachiasmatic clock. How the circadian clock impacts on ORX signalling and feeding-reward rhythms is, however, unknown. Here we used mice lacking the nuclear receptor REV-ERBα, a transcription repressor and a key component of the molecular clockwork, to study food-reward behaviour. Rev-Erbα mutant mice showed highly motivated behaviours to obtain palatable food, an increase in the intake and preference for tasty diets, and in the expression of the ORX protein in the hypothalamus. Palatable food intake was inhibited in animals treated with the ORX1R antagonist. Analyzing the Orx promoter, we found Retinoic acid-related Orphan receptor Response Element binding sites for Rev-Erbα. Furthermore, Rev-Erbα dampened the activation of Orx in vitro and in vivo. Our data provide evidence for a possible repressive role of Rev-Erbα in the regulation of ORX signalling, highlighting an implication of the circadian clockwork in modulating food-reward behaviours with an important impact for the central regulation of overeating.
26632171	We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3±1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134±3.9 mg/dL and 7.9±0.2% at baseline to 116±2.2 mg/dL and 7.4±0.2% at 12 months after starting IDeg (P<0.0001 and P≤0.001, respectively). Overall and nocturnal hypoglycemia (PG<70 mg/dL) frequencies also decreased significantly from 4.9±0.7 and 2.0±0.3 times/month to 2.4±0.3 and 0.4±0.1 times/month at 12 months after starting IDeg (P≤0.005 and P<0.0005, respectively). The daily basal insulin dose was significantly reduced from 0.48±0.04 units/kg/day at baseline to 0.38±0.03 units/kg/day at the end of the study period (P<0.0001), which corresponded to 79.2% of the baseline value. Trends were similar in patients receiving the once-daily injection and those given twice-daily injections, but basal-insulin value reductions from baseline were more marked in patients receiving twice-daily injections of basal insulin (76.0% vs. 82.6% of the baseline value). These results suggest that switching from IGlar to an appropriate dose of IDeg may effectively control hyperglycemia while reducing the frequency of hypoglycemia episodes in young Japanese people with type 1 diabetes. 
26630970	Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease.Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE).	No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03).	MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.	
26630494	The purpose of this study is to clarify the effects of chronic powder diet feeding on sleep patterns and other physiological/anatomical changes in mice. C57BL/6 male mice were divided into two groups from weaning: a group fed with solid food (SD) and a group fed with powder food (PD), and sleep and physiological and anatomical changes were compared between the groups. PD exhibited less cranial bone structure development and a significant weight gain. Furthermore, these PD mice showed reduced number of neurogenesis in the hippocampus. Sleep analysis showed that PD induced attenuated diurnal sleep/wake rhythm, characterized by increased sleep during active period and decreased sleep during rest period. With food deprivation (FD), PD showed less enhancement of wake/locomotor activity compared to SD, indicating reduced food-seeking behavior during FD. These results suggest that powder feeding in mice results in a cluster of detrimental symptoms caused by abnormal energy metabolism and anatomical/neurological changes. 
26630391	Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated.Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin.	Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin.	These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.	
26629908	Schizophrenia is accompanied by altered motor activity and abnormal thermoregulation; therefore, the presence of these symptoms can enhance the face validity of a schizophrenia animal model. The goal was to characterize these parameters in freely moving condition of a new substrain of rats showing several schizophrenia-related alterations.Male Wistar rats were used: the new substrain housed individually (for four weeks) and treated subchronically with ketamine, and naive animals without any manipulations. Adult animals were implanted with E-Mitter transponders intraabdominally to record body temperature and locomotor activity continuously. The circadian rhythm of these parameters and the acute effects of changes in light conditions were analyzed under undisturbed circumstances, and the effects of different interventions (handling, bed changing or intraperitoneal vehicle injection) were also determined.	Decreased motor activity with fragmented pattern was observed in the new substrain. However, these animals had higher body temperature during the active phase, and they showed wider range of its alterations, too. The changes in light conditions and different interventions produced blunted hyperactivity and altered body temperature responses in the new substrain. Poincaré plot analysis of body temperature revealed enhanced short- and long-term variabilities during the active phase compared to the inactive phase in both groups. Furthermore, the new substrain showed increased short- and long-term variabilities with lower degree of asymmetry suggesting autonomic dysregulation.	In summary, the new substrain with schizophrenia-related phenomena showed disturbed motor activity and thermoregulation suggesting that these objectively determined parameters can be biomarkers in translational research.	
26629774	Circadian rhythms regulate many aspects of behavior and physiological processes, and, through external signals, help an organism entrain to its environment. These rhythms are driven by circadian clocks in many cells and tissues within our bodies, and are synchronized by a central pacemaker in the brain, the suprachiasmatic nucleus. Peripheral oscillators include the liver, whose circadian clock controls persistent daily rhythms in gene expression and in liver-specific functions such as metabolic homeostasis and drug metabolism. Chronic circadian clock disruption, as in rotating shiftwork, has been linked to disorders including obesity, diabetes, and cardiovascular disease. The mouse primary hepatocyte culture model allows the examination of circadian rhythms in these cells. This article describes a transgenic mouse model that uses a bioluminescent reporter to examine the circadian properties of a core clock gene Period2. Hepatocytes are isolated using a modified collagenase perfusion technique and cultured in a sandwich configuration, then sealed in a buffered medium containing luciferin for detection of whole-culture or single-cell bioluminescence. After synchronization by a medium change, cultures demonstrate coherent circadian period and phase measures of bioluminescence from the PERIOD2::LUCIFERASE reporter.
26629407	Circadian clocks are functional in all light-sensitive organisms, allowing an adaptation to the external world in anticipation of daily environmental changes. In view of the potential role of the skeletal muscle clock in the regulation of glucose metabolism, we aimed to characterize circadian rhythms in primary human skeletal myotubes and investigate their roles in myokine secretion.We established a system for long-term bioluminescence recording in differentiated human myotubes, employing lentivector gene delivery of the Bmal1-luciferase and Per2-luciferase core clock reporters. Furthermore, we disrupted the circadian clock in skeletal muscle cells by transfecting siRNA targeting CLOCK. Next, we assessed the basal secretion of a large panel of myokines in a circadian manner in the presence or absence of a functional clock.	Bioluminescence reporter assays revealed that human skeletal myotubes, synchronized in vitro, exhibit a self-sustained circadian rhythm, which was further confirmed by endogenous core clock transcript expression. Moreover, we demonstrate that the basal secretion of IL-6, IL-8 and MCP-1 by synchronized skeletal myotubes has a circadian profile. Importantly, the secretion of IL-6 and several additional myokines was strongly downregulated upon siClock-mediated clock disruption.	Our study provides for the first time evidence that primary human skeletal myotubes possess a high-amplitude cell-autonomous circadian clock, which could be attenuated. Furthermore, this oscillator plays an important role in the regulation of basal myokine secretion by skeletal myotubes.	
26629406	Physical activity and circadian rhythms are well-established determinants of human health and disease, but the relationship between muscle activity and the circadian regulation of muscle genes is a relatively new area of research. It is unknown whether muscle activity and muscle clock rhythms are coupled together, nor whether activity rhythms can drive circadian gene expression in skeletal muscle.We compared the circadian transcriptomes of two mouse hindlimb muscles with vastly different circadian activity patterns, the continuously active slow soleus and the sporadically active fast tibialis anterior, in the presence or absence of a functional skeletal muscle clock (skeletal muscle-specific Bmal1 KO). In addition, we compared the effect of denervation on muscle circadian gene expression.	We found that different skeletal muscles exhibit major differences in their circadian transcriptomes, yet core clock gene oscillations were essentially identical in fast and slow muscles. Furthermore, denervation caused relatively minor changes in circadian expression of most core clock genes, yet major differences in expression level, phase and amplitude of many muscle circadian genes.	We report that activity controls the oscillation of around 15% of skeletal muscle circadian genes independently of the core muscle clock, and we have identified the Ca(2+)-dependent calcineurin-NFAT pathway as an important mediator of activity-dependent circadian gene expression, showing that circadian locomotor activity rhythms drive circadian rhythms of NFAT nuclear translocation and target gene expression.	
26629141	Considering the high prevalence rates and growing incidences of hypertension (HT) and anxiety disorders in the modern world, a full understanding of anxiety's relationship to HT is crucial. In this study we aimed to investigate the effects of anxiety level on circadian rhythm of blood pressure (BP) in hypertensive patients.This cross-sectional study included 160 previously diagnosed essential hypertensive patients (80 female, 80 male, mean age: 55.3±15.1 years). All participants underwent 24 h ambulatory blood pressure monitoring (ABPM) and filled State-Trait Anxiety Inventory (STAI) (trait) Questionnaire. The study population was divided into 2 groups according to their STAI scores; an anxiety group (n=97; STAI ≥45) and a control group (n=63; STAI<44). Clinical characteristics, laboratory findings and ABPM measurements were compared between the groups.	There was no significant difference between the groups for ABPM parameters except morning blood pressure surge (MBPS). Anxiety group had a significantly higher MBPS compared to control group (14.4±17.0 vs 9.1±11.9 mmHg, P:0.03). Multivariate analysis showed that duration of HT and STAI score were the only independent predictors of MBPS.	Patients' anxiety level is associated with MBPS which is an independent risk factor for cardiovascular complications. Assessment and control of anxiety seems to be worthy in effective treatment of hypertension.	
26628099	To highlight recent developments in understanding the dynamic relationship between circadian rhythms, the gut microbiome, and gastrointestinal infections.In humans and mice, the composition and functions of the intestinal microbiome display diurnal rhythms orchestrated by feeding behaviors and host circadian gene expression. Jet lag, or circadian disruption, perturbs these rhythms to produce gut dysbiosis. When mice are orally infected with Salmonella typhimurium in the morning (the beginning of their rest period) they show higher levels of colonization and gut inflammation vs. infection at other times of day. At the cellular level, recent studies highlight circadian regulation of innate and adaptive gut immunity in coordination with the microbiome, as well as intestinal stem cell growth and regeneration.	Taken together, these reports support a key role for circadian rhythms in regulating the gut microbiome and host responses to gastrointestinal pathogens. Further research is needed to translate these findings to improving outcomes for patients with gastrointestinal infections by guiding the right interventions for the right patients at the right time.	
26627260	The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12-h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARα and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules. 
26626581	Significant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2-compartment model with first-order absorption and first-order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function. An indirect response model with inhibition of testosterone production was used to link the AZD4901 concentration to testosterone response. The AZD4901 concentration to yield 50% maximum testosterone suppression (IC50) was estimated to be 230 ng/mL. Based on simulations, following 40 mg twice daily (BID) treatment, the AZD4901 steady-state trough concentration will be much higher compared to 80 mg once daily (QD). The AZD4901 concentration time above IC50 after 40 mg BID is 84% of the time of the dosing interval compared to only 49% after 80 mg QD. The mean predicted testosterone concentrations at steady state are lower and overall less variable over 24 hours for 40 mg BID dosing compared to 80 mg QD dosing. Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval. Consequently, 40 mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo. 
26625126	The network structure of the plant circadian clock is complex and direct regulatory interactions between individual components have proven particularly difficult to predict from genetic analyses. Here, we systematically investigate in vivo binding interactions between the morning-specific transcription factor, LATE ELONGATED HYPOCOTYL (LHY) and the promoters of other components of the network. We then demonstrate the functionality of these interactions by testing the responsiveness of the target gene to an ethanol-induced change in expression level of the LHY protein. We uncover novel, negative autoregulatory feedback loops from LHY and the closely related CIRCADIAN CLOCK ASSOCIATED-1 (CCA1) onto their own and each other's expression. Furthermore we show that LHY acts as a repressor of all other clock components, including PSEUDO-RESPONSE REGULATORs (PRRs) 9 and 7, which were previously thought to be positive regulatory targets. These experimental results lead to a substantial revision of the morning loops of the clock. 
26624004	In plant factories, measurements of plant conditions are necessary at an early stage of growth to predict harvest times of high value-added crops. Moreover, harvest qualities depend largely on environmental stresses that elicit plant hormone responses. However, the complexities of plant hormone networks have not been characterized under nonstress conditions. In the present study, we determined temporal expression profiles of all genes and then focused on plant hormone pathways using RNA-Seq analyses of gene expression in tomato leaves every 2 h for 48 h. In these experiments, temporally expressed genes were found in the hormone synthesis pathways for salicylic acid, abscisic acid, ethylene, and jasmonic acid. The timing of CAB expression 1 (TOC1) and abscisic acid insensitive 1 (ABA1) and open stomata 1 (OST1) control gating stomata. In this study, compare with tomato and Arabidopsis thaliana, expression patterns of TOC1 have similarity. In contrast, expression patterns of tomato ABI1 and OST1 had expression peak at different time. These findings suggest that the regulation of gating stomata does not depend predominantly on TOC1 and significantly reflects the extracellular environment. The present data provide new insights into relationships between temporally expressed plant hormone-related genes and clock genes under normal sunlight conditions. 
26621387	Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted. 
26620558	Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic. 
26619288	We report the identification and characterization of a novel gene, AtHesperin (AtHESP) that codes for a deadenylase in Arabidopsis thaliana. The gene is under circadian clock-gene regulation and has similarity to the mammalian Nocturnin. AtHESP can efficiently degrade poly(A) substrates exhibiting allosteric kinetics. Size exclusion chromatography and native electrophoresis coupled with kinetic analysis support that the native enzyme is oligomeric with at least 3 binding sites. Knockdown and overexpression of AtHESP in plant lines affects the expression and rhythmicity of the clock core oscillator genes TOC1 and CCA1. This study demonstrates an evolutionary conserved poly(A)-degrading activity in plants and suggests deadenylation as a mechanism involved in the regulation of the circadian clock. A role of AtHESP in stress response in plants is also depicted. 
26618783	Crop selection often leads to dramatic morphological diversification, in which allocation to the harvestable component increases. Shifts in allocation are predicted to impact (as well as rely on) physiological traits; yet, little is known about the evolution of gas exchange and related anatomical features during crop diversification. In Brassica rapa, we tested for physiological differentiation among three crop morphotypes (leaf, turnip, and oilseed) and for correlated evolution of circadian, gas exchange, and phenological traits. We also examined internal and surficial leaf anatomical features and biochemical limits to photosynthesis. Crop types differed in gas exchange; oilseed varieties had higher net carbon assimilation and stomatal conductance relative to vegetable types. Phylogenetically independent contrasts indicated correlated evolution between circadian traits and both gas exchange and biomass accumulation; shifts to shorter circadian period (closer to 24 h) between phylogenetic nodes are associated with higher stomatal conductance, lower photosynthetic rate (when CO2 supply is factored out), and lower biomass accumulation. Crop type differences in gas exchange are also associated with stomatal density, epidermal thickness, numbers of palisade layers, and biochemical limits to photosynthesis. Brassica crop diversification involves correlated evolution of circadian and physiological traits, which is potentially relevant to understanding mechanistic targets for crop improvement.
26618598	The aim of study was to determine the mechanisms regulating melatonin secretion in the pineal organs of 1-day-old and 9-month-old domestic ducks. The pineals were cultured in a superfusion system under different light conditions. Additionally, some explants were treated with norepinephrine. The pineal glands of 1-day-old ducks released melatonin in a well-entrained, regular rhythm during incubation under a 12 hrs light:12 hrs dark cycle and adjusted their secretory activity to a reversed 12 hrs dark:12 hrs light cycle within 2 days. In contrast, the diurnal changes in melatonin secretion from the pineals of 9-month-old ducks were largely irregular and the adaptation to a reversed cycle lasted 3 days. The pineal organs of nestling and adult ducks incubated in a continuous light or darkness secreted melatonin in a circadian rhythm. The treatment with norepinephrine during photophases of a light-dark cycle resulted in: 1) a precise adjustment of melatonin secretion rhythm to the presence of this catecholamine in the culture medium, 2) a very high amplitude of the rhythm, 3) a rapid adaptation of the pineal secretory activity to a reversed light-dark cycle. The effects of norepinephrine were similar in the pineal organs of nestlings and adults. In conclusion, melatonin secretion in the duck pineal organ is controlled by three main mechanisms: the direct photoreception, the endogenous generator and the noradrenergic transmission. The efficiency of intra-pineal, photosensitivity-based regulatory mechanism is markedly lower in adult than in nestling individuals.
26617816	Preoperative neoadjuvant chemoradiation therapy may be useful in patients with operable rectal cancer, but treatment responses are variable. We examined whether expression levels of circadian clock genes could be used as biomarkers to predict treatment response. We retrospectively analyzed clinical data from 250 patients with rectal cancer, treated with neoadjuvant chemoradiation therapy in a single institute between 2011 and 2013. Gene expression analysis (RT-PCR) was performed in tissue samples from 20 patients showing pathological complete regression (pCR) and 20 showing non-pCR. The genes analyzed included six core clock genes (Clock, Per1, Per2, Cry1, Cry2 and Bmal1) and three downstream target genes (Wee1, Chk2 and c-Myc). Patient responses were analyzed through contrast-enhanced pelvic MRI and endorectal ultrasound, and verified by histological assessment. pCR was defined histologically as an absence of tumor cells. Among the 250 included patients, 70.8% showed regression of tumor size, and 18% showed pCR. Clock, Cry2 and Per2 expressions were significantly higher in the pCR group than in the non-pCR group (P<0.05), whereas Per1, Cry1 and Bmal1 expressions did not differ significantly between groups. Among the downstream genes involved in cell cycle regulation, c-Myc showed significantly higher expression in the pCR group (P<0.05), whereas Wee1 and Chk2 expression did not differ significantly between groups. Circadian genes are potential biomarkers for predicting whether a patient with rectal cancer would benefit from neoadjuvant chemoradiation therapy. 
26617050	Self-sustaining oscillations are essential for diverse physiological functions such as the cell cycle, insulin secretion and circadian rhythms. Synthetic oscillators using biochemical feedback circuits have been generated in cell culture. These synthetic systems provide important insight into design principles for biological oscillators, but have limited similarity to physiological pathways. Here we report the generation of an artificial, mammalian circadian clock in vivo, capable of generating robust, tunable circadian rhythms. In mice deficient in Per1 and Per2 genes (thus lacking circadian rhythms), we artificially generate PER2 rhythms and restore circadian sleep/wake cycles with an inducible Per2 transgene. Our artificial clock is tunable as the period and phase of the rhythms can be modulated predictably. This feature, and other design principles of our work, might enhance the study and treatment of circadian dysfunction and broader aspects of physiology involving biological oscillators. 
26616017	Short, nighttime naps are used as a fatigue countermeasure in night shift work, and may offer protective benefits on the morning commute. However, there is a concern that nighttime napping may impact upon the quality of daytime sleep. The aim of the current project was to investigate the influence of short nighttime naps (<30min) on simulated driving performance and subsequent daytime recovery sleep. Thirty-one healthy subjects (aged 21-35 y; 18 females) participated in a 3-day laboratory study. After a 9-h baseline sleep opportunity (22:00h-07:00h), subjects were kept awake the following night with random assignment to: a 10-min nap ending at 04:00h plus a 10-min nap at 07:00h; a 30-min nap ending at 04:00h; or a no-nap control. A 40-min driving simulator task was administered at 07:00h and 18:30h post-recovery sleep. All conditions had a 6-h daytime recovery sleep opportunity (10:00h-16:00h) the next day. All sleep periods were recorded polysomnographically. Compared to control, the napping conditions did not significantly impact upon simulated driving lane variability, percentage of time in a safe zone, or time to first crash on morning or evening drives (p>0.05). Short nighttime naps did not significantly affect daytime recovery total sleep time (p>0.05). Slow wave sleep (SWS) obtained during the 30-min nighttime nap resulted in a significant reduction in SWS during subsequent daytime recovery sleep (p<0.05), such that the total amount of SWS in 24-h was preserved. Therefore, short naps did not protect against performance decrements during a simulated morning commute, but they also did not adversely affect daytime recovery sleep following a night shift. Further investigation is needed to examine the optimal timing, length or combination of naps for reducing performance decrements on the morning commute, whilst still preserving daytime sleep quality.
26615621	Prognostic value of central aortic pressure and peripheral blood pressure in relation to the development of pre-eclampsia was assessed in pregnant women with different forms of hypertension. It was shown that development of pre-eclampsia was associated with higher mean 24-hour systolic blood pressure (BP), time index of systolic BP, variability of diastolic BP, and pulse BP measured on weeks 16-22 of gestation. Pregnant women with hypertension, especially those with pre-eclampsia were characterized by absence of proper nocturnal BP lowering or BP elevation during night hours (non-dippers and night-peakers). Critical values for prediction of preeclampsia were daily average central (aortic) systolic BP higher than 115 mm Hg and a mean daily brachial systolic BP above 131 mm Hg.
26614542	Sleep disorders among shift workers are common problems due to the disturbed circadian rhythm. The Bergen Shift Work Sleep Questionnaire assesses discrete sleep problems related to work shifts (day, evening and night shifts) and rest days.The aim of the study was to develop the Hungarian version of this questionnaire and to compare the sleep quality of nurses in different work schedules.	326 nurses working in shifts filled in the questionnaire. The authors made convergent and discriminant validation of the questionnaire with the Athens Insomnia Scale and the Perceived Stress Questionnaire.	The questionnaire based on psychometric characteristics was suitable to assess sleep disorders associated with shift work in a Hungarian sample. The frequency of discrete symptoms significantly (p<0.001) differed with the shifts. Nurses experienced the worst sleep quality and daytime fatigue after the night shift. Nurses working in irregular shift system had worse sleep quality than nurses working in regular and flexible shift system (p<0.001).	The sleep disorder of nurses working in shifts should be assessed with the Hungarian version of the Bergen Shift Work Sleep Questionnaire on a nationally representative sample, and the least burdensome shift system could be established.	
26612390	Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements.EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day.	EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice.	Our results suggest that EphA4 is involved in circadian sleep regulation.	
26612385	Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake.In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions.	A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks.	Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep.	A commentary on this article appears in this issue on page 495.	
26611952	The aim of this study is to investigate premorbid sleep reactivity as a vulnerability to incident shift work disorder (SWD), and related changes in depression as well as anxiety following a transition to a rotating shifts work schedule.This is a longitudinal study with two waves of data collection. The community-based sample included normal sleeping non-shift workers (N = 96; 62.5% female; 47.9 ± 13.3 years) without a lifetime history of insomnia or baseline excessive daytime sleepiness who transitioned to rotating shift work one year later. Participants reported demographic characteristics, trait sleep reactivity on the Ford Insomnia Response to Stress Test, depression symptoms on the Quick Inventory of Depression Symptomatology, and anxiety symptoms on the Beck Anxiety Inventory. SWD was determined based on significant sleep disturbance and/or excessive sleepiness in the context of working in a rotating-shift schedule.	Analyses revealed that the odds were over five times greater for highly sleep-reactive individuals to develop SWD after transitioning to rotating shifts (OR = 5.59, p = 0.04). Nearly 90% of participants who suffered from SWD were accurately identified as high risk at one year before disease onset. Furthermore, individuals who developed SWD reported greater increases in symptoms of depression and anxiety. Finally, analyses revealed significant indirect effects wherein high sleep reactivity increased risk for SWD, which led to greater severity of anxiety and depression symptoms.	The Ford Insomnia Response to Stress Test (FIRST) accurately identifies a focused target population in which the premorbid psychobiological processes complicit in SWD onset and progression, as well as shift work-related depression and anxiety changes, can be better investigated, thus improving future preventative efforts.	
26611815	Pheromone and plant odorants are important for insect mating, foraging food sources and oviposition. To understand the molecular mechanisms regulating pheromone and odorant signaling, we employed qRT-PCR to study the circadian rhythms of ABP, OBP, PBP, and OR gene expression in the beet armyworm, Spodoptera exigua and their responses after a pre-exposure to sex pheromone compounds or plant volatiles. The neuronal responses of male S. exigua to 20 chemical compounds were recorded at three specific time periods using the electroantennogram. The results showed a circadian rhythm in the expression profiles of some chemosensory genes in the antennae similar to their behavioral rhythm. The expression profiles of OR3, OR6, OR11, OR13, OR16, OR18, Orco, ABP2, OBP1, OBP7, and PBP1, and EAG responses to chemical compounds, as well as their circadian rhythm were significantly affected after exposure to synthetic sex pheromones and plant volatiles. These findings provide the first evidence that the gene expression of chemosensory genes and olfactory sensitivity to sex pheromones are affected by pre-exposing insects to pheromone compounds and plant volatiles. It helps to understand the molecular mechanisms underlying pheromone activity, and the application of sex pheromones and plant volatiles in mating disruption or mass trapping. 

26611104	A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a "facilitated repression (FR)" model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine-tuning circadian rhythm.
26610330	Hoverflies are found across the globe, with approximately 6000 species described worldwide. Many hoverflies are being used in agriculture and some are emerging as model species for laboratory experiments. As such it is valuable to know more about their activity. Like many other dipteran flies, Eristalis hoverflies have been suggested to be strongly diurnal, but this is based on qualitative visualization by human observers. To quantify how hoverfly activity depends on internal and external factors, we here utilize a locomotor activity monitoring system. We show that Eristalis hoverflies are active during the entire light period when exposed to a 12 h light:12 h dark cycle, with a lower activity if exposed to light during the night. We show that the hoverflies' locomotor activity is stable over their lifetime and that it does not depend on the diet provided. Surprisingly, we find no difference in activity between males and females, but the activity is significantly affected by the sex of an accompanying conspecific. Finally, we show that female hoverflies are more resilient to starvation than males. In summary, Eristalis hoverflies are resilient to a range of internal and external factors, supporting their use in long-term laboratory experiments.
26608355	To clarify the effect of digesta weight in the reticulorumen on diurnal and seasonal fluctuations in herbage intake, six ruminally cannulated, non-lactating dairy cows were grazed on perennial ryegrass/white clover pasture during morning and evening sessions in spring and autumn. The digesta weight of fresh matter, dry matter (DM) and fiber in the reticulorumen at the beginning and the end of each grazing session was lower in spring than in autumn (P < 0.01). Although the digesta weight was similar between the sessions at the beginning of grazing, it was greater for the evening than for the morning at the end of grazing (P < 0.01). The large particles proportion in the digesta was lower for the morning than the evening (P < 0.01), and it was lower in spring than in autumn (P < 0.01). The concentrations of volatile fatty acids in rumen fluid were generally higher in spring compared with autumn. The herbage DM intake during the evening was greater compared with the morning in both seasons (P < 0.01). However, there was no difference in herbage DM intake between seasons. The results showed that the rumen digesta fill was not the sole factor explaining diurnal and seasonal variation of herbage intake in grazing dairy cows. 
26608258	In the Japanese quail, 7α-hydroxypregnenolone, a previously undescribed avian neurosteroid, is actively produced in the brain. 7α-Hydroxypregnenolone acts as a novel neuronal activator to stimulate locomotor activity of quail. Therefore, in this study, we determined whether 7α-hydroxypregnenolone changes the expression of sexual behavior in Japanese quail. We first measured diurnal changes in sexual behavior of male quail exposed to a long-day photoperiod. We found that sexual behavior of male quail was high in the morning when endogenous 7α-hydroxypregnenolone level is high. Subsequently, we centrally administered 7α-hydroxypregnenolone in the evening when endogenous 7α-hydroxypregnenolone level is low. In the 30 min after intracerebroventricular (ICV) injection, 7α-hydroxypregnenolone dose dependently increased the frequency of sexual behavior of male quail. However, 7β-hydroxypregnenolone, a stereoisomer of 7α-hydroxypregnenolone, did not effect on the frequency of sexual behavior of male quail. In addition, to confirm the action of 7α-hydroxypregnenolone on sexual behavior, male birds received an ICV injection of ketoconazole, an inhibitor of cytochrome P450s, and behavioral experiments were performed in the morning. Ketoconazole significantly decreased the frequency of sexual behavior of male quail, whereas administration of 7α-hydroxypregnenolone to ketoconazole-treated males increased the frequency of their sexual behavior. These results indicate that 7α-hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail.
26607997	This study aimed to clarify diurnal fluctuations of herbage intake, ruminal fermentation of herbage carbohydrates and proteins, and digesta particulate weight in the rumen of grazing dairy cows. Six ruminally cannulated, non-lactating dairy cows were grazed on perennial ryegrass/white clover pasture either in the morning (04.00 to 08.00 hours) or the evening (16.00 to 20.00 hours). Cows grazed in the evening spent more time (P < 0.01) and consumed more herbage (P < 0.01) compared with cows grazed in the morning. Higher (P < 0.05) daily mean concentrations of total volatile fatty acid, propionate and n-butyrate in rumen fluid were observed for cows grazed in the evening compared with cows grazed in the morning. Although cows grazed in the evening ingested more crude protein compared with cows grazed in the morning, no significant difference in NH3 -N concentration in rumen fluid was observed between them. The ratio of purine-derivative concentration to creatinine concentrations was higher (P < 0.01) in the urine of cows grazed in the evening than in cows grazed in the morning. These results clearly indicated that evening grazing was advantageous for dairy cows compared with morning grazing, in terms of ruminal fermentable energy intake and nitrogen utilization efficiency. 
26607963	Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a circadian rhythm, however the association between spindles and intelligence has not been investigated in daytime nap sleep so far. In a sample of 86 healthy male human subjects, we investigated the correlation between fluid intelligence and sleep spindle parameters in an afternoon nap of 100 minutes. Mean sleep spindle length, amplitude and density were computed for each subject and for each derivation for both slow and fast spindles. A positive association was found between intelligence and slow spindle duration, but not any other sleep spindle parameter. As a positive correlation between intelligence and slow sleep spindle duration in full-night polysomnography has only been reported in females but not males, our results suggest that the association between intelligence and sleep spindles is more complex than previously assumed.
26607039	Recent studies have led to an expansion of potential factors capable of stimulating obesity. Increasing evidence indicates that environmental factors, including disturbance of circadian rhythms, also contribute to its etiology.To determine the effects of altered circadian rhythms on adipogenesis and to better understand how circadian and adipogenic regulatory pathways are linked, zebrafish larvae were exposed to various light/dark cycles or hypercaloric feeding (HCF).	Clock and adipogenic gene expression was quantitative real time PCR. Adipogenesis was characterized using coherent anti-Stokes Raman scattering microscopy (CARS) and whole-mount lipid composition was analyzed by gas chromatography. The clock protein Rev-erbα and the adipogenesis-regulating protein Pparγ were localized by immunohistochemistry.	Zebrafish larvae exposed to continuous light (LL) had a sevenfold higher prevalence of adipocytes compared with control fish under a 14 h light and 10 h dark cycle. It was also significantly higher compared with that in HCF larvae with control light/dark cycle, which showed a 5.5-fold increase compared with control animals. Although total fatty acid content was unaffected, adipocyte lipid composition was altered in LL zebrafish. In contrast, shifting the onset and duration of the light periods did not affect adipogenesis or total fatty acid content. Gene expression analysis revealed effects of LL and HCF on circadian cyclicity, with increased expression of the clock gene period2 and altered circadian rev-erbα expression in LL larvae. Immunostaining revealed for the first time that Rev-erbα and Pparγ colocalize in adipocytes, which together with the gene expression analysis suggests interplay between Rev-erbα and Ppar isoforms.	The amount of light, but not shifted light/dark cycles, affected adipogenesis and lipid composition, possibly due to increased period2 expression, which, in turn, enhances Rev-erbα-regulated gene expression. As the pparβδ promoter includes three Rev-erbα binding sites, we hypothesize that pparβδ may be a direct target that ultimately activates Pparγ.	
26606900	The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood and the cerebrospinal fluid (CSF), which is mostly produced by the CP itself. Because the CP transcriptome is regulated by the sex hormone background, the present study compared gene/protein expression profiles in the CP and CSF from male and female rats aiming to better understand sex-related differences in CP functions and brain physiology. We used data previously obtained by cDNA microarrays to compare the CP transcriptome between male and female rats, and complemented these data with the proteomic analysis of the CSF of castrated and sham-operated males and females. Microarray analysis showed that 17 128 and 17 002 genes are expressed in the male and female CP, which allowed the functional annotation of 141 and 134 pathways, respectively. Among the most expressed genes, canonical pathways associated with mitochondrial dysfunctions and oxidative phosphorylation were the most prominent, whereas the most relevant molecular and cellular functions annotated were protein synthesis, cellular growth and proliferation, cell death and survival, molecular transport, and protein trafficking. No significant differences were found between males and females regarding these pathways. Seminal functions of the CP differentially regulated between sexes were circadian rhythm signalling, as well as several canonical pathways related to stem cell differentiation, metabolism and the barrier function of the CP. The proteomic analysis identified five down-regulated proteins in the CSF samples from male rats compared to females and seven proteins exhibiting marked variation in the CSF of gonadectomised males compared to sham animals, whereas no differences were found between sham and ovariectomised females. These data clearly show sex-related differences in CP gene expression and CSF protein composition that may impact upon neurological diseases. 
26606319	Although bright light therapy seems a promising treatment for sleep problems, research shows inconclusive results. This meta-analysis is the first to systematically review the effect of light therapy on sleep problems in general and on specific types of sleep problems in particular (circadian rhythm sleep disorders, insomnia, sleep problems related to Alzheimer's disease and dementia). Fifty-three studies with a total of 1154 participants were included. Overall effects and effects on separate circadian and sleep outcomes were examined. We calculated Hedges' g effect sizes and we investigated the effects of twelve moderators (design-related, treatment-related, participant-related). Light therapy was found effective in the treatment of sleep problems in general (g = 0.39), and for circadian rhythm sleep disorders (g = 0.41), insomnia (g = 0.47), and sleep problems related to Alzheimer's disease/dementia (g = 0.30) specifically. For circadian rhythm sleep disorders, effects were smaller for randomised controlled trials. For insomnia, we found larger effects for studies using a higher light intensity, and for sleep problems related to Alzheimer's disease/dementia larger effects were found for studies with more female participants. There was indication of publication bias. To conclude, light therapy is effective for sleep problems in general, particularly for circadian outcomes and insomnia symptoms. However, most effect sizes are small to medium. 
26605056	Entrainment to light cycle is a prerequisite for circadian rhythms to set daily physiological events to occur at an appropriate time of day. In hemimetabolous insects, the photoreceptor molecule for photic entrainment is still unknown. Since the compound eyes are the only circadian photoreceptor in the cricket Gryllus bimaculatus, we have investigated the role of three opsin genes expressed there, opsin-Ultraviolet (opUV), opsin-Blue (opB), and opsin-Long Wave (opLW) encoding a green-sensitive opsin in photic entrainment.A daily rhythm was detected in mRNA expressions of opB and opLW but not of opUV gene. When photic entrainment of circadian locomotor rhythms was tested after injection of double-stranded RNA (dsRNA) of three opsin genes, no noticeable effects were found in opUV RNAi and opB RNAi crickets. In opLW RNAi crickets, however, some crickets lost photic entrainability and the remaining crickets re-entrained with significantly longer transient cycles to a phase-advanced light-dark cycle as compared to control crickets. Crickets often lost entrainability when treated doubly with dsRNAs of two opsin genes including opLW.	These results show that green-sensitive OpLW is the major circadian photoreceptor molecule for photic entrainment of locomotor rhythms in the cricket G. bimaculatus. Our finding will lead to further investigation of the photic entrainment mechanism at molecular and cellular levels, which still remains largely unknown.	
26605055	This review describes common features among diverse biological clocks in insects, including circadian, circatidal, circalunar/circasemilunar, and circannual clocks. These clocks control various behaviors, physiological functions, and developmental events, enabling adaptation to periodic environmental changes. Circadian clocks also function in time-compensation for celestial navigation and in the measurement of day or night length for photoperiodism. Phase response curves for such clocks reported thus far exhibit close similarities; specifically, the circannual clock in Anthrenus verbasci shows striking similarity to circadian clocks in its phase response. It is suggested that diverse biological clocks share physiological properties in their phase responses irrespective of period length. Molecular and physiological mechanisms are best understood for the optic-lobe and mid-brain circadian clocks, although there is no direct evidence that these clocks are involved in rhythmic phenomena other than circadian rhythms in daily events. Circadian clocks have also been localized in peripheral tissues, and research on their role in various rhythmic phenomena has been started. Although clock genes have been identified as controllers of circadian rhythms in daily events, some of these genes have also been shown to be involved in photoperiodism and possibly in time-compensated celestial navigation. In contrast, there is no experimental evidence indicating that any known clock gene is involved in biological clocks other than circadian clocks. 

26604006	For individuals with chronic pain, the within-person influence of affect and goal cognition on daily work-related goal striving is not yet well understood. The present study tested the hypothesis that anticipatory goal cognition in the form of a morning work goal schema mediates the relations between morning affect and later (afternoon and evening) work goal striving. Working adults with chronic pain (N = 131) completed a 21-day diary with morning, afternoon, and evening assessments analyzed via multi-level structural equation modeling. At the within-person level, morning positive and negative affect were positively associated with morning work goal schemas; and morning work goal schemas, in turn, positively predicted both afternoon and evening work goal striving. Our findings underscore the complex dynamics over time of the relationship between affect and self-regulatory processes and have implications for future studies and for interventions to assist working adults with chronic pain.
26603673	Patients taking hydrocortisone (HC) replacement for primary or secondary adrenal failure require individual adjustment of their dose. In addition to modifying the administered doses of HC for each patient, physicians are increasingly interested in variations in the bioavailability of glucocorticoid replacement. One potential determinant of the bioavailability of replaced HC is a variation in serum cortisol-binding globulin (CBG) concentration, which may, in turn, affect interpretation of cortisol profiles and individual dose selection for patients on hydrocortisone replacement therapy.To investigate the hypothesis that there is a circadian variation in CBG levels.	A total of 34 male patients divided into 3 groups (10 patients with non-somatotroph structural pituitary disease on HC replacement, 11 patients with treated acromegaly on HC replacement and 13 patients with treated acromegaly not on HC replacement) and 10 healthy volunteers were included. Cortisol and CBG levels were measured at 6 time points (0800, 1100, 1300, 1500, 1700 and 1900). No significant circadian variation in CBG concentration was found in any of the 4 groups.	Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentration. Changes in serum cortisol levels may thus be explained by other factors including 11 β-hydroxysteroid dehydrogenase type 1 activity or circadian changes in the binding properties of CBG.	
26603409	This review looked at the effect of cataract surgery on the regulation of circadian rhythms and compared the effect of blue light-filtering and clear intraocular lenses (IOLs) on circadian rhythms. A systematic review and metaanalysis were performed, and the level of evidence was evaluated based on the principles described in the Grading of Recommendations Assessment, Development, and Evaluation system. A literature search of PubMed, Embase, and Cochrane Library databases was performed, as well as a search for unpublished trials at the U.S. National Institutes of Health Clinical Trials web site. Trials that reported the effect of cataract surgery on circadian rhythms were included. Outcomes were the Pittsburgh Sleep Quality Index (PSQI) global score, number of poor sleepers, Epworth Sleepiness Score, sleep efficiency, and mean concentration of melatonin. Cataract surgery improved regulation of circadian rhythms measured by the PSQI questionnaire, but the clinical relevance is uncertain. There was no difference between the effect of the 2 IOL types.No author has a financial or proprietary interest in any material or method mentioned.	

26603274	In freely behaving rats, variations in heart rate (HR) and blood pressure (BP) are coupled closely with changes in locomotor activity (Act). We have attempted to characterize this relationship mathematically. In 10- and 16-week-old rats, HR, BP and Act were recorded telemetrically every minute for 2 days under 12h:12h light-dark cycling. After examining data for individual rats, we found that the relationship between Act and HR could be approximated by the negative exponential function HR(Act)=HRmax-(HRmax-HRmin)∗exp(-Act/Acte), where HRmax, HRmin, and Acte are constants. These constants were calculated separately for light and dark periods by non-linear curve fitting. HR corresponding to maximal locomotion was similar during the light and dark phases, while HR at rest during the dark phase was higher than during the light phase. The range of HR variability associated with Act during the dark phase was similar in young and older animals, but minimal HR was significantly lower in older rats. The relationship between Act and BP was approximated with a similar function. We have found no differences between BP at rest and at maximal locomotion between light and dark and between 10-week and 16-week-old rats. Our results indicate that in rats, cardiovascular parameters are coupled to locomotion to a high degree; however both the HR and the BP reach maximal values when locomotor activity is relatively low. We also found that the phase of daily cycle affects HR in conscious rats independent of locomotor activity.
26602866	Alteration of circadian rhythmicity with aging might depend on physical aerobic capacity.Three groups of participants were established based on their peak oxygen consumption (Group 1 < 20mL/min/kg; Group 2 > 20mL/min/kg and <30mL/min/kg; Group 3 > 30mL/min/kg). Each participant had an individual evaluation of their circadian rhythmicity characteristics through two well-known circadian rhythms: core temperature and rest/activity cycles. Nocturnal sleep was also recorded using actimetry and diurnal vigilance tested in a car driving simulator.	The amplitude of the oral temperature fluctuations for Group 1 is significantly lower (p < .05) than that of Group 3. Group 2 (p < .01) and Group 3 (p < .05) were significantly more active during the day than Group 1. The index of inactivity during the night for Groups 2 (p < .05) and 3 (p < .01) was higher than Group 1. Results of the car driving simulation showed that for Group 1, the number of lane crossings was significantly higher than Groups 2 (p < .01) and 3 (p < .01). In addition, diurnal vigilance was lower in Group 1.	The biological clock seems to be enhanced in older participants with a higher level of physical capacity.	
26601525	The article presents an assessment of anticoagulant effect of rivaroxaban in 35 patients with thromboembolic diseases. The results of expressed anticoagulant effect of rivaroxaban were obtained during a day (or more). The data of increase in sensitivity to thrombomodulin indicated about work enchancement of protein C system against the background of rivaroxaban therapy.
26600110	The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options. 
26600107	Sleep disturbance is frequently associated with generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. This article reviews recent advances in understanding the mechanisms of the sleep disturbances in these disorders and discusses the implications for developing improved treatments. 
26600106	The article provides an overview of common and differentiating self-reported and objective sleep disturbances seen in mood-disordered populations. The importance of considering sleep disturbances in the context of mood disorders is emphasized, because a large body of evidence supports the notion that sleep disturbances are a risk factor for onset, exacerbation, and relapse of mood disorders. In addition, potential mechanisms for sleep disturbance in depression, other primary sleep disorders that often occur with mood disorders, effects of antidepressant and mood-stabilizing drugs on sleep, and the adjunctive effect of treating sleep in patients with mood disorders are discussed. 
26600104	Sleep deprivation and sleep disorders are commonly seen in children and adolescents. They are often undiagnosed and undertreated. A balance of circadian rhythm and homeostatic drive determine sleep quality, quantity, and timing, which changes across the developmental years. Environmental and lifestyle factors can affect sleep quality and quantity and lead to sleep deprivation. A comprehensive assessment of sleep disorders includes parental report, children's self-report, and school functioning. Diagnostic tools are used in diagnosing and treating sleep disorders. 
26600102	Sleep disorders are, in part, attributable to genetic variability across individuals. There has been considerable progress in understanding the role of genes for some sleep disorders, such as the identification of a human leukocyte antigen gene for narcolepsy. For other sleep disorders, such as insomnia, little work has been done. Optimizing phenotyping strategies is critical, as is the case for sleep apnea, for which intermediate traits such as obesity and craniofacial features may prove to be more tractable for genetic studies. Rapid advances in genotyping and statistical genetics are likely to lead to greater discoveries in the near future. 
26600101	There is a growing recognition that the coordinated timing of behavioral, physiologic, and metabolic circadian rhythms is a requirement for a healthy body and mind. In mammals, the primary circadian oscillator is the hypothalamic suprachiasmatic nucleus (SCN), which is responsible for circadian coordination throughout the organism. Temporal homeostasis is recognized as a complex interplay between rhythmic clock gene expression in brain regions outside the SCN and in peripheral organs. Abnormalities in this intricate circadian orchestration may alter sleep patterns and contribute to the pathophysiology of affective disorders. 
26600100	Cortical electroencephalographic activity arises from corticothalamocortical interactions, modulated by wake-promoting monoaminergic and cholinergic input. These wake-promoting systems are regulated by hypothalamic hypocretin/orexins, while GABAergic sleep-promoting nuclei are found in the preoptic area, brainstem and lateral hypothalamus. Although pontine acetylcholine is critical for REM sleep, hypothalamic melanin-concentrating hormone/GABAergic cells may "gate" REM sleep. Daily sleep-wake rhythms arise from interactions between a hypothalamic circadian pacemaker and a sleep homeostat whose anatomical locus has yet to be conclusively defined. Control of sleep and wakefulness involves multiple systems, each of which presents vulnerability to sleep/wake dysfunction that may predispose to physical and/or neuropsychiatric disorders. 
26599806	Monochromatic light is widely applied to promote poultry reproductive performance, yet little is currently known regarding the mechanism by which light wavelengths affect pigeon reproduction. Recently, high-throughput sequencing technologies have been used to provide genomic information for solving this problem. In this study, we employed Illumina Hiseq 2000 to identify differentially expressed genes in ovary tissue from pigeons under blue and white light conditions and de novo transcriptome assembly to construct a comprehensive sequence database containing information on the mechanisms of follicle development. A total of 157,774 unigenes (mean length: 790 bp) were obtained by the Trinity program, and 35.83% of these unigenes were matched to genes in a non-redundant protein database. Gene description, gene ontology, and the clustering of orthologous group terms were performed to annotate the transcriptome assembly. Differentially expressed genes between blue and white light conditions included those related to oocyte maturation, hormone biosynthesis, and circadian rhythm. Furthermore, 17,574 SSRs and 533,887 potential SNPs were identified in this transcriptome assembly. This work is the first transcriptome analysis of the Columba ovary using Illumina technology, and the resulting transcriptome and differentially expressed gene data can facilitate further investigations into the molecular mechanism of the effect of blue light on follicle development and reproduction in pigeons and other bird species. 
26599376	Daily generation of novel platelets may compromise aspirin's platelet inhibitory action, especially near the end of the regular 24-h dosing interval. A contributor to this attenuation could be the endogenous circadian rhythm. The primary objective of this study was to assess platelet activity 12 and 24 h after different times of aspirin intake (c.q. 8.00 AM and 8.00 PM). A randomized open-label crossover study was conducted, comprising outpatients with stable cardiovascular disease taking aspirin once daily. We measured platelet aggregation with the platelet function analyzer (PFA)-200(®) and light transmission aggregometry (LTA). The attenuation of aspirin's inhibitory action was most apparent in the 8.00 AM regimen. The platelet function analyzer-closure time was 78 s faster at 24 h than at 12 h after intake in the 8.00 AM regimen (IQR: 166.8-301 vs. 132.8-301; p = 0.006) and 0 s faster at 24 h than at 12 h after intake in the 8.00 PM regimen (IQR: 198.8-837.0 vs. 169.8-301; p = 0.653). The adenosine diphosphate 1.0 µmol/L maximum amplitude was 5.40% higher at 24 h than at 12 h after intake in the 8.00 AM regimen (95% confidence interval (CI): -0.03--10.8; p = 0.040) and was 0.75% higher 24 h than at 12 h after intake in the 8.00 PM regimen (95% CI: -4.83-3.33; p = 0.705). The platelet inhibitory effect of aspirin decreases after 24 h, particularly after intake in the morning. These results suggest that patients might benefit from evening intake or twice daily intake regimens. 
26598903	Well-regulated eating habits are said to be important for health. A major breakthrough was the discovery of the negative regulatory feedback for transcription via the binding of Clock/Bmal1 to E-box, which forms the basis of biological clocks. Well-regulated eating habits normalize the liver clock gene, the rhythm of CYP7A1 gene, and blood cholesterol levels through insulin secretion. Moreover, well-regulated eating habits actively contribute to better lipid metabolism such as obesity, even if animals ingest a high-fat diet. From reported results so far, chrononutition has two important functions: 1) meal timing is important for our health, and 2) meal timing entrains our body clock. 
26598902	The circadian rhythm is generally existed in mammalian behavior and metabolic processes, which results from the self-sustained circadian clocks. The mammalian circadian clocks are composed of a master clock located in the hypothalamic suprachiasmatic nucleus (SCN), and of many peripheral clocks in tissues and extra-SCN brain regions. It is indicated that feeding could take over part of the SCN signaling, and affect internal synchrony between the master clock and the peripheral clocks. Thus, recent studies focus more on the relationship between the nutrients and circadian rhythms. Various nutrient components (glucose, amino acid, alcohol) are found to be able to directly affect the circadian rhythm of clock genes. Moreover, the feeding schedule of nutrients is as important as the nutrient components in maintaining a healthy circadian rhythm. Therefore, the circadian homeostasis needs not only balanced nutrient components but also regular timed nutrients. 
26597486	The aim of this review was to determine the link between night/shift work and breast cancer.The analysed articles were taken from the PUBMED database between 1996 and 2015. The keywords used were "breast cancer risk", "night work" and "shift work". In total, 25 articles were selected.	Night/shift workers are more at risk to develop a breast cancer (relative risk (RR) between 1.09; 95% CI: 1.02-1.20 and 1.48; 95% CI: 1.36-1.61 in the meta-analyses). However, this risk is not found by some cohort and case-control studies. The circadian rhythm disruption, responsible of disorderliness of melatonin secretion, could be one of the mechanisms involved in the increase of that risk. Hormonal status of night/shift workers, their geographic origin, their lifestyle and their vitamin D deficiency appear as other mechanisms potentially responsible for increased risk of cancer in this professional population. Moreover, a dose-effect connection may exist, with an increase of the risk with the number of years of night/shift work.	Night/shift work is associated with a moderate increased risk of breast cancer, especially among women who worked over 20 years. Recommendations concerning the breast monitoring in this population could be diffused. The benefit of melatonin supplementation remains to be assessed.	
26595902	Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation.Subjects were 1728 individuals ages 30-79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF.	Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals.	Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors.	
26595483	There is evidence that the sleep and circadian systems play a role in glucose metabolism. In addition to physiological factors, sleep is also affected by behavioral, environmental, cultural and social factors. In this study, we examined whether morning or evening preference, sleep timing and sleep duration are associated with glycemic control in patients with type 2 diabetes residing in Thailand. Two hundred and ten type 2 diabetes patients who were not shift workers completed an interview and questionnaires to collect information on diabetes history, habitual sleep duration and sleep timing. Chronotype, an individual's tendency for being a "morning" or "evening" person, was assessed using the Composite Score of Morningness (CSM), which reflects an individual's subjective preference for activities in the morning or evening, as well as mid-sleep time on weekend nights (MSF), which reflects their actual sleep behavior. Most recent hemoglobin A1c (HbA1c) values were retrieved from medical records. Evening preference (as indicated by lower CSM), later bedtime on weekends, and shorter sleep duration correlated with higher HbA1c (r = -0.18, p = 0.01; r = 0.17, p = 0.01 and r = -0.17, p = 0.01, respectively), while there was no association between MSF or wake up time and glycemic control. In addition, later bedtime on weekends significantly correlated with shorter sleep duration (r = -0.34, p < 0.001). Hierarchical regression analyses adjusting for age, sex, body mass index, insulin use and diabetes duration revealed that later bedtime on weekends was significantly associated with poorer glycemic control (B = 0.018, p = 0.02), while CSM was not. Mediation analysis revealed that this association was fully mediated by sleep duration. In summary, later bedtime on weekends was associated with shorter sleep duration and poorer glycemic control in patients with type 2 diabetes. It is likely that patients with later weekend bedtimes curtail their sleep by waking up earlier. Exploring the potential reasons for this phenomenon (e.g. cultural influences, metropolitan lifestyle, environmental factors, family and social obligations) specific to a Thai population may help identify behavioral modifications (i.e. earlier bedtime and/or sleep duration extension) that could possibly lead to improved glycemic control in this population. 
26595472	Interactions between biological vulnerability and environmental adversity are central to the pathophysiology of depression. Given evidence that the hypothalamic-pituitary-adrenal (HPA) axis influences biological responses to environmental events, in the current longitudinal study the authors examined HPA-axis functioning, negative life events, and their interaction as predictors of the first onset of depression. At baseline, girls ages 9 to 14 years provided saliva samples to assess levels of diurnal cortisol production, quantified by total cortisol production (area under the curve with respect to ground; AUCg) and the cortisol awakening response (CAR). The authors then followed these participants until they reached age 18 in order to assess their subsequent experience of negative life events and the onset of a depressive episode. They found that the influence of negative life events on the subsequent onset of depression depended on HPA-axis functioning at baseline. Specifically, negative life events predicted the onset of depression in girls with higher levels of AUCg, but not in girls with lower levels of AUCg. In contrast, CAR did not predict the onset of depression either alone or in interaction with negative life events. These findings suggest that elevated total cortisol production in daily life potentiates susceptibility to environmental adversity and signals the need for early intervention.
26595385	Synchrony between circadian and metabolic processes is critical to the maintenance of energy homeostasis. Studies on essence of chicken (EC), a chicken meat extract rich in proteins, amino acids and peptides, showed its effectiveness in alleviating fatigue and promoting metabolism. A recent study revealed that it facilitated the re-entrainment of clock genes (Bmal1, Cry1, Dec1, Per1 and Per2) in the pineal gland and liver in a rat model of circadian disruption. Here, we investigated the role of EC-facilitated circadian synchrony in the maintenance of the energy homeostasis using a mouse model of prolonged circadian disruption. Prolonged circadian disruption (12 weeks) resulted in hepatic maladaptation, manifested by a mild but significant (p < 0.05) hepatomegaly, accompanied by disturbed hepatic lipid metabolism and liver injury (indicated by increased circulating hepatic enzymes). Evidently, there was marked elevations of hepatic inflammatory mediators (interleukin-1beta and interleukin-6), suggesting an underlying inflammation leading to the hepatic injury and functional impairment. Importantly, the disruption paradigm caused the decoupling between key metabolic regulators (e.g. mTOR and AMPK) and hepatic clock genes (Per1, Cry1, Dec1, Bmal1). Further, we showed that the loss of circadian synchrony between the master and hepatic clock genes (Per1, Cry1, Dec1, Bmal1) could be the underlying cause of the maladaptation. When supplemented with EC, the functional impairment and inflammation were abolished. The protective effects could be linked to its effectiveness in maintaining the synchrony between the master and hepatic clocks, and the resultant improved coupling of the circadian oscillators (Per1, Cry1, Dec1, Bmal1) and metabolic regulators (mTOR, AMPK). Overall, EC supplementation promoted the physiological adaptation to the prolonged circadian disruption through facilitation of endogenous circadian synchrony and the coupling of circadian oscillators and metabolic regulators. This forms an important basis for further elucidation of the physiological benefits of EC-facilitated circadian synchrony. 
26595278	Brain monoamines - such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) - regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (Tc), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (Ta) of 23 °C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12 h:12 h) or artificial (6 h:6 h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of Tc, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour. 
26595175	Inter-individual variation in phase-of-entrainment (chronotype) is widely observed in many species, but the underlying mechanisms and its consequences remain largely unexplored. In light of considerable limitations of previous studies proposing that the late chronotypes exhibit weakly stable rhythms, we employed outbred Drosophila populations exhibiting early and late emergence chronotypes to re-visit such associations. Contrary to previous reports, we observed that the late chronotypes consistently exhibit higher stability in emergence and activity-rest rhythms as compared to the early chronotypes, both under laboratory and semi-natural conditions, which is not associated with higher precision of circadian clocks, thus demonstrating the existence of genetic correlations between accuracy of entrainment and chronotype. Our results, along with the previously reported clock property differences between the early and the late emergence chronotypes highlights a possible complex interplay of clock period, phase response curve and accuracy in determining phase-of-entrainment. 
26595085	Despite numerous studies about fish nutrition and lipid metabolism, very little is known about the daily rhythm expression of lipogenesis and lipolysis genes. This research aimed to investigate the existence of daily rhythm expressions of the genes involved in lipid metabolism and their synchronization to different light/dark (LD) and feeding cycles in zebra fish liver. For this purpose, three groups of zebra fish were submitted to a 12:12 h LD cycle. A single daily meal was provided to each group at various times: in the middle of the light phase (ML); in the middle of the dark phase (MD); at random times. After 20 days of acclimation to these experimental conditions, liver samples were collected every 4 h in one 24-h cycle. The results revealed that most genes displayed a significant daily rhythm with an acrophase of expression in the dark phase. The acrophase of lipolytic genes (lipoprotein lipase - lpl, peroxisome proliferator-activated receptor - pparα and hydroxyacil CoA dehydrogenase - hadh) was displayed between ZT 02:17 h and ZT 18:31 h. That of lipogenic genes (leptin-a - lepa, peroxisome proliferator-activated receptor - pparγ, liver X receptor - lxr, insulin-like growth factor - igf1, sterol regulatory element-binding protein - srebp and fatty acid synthase - fas) was displayed between ZT 15:25 h and 20:06 h (dark phase). Feeding time barely influenced daily expression rhythms, except for lxr in the MD group, whose acrophase shifted by about 14 h compared with the ML group (ZT 04:31 h versus ZT 18:29 h, respectively). These results evidence a strong synchronization to the LD cycle, but not to feeding time, and most genes showed a nocturnal acrophase. These findings highlight the importance of considering light and feeding time to optimize lipid metabolism and feeding protocols in fish farming. 
26594893	Activity rhythm disturbances and depression often co-occur among older adults. However, little is known about how activity rhythm disturbances themselves co-occur, or how disturbances to multiple aspects of the activity rhythm relate to depression over time. In this study, we performed a Latent Class Analysis to derive sub-groups of older men [total n = 2933, mean age = 76.28, standard deviation (SD) = 5.48] who shared similar patterns of activity rhythm disturbances (defined as extreme values of modeled activity rhythm parameters). We found eight sub-groups with distinct combinations of activity rhythm disturbances: one had all normative activity rhythm parameters (32.09%), one had only lower activity (10.06%), three had earlier activity (totaling 26.96%) and three had later activity (totaling 30.89%). Groups with similar timing were distinguished depending on whether the relative length of the active period was shorter and/or if the activity rhythm had lesser amplitude/robustness. We next examined whether the derived activity rhythm sub-groups were associated with different rates of change in depression symptom levels over an average of 5.5 (0.52 SD) follow-up years. The sub-group with lower activity only had faster increases in depressive symptoms over time (compared with the group with normative rhythm parameters), but this association was accounted for by adjustments for concurrently assessed health status covariates. Independent of these covariates, we found that four activity rhythm disturbance sub-groups experienced faster depressive symptom increases (compared with the normative sub-group): These included all three sub-groups that had later activity timing and one sub-group that had earlier activity timing plus a shorter active period and a dampened rhythm. Low activity rhythm height/robustness with normal timing therefore may mark depression risk that is attributable to co-occurring disease processes; in contrast, having late or combined early/compressed/dampened activity rhythms may independently contribute to depression symptom development. Our findings suggest that activity rhythm-related depression risk is heterogeneous, and may be detected when multiple aspects of rhythm timing are delayed or when early timing is accompanied by compressed/dampened activity rhythms. Future studies should consider how distinct combinations of altered activity rhythm timing and height/robustness develop and conjointly determine health risks. Further research is also needed to determine whether/how activity rhythms can be modified to improve depression outcomes. 
26592843	Obstructive Sleep Apnoea Syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. OSAS is an established independent factor of cardiovascular risk together with other risk factors such as smoking and increased lipids. The aim of our study was to measure serum levels of aldosterone and renin in OSAS patients that did not suffer from arterial hypertension and compare them to matched healthy subjects in order to reveal the impact of chronic intermittent hypoxia on the renin-angiotensin-aldosterone system.The patients that enrolled in this study were 19 OSAS patients who had undergone overnight polysomnography and had an Apnoea Hypopnoea Index (AHI) greater than 10 events/hour. They were compared to 20 healthy non-OSAS closely matched controls. Serum aldosterone and direct renin concentration were measured by radioimmunoassay.	Aldosterone concentration follows a diurnal variation; therefore, all blood samples were obtained at the same time (6 AM). There were no significant differences in serum aldosterone levels between the two studied groups of OSAS patients and the healthy subjects group (140.6 pg/ml ± 25.2 vs. 133.2 pg/ml ± 18.5 with p = 0.223). Similar were the results for the renin levels (25.0 ± 6.9 vs. 24.9 ± 4.4 with p = 0.360).	Our study suggests that patients with OSAS, but without existing hypertension have aldosterone and renin levels similar to healthy subjects. According to our findings a direct connection between OSAS and the development of arterial hypertension may not be established via sympathetic system activation.	
26591032	Blood pressure (BP) has a circadian rhythm, decreases at night and increases in the morning (dipper), have been observed in patients with impaired in this profile, increased at night and lower in the morning (no dipper) have increased cardiovascular risk. Preeclampsia-eclampsia complicates about 7% of pregnancies, preeclampsia is known to reverse the normal circadian cycle of the BP.To determine the profile dipper/non-dipper in patients with severe preeclampsia, eclampsia and HELLP syndrome patients in Intensive Care and Obstetrics Hospital Juárez of México.	15 patients were reviewed, 10 with severe preeclampsia, 4 with HELLP syndrome and 1 eclampsia, systolic, diastolic, mean and pulse PA were analyzed during the day/night and pregnancy/postpartum. Using ratios pregnancy day/night pregnancy, puerperium day/night postpartum dipper/non-dipper profile is determined	Maternal age 30 ± 6.34 years, 7 primiparous (46%) 8 multiparous (54%), pregnancy was 31.67 ± 4.59 weeks. In all but two results in the ratio of pulse pressure during pregnancy was not the result dipper raiser and did not change during the postpartum period.	in all patients during pregnancy profile was observed no dipper no change during the postpartum period. The established treatment did not modify this result. So it is appropriate to establish strategies to change this behavior and try to get the patient to regain normal circadian BP rhythm.	
26590710	In a recent paper in Cell Metabolism, Altman et al. (2015) report that MYC disrupts the molecular clock in cancer cells and describe a link between oncogenesis, circadian rhythms, and metabolism.
26590506	Fatigue is a risk factor for flight performance and safety in commercial aviation. In US commercial aviation, to help to curb fatigue, the maximum duration of flight duty periods is regulated based on the scheduled start time and the number of flight segments to be flown. There is scientific support for regulating maximum duty duration based on scheduled start time; fatigue is well established to be modulated by circadian rhythms. However, it has not been established scientifically whether the number of flight segments, per se, affects fatigue. To address this science gap, we conducted a randomized, counterbalanced, cross-over study with 24 active-duty regional airline pilots. Objective and subjective fatigue was compared between a 9-hour duty day with multiple take-offs and landings versus a duty day of equal duration with a single take-off and landing. To standardize experimental conditions and isolate the fatiguing effect of the number of segments flown, the entire duty schedules were carried out in a high-fidelity, moving-base, full-flight, regional jet flight simulator. Steps were taken to maintain operational realism, including simulated airplane inspections and acceptance checks, use of realistic dispatch releases and airport charts, real-world air traffic control interactions, etc. During each of the two duty days, 10 fatigue test bouts were administered, which included a 10-minute Psychomotor Vigilance Test (PVT) assessment of objective fatigue and Samn-Perelli (SP) and Karolinska Sleepiness Scale (KSS) assessments of subjective sleepiness/fatigue. Results showed a greater build-up of objective and subjective fatigue in the multi-segment duty day than in the single-segment duty day. With duty start time and duration and other variables that could impact fatigue levels held constant, the greater build-up of fatigue in the multi-segment duty day was attributable specifically to the difference in the number of flight segments flown. Compared to findings in previously published laboratory studies of simulated night shifts and nighttime sleep deprivation, the magnitude of the fatiguing effect of the multiple take-offs and landings was modest. Ratings of flight performance were not significantly reduced for the simulated multi-segment duty day. The US duty and flight time regulations for commercial aviation shorten the maximum duty duration in multi-segment operations by up to 25% depending on the duty start time. The present results represent an important first step in understanding fatigue in multi-segment operations, and provide support for the number of flight segments as a relevant factor in regulating maximum duty duration. Nonetheless, based on our fatigue results, a more moderate reduction in maximum duty duration as a function of the number of flight segments might be considered. However, further research is needed to include investigation of flight safety, and to extend our findings to nighttime operations. 
26590423	Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles. 
26589759	Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from (137)Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood. 
26589395	In bipolar disorder (BD), seasonality of symptoms is common and disturbances in circadian rhythms have been reported.We identified high-penetrance families in a geographically restricted area in Northern Fennoscandia and studied the seasonal variation of clinical symptoms among BD subjects and their healthy relatives.	We explored the clinical characteristics of subjects living in Northern Fennoscandia, with extreme annual variation in daylight. Among known indigenous high-risk families for BD, we compared the affected ones (N=16) with their healthy relatives (N=15), and also included 18 healthy non-related controls from the same geographical area. Seasonal fluctuation in clinical measures was followed up at the 4 most demarcated photoperiodic time points of the annual cycle: around the summer solstice and autumn equinox in 2013, the winter solstice in 2013/2014, and the spring equinox in 2014. In the baseline, lifetime manic symptoms [Mood Disorder Questionnaire (MDQ)] and morningness-eveningness questionnaire type (MEQ) were registered, whereas in the follow-up, depressive [Beck Depression Inventory (BDI)] and distress [General Health Questionnaire (GHQ-12)] symptoms and alcohol consumption and sleep were recorded.	Possibly indicative or statistically significant differences in symptoms between the affected subjects and their healthy relatives were the BDI winter (13.3 vs. 2.6, t=-2.51, p=0.022) and spring scores (12.6 vs. 3.2, t=-1.97, p=0.063) and GHQ winter (4.2 vs. 0.82, t=-2.08, p=0.052) and spring scores (3.8 vs. 0.82, t=-1.97, p=0.063). Scores were higher among the affected subjects, exceeding a possibly diagnostic threshold (10 and 3) at all the time points, and without the notable seasonality which was observed among the healthy relatives. In the overall population, MDQ and MEQ scores had an inverse correlation (-0.384, significant at 0.016), indicating increased lifetime manic behaviour among "the night owl" chronotype subjects.	In an Arctic population sample, we found different seasonal fluctuation in mood and distress symptoms and sleep duration scores between subjects with bipolar spectrum disorders and their healthy relatives. Despite the relatively small sample size, the results indicate that the symptoms and signs of BD relate to a disturbance in seasonal variation. Seasonal variation can be considered as an interesting endophenotype for BD and a promising target for further genetic studies.	
26589387	Night shift workers are at risk of road accidents due to sleepiness on the commute home. A brief nap at the end of the night shift, before the commute, may serve as a sleepiness countermeasure. However, there is potential for sleep inertia, i.e. transient impairment immediately after awakening from the nap. We investigated whether sleep inertia diminishes the effectiveness of napping as a sleepiness countermeasure before a simulated commute after a simulated night shift. N=21 healthy subjects (aged 21-35 y; 12 females) participated in a 3-day laboratory study. After a baseline night, subjects were kept awake for 27h for a simulated night shift. They were randomised to either receive a 10-min nap ending at 04:00 plus a 10-min pre-drive nap ending at 07:10 (10-NAP) or total sleep deprivation (NO-NAP). A 40-min York highway driving task was performed at 07:15 to simulate the commute. A 3-min psychomotor vigilance test (PVT-B) and the Samn-Perelli Fatigue Scale (SP-Fatigue) were administered at 06:30 (pre-nap), 07:12 (post-nap), and 07:55 (post-drive). In the 10-NAP condition, total pre-drive nap sleep time was 9.1±1.2min (mean±SD), with 1.3±1.9min spent in slow wave sleep, as determined polysomnographically. There was no difference between conditions in PVT-B performance at 06:30 (before the nap). In the 10-NAP condition, PVT-B performance was worse after the nap (07:12) compared to before the nap (06:30); no change across time was found in the NO-NAP condition. There was no significant difference between conditions in PVT-B performance after the drive. SP-Fatigue and driving performance did not differ significantly between conditions. In conclusion, the pre-drive nap showed objective, but not subjective, evidence of sleep inertia immediately after awakening. The 10-min nap did not affect driving performance during the simulated commute home, and was not effective as a sleepiness countermeasure.
26588724	Increasing evidence suggests that physical activity (PA) improves the quality of life (QoL) of cancer survivors. However, the biological mechanisms underlying the relationship between PA and QoL are unclear. The purpose of this study was to determine whether the relationship between PA and QoL differs in younger and older cancer survivors and whether circadian rhythm (CR) mediates this relationship. We also explored the effect of the CR on QoL. The participants were 235 cancer survivors, comprising 143 younger and 92 older patients. Data were collected using the Taiwanese versions of the Physical Activity Scale for the Elderly and Short Form-36. The robustness and stability of the CR were measured using an actigraph. Mediation was tested using multiple mediation analyses. The CR mediated the relationship between PA and the physical domain of QoL in younger and older cancer survivors (23% and 59% mediating effects, respectively). The CR partially mediated the effect of PA on the mental dimension of QoL in older cancer survivors (36% mediating effect), but not in younger cancer survivors. Cancer survivors with a more robust CR had a significantly higher QoL, particularly in the physical functioning domain (d = 0.43, p < 0.001). The results provided evidence that the CR mediated the relationship between PA and QoL. Moreover, this mediating effect differed in younger and older cancer survivors. These results can serve as a reference for designing individualized PA programs for cancer survivors. 
26588574	In mammals, a network of coupled neurons within the hypothalamus coordinates physiological rhythms with daily changes in the environment. In each neuron, delayed negative transcriptional feedbacks generate oscillations, albeit noisy and unreliable ones. Coupling mediated by diffusible neuropeptides lends precision and robustness to circadian rhythms. The double knockout of Cryptochrome Cry turns adult mice arrhythmic. But, remarkably, double knockout neonates continue to show robust oscillation much like wild-type neonates and appear to lose rhythmicity with development. We study quantitatively dispersed neurons and brain slices from wild-type and Cry double knockout mice to understand the links between single cell rhythmicity and intercellular coupling. We quantify oscillator properties of dispersed cells using nonlinear regression and study bifurcations diagrams of network models. We find that varying just three parameters-oscillator strength, strength of coupling, and timing of coupling-can reproduce experimentally observed features. In particular, modeling reveals that minor changes in timing of coupling can destroy synchronization as observed in adult slices from knockout mice. 
26588495	Pineal melatonin (MLT) is produced at highest levels during the night, under dark conditions. We evaluated differences in MLT-concentration by comparing daytime versus night time milk samples, from two dairy farms with different night illumination conditions: (1) natural dark (Dark-Night); (2) short wavelength Artificial Light at Night (ALAN, Night-Illuminated). Samples were collected from 14 Israeli Holstein cows from each commercial dairy farm at 04:30 h ("Night-milk") 12:30 h ("Day-milk") and analyzed for MLT-concentration. In order to study the effects of night illumination conditions on cows circadian rhythms, Heart Rate (HR) daily rhythms were recorded. MLT-concentrations of Night-milk samples from the dark-night group were significantly (p < 0.001) higher than those of Night-illuminated conditions (30.70 ± 1.79 and 17.81 ± 0.33 pg/ml, respectively). Interestingly, night illumination conditions also affected melatonin concentrations at daytime where under Dark-Night conditions values are significantly (p < 0.001) higher than Night-Illuminated conditions, (5.36 ± 0.33 and 3.30 ± 0.18 pg/ml, respectively). There were no significant differences between the two treatments in the milk yield and milk composition except somatic cell count (SCC), which was significantly lower (p = 0.02) in the Dark-Night group compared with the Night-Illuminated group. Cows in both groups presented a significant (p < 0.01) HR daily rhythm, therefore we assume that in the night illuminated cows feeding and milking time are the "time keeper", while in the Dark-night cows, HR rhythms were entrained by the light/dark cycle. The higher MLT-concentration in Dark-night cows with the lower SCC values calls upon farmers to avoid exposure of cows to ALAN. Therefore, under Dark-night conditions milk quality will improve by lowering SCC values where separation between night and day of such milk can produce chrono-functional milk, naturally rich with MLT. 
26588261	Heart rate (HR) recovery (HRR) and variability (HRV) after exercise are non-invasive tools used to assess cardiac autonomic regulation and cardiovascular prognosis. Autonomic recovery is slower after evening than morning exercise in healthy individuals, but this influence is unknown in subjects with autonomic dysfunction, although it may affect prognostic evaluation. This study compared post-exercise HRR and HRV after maximal morning and evening exercise in pre-hypertensive men. Ten volunteers randomly underwent two maximal exercise tests conducted in the morning (8-10 a.m.) and evening (6-8 p.m.). HRR60s (HR reduction at 60 s of recovery - prognostic index), T30 (short-term time-constant of HRR - parasympathetic reactivation marker), rMSSD30s (square root of the mean of the sum of the squares of differences between adjacent R-R intervals on subsequent 30 s segments - parasympathetic reactivation marker), and HRRτ (time constant of the first order exponential fitting of HRR - marker of sympathetic withdraw and parasympathetic reactivation) were measured. Paired t-test and two-way ANOVA were used. HRR60s and HRRτ were similar after exercise in the morning and evening (27 ± 7 vs. 29 ± 7 bpm, p = 0.111, and 79 ± 14 vs. 96 ± 29 s, p = 0.119, respectively). T30 was significantly greater after evening exercise (405 ± 215 vs. 295 ± 119 s, p = 0.002) and rMSSD30s was lower in the evening (main factor session, p = 0.009). In conclusion, in pre-hypertensive men, the prognostic index of HRR, HRR60s, is not affected by the time of day when exercise is conducted. However, post-exercise parasympathetic reactivation, evaluated by T30 and rMSSD30s, is blunted after evening exercise. 
26588000	Stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise-even as increasing numbers of high-throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gained by applying our method to a genome-wide siRNA screen, revealing that stochastic noise is altered independently from period, amplitude, and phase. Finally, we hypothesize that the unperturbed clock is highly optimized for robust rhythms, as very few gene perturbations are capable of simultaneously increasing amplitude and lowering stochastic noise. Ultimately, this study demonstrates the importance of considering the effect of circadian perturbations on stochastic noise, particularly with regard to the development of small-molecule circadian therapeutics. 
26587750	The present research aimed to investigate in a model of teleost fish (rainbow trout) the existence of daily changes in activity and mRNA abundance of several proteins involved in major pathways of carbohydrate and lipid metabolism in liver, and to test whether or not both the light-dark cycle and food availability might influence such rhythms. For this purpose, four cohorts of animals previously adapted to normal housing conditions (12L:12D; Lights on at ZT0; feeding time at ZT2) were subjected to: normal conditions (LD); 48-h constant darkness (DD); 96-h food deprivation (LD + Fasting); or constant darkness and food deprivation (DD + Fasting) respectively. After such time periods, fish were sacrificed and sampled every 4-h on the following 24-h period (ZT/CT0, 4, 8, 12, 16, 20 and 0'). Our results reveal that cortisol and all the analysed genes (gk, pepck, g6pase, pk, glut2, hoad and fas) exhibited well defined daily rhythms, which persisted even in the absence of light and/or food indicating the endogenous nature of such rhythms. Even when the variations of enzyme activities were not significant, their rhythms mostly paralleled those of the respective gene expression. The rhythms of mRNA abundance were apparently dependent on the presence of food, but the light/dark cycle also influenced such rhythms. Since cortisol does not appear to be mainly involved in generating such daily rhythms in liver, alternative mechanisms might be involved, such as a direct interaction between metabolism and the circadian system. 
26587588	New information has become available since the ISC, AAMCC, and SECAC released their first extensive guidedelines to improve the diagnosis and treatment of adult arterial hypertension. A critical assessment of evidence and a comparison of what international guidelines now propose are the basis for the following statements, which update the recommendations first issued in 2013. Office blood pressure (BP) measurements should no longer be considered to be the "gold standard" for the diagnosis of hypertension and assessment of cardiovascular risk. Relying on office BP, even when supplemented with at-home wake-time self-measurements, to identify high-risk individuals, disregarding circadian BP patterning and asleep BP level, leads to potential misclassification of 50% of all evaluated persons. Accordingly, ambulatory BP monitoring is the recommended reference standard for the diagnosis of true hypertension and accurate assessment of cardiovascular risk in all adults ≥18 yrs of age, regardless of whether office BP is normal or elevated. Asleep systolic BP mean is the most significant independent predictor of cardiovascular events. The sleep-time relative SBP decline adds prognostic value to the statistical model that already includes the asleep systolic BP mean and corrected for relevant confounding variables. Accordingly, the asleep systolic BP mean is the recommended protocol to diagnose hypertension, assess cardiovascular risk, and predict cardiovascular event-free interval. In men, and in the absence of compelling clinical conditions, reference thresholds for diagnosing hypertension are 120/70 mmHg for the asleep systolic/diastolic BP means derived from ambulatory BP monitoring. However, in women, in the absence of complicating co-morbidities, the same thresholds are lower by 10/5 mmHg, i.e., 110/65 mmHg for the asleep means. In high-risk patients, including those diagnosed with diabetes or chronic kidney disease, and/or those having experienced past cardiovascular events, the thresholds are even lower by 15/10 mmHg, i.e., 105/60 mmHg. Bedtime treatment with the full daily dose of ≥1 hypertension medications is recommended as a cost-effective means to improve the management of hypertension and reduce hypertension-associated risk. Bedtime treatment entailing the full daily dose of ≥1 conventional hypertension medications must be the therapeutic regimen of choice for the elderly and those with diabetes, resistant and secondary hypertension, chronic kidney disease, obstructive sleep apnea, and medical history of past cardiovascular events, among others, given their documented high prevalence of sleep-time hypertension.
26586835	PSEUDO-RESPONSE REGULATORs (PRRs) play overlapping and distinct roles in maintaining circadian rhythms and regulating diverse biological processes, including the photoperiodic control of flowering, growth, and abiotic stress responses. PRRs act as transcriptional repressors and associate with chromatin via their conserved C-terminal CCT (CONSTANS, CONSTANS-like, and TIMING OF CAB EXPRESSION 1 [TOC1/PRR1]) domains by a still-poorly understood mechanism. Here, we identified genome-wide targets of PRR9 using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and compared them with PRR7, PRR5, and TOC1/PRR1 ChIP-seq data. We found that PRR binding sites are located within genomic regions of low nucleosome occupancy and high DNase I hypersensitivity. Moreover, conserved noncoding regions among Brassicaceae species are enriched around PRR binding sites, indicating that PRRs associate with functionally relevant cis-regulatory regions. The PRRs shared a significant number of binding regions, and our results indicate that they coordinately restrict the expression of target genes to around dawn. A G-box-like motif was overrepresented at PRR binding regions, and we showed that this motif is necessary for mediating transcriptional regulation of CIRCADIAN CLOCK ASSOCIATED 1 and PRR9 by the PRRs. Our results further our understanding of how PRRs target specific promoters and provide an extensive resource for studying circadian regulatory networks in plants. 
26586828	In mammals, daily changes in body temperature (Tb) depend on the integrity of the suprachiasmatic nucleus (SCN). Fasting influences the Tb in the resting period and the presence of the SCN is essential for this process. However, the origin of this circadian/metabolic influence is unknown. We hypothesized that, not only the SCN but also the arcuate nucleus (ARC), are involved in the Tb setting through afferents to the thermoregulatory median preoptic nucleus (MnPO). Therefore, we investigated by neuronal tracing and microdialysis experiments the possible targeting of the MnPO by the SCN and the ARC in male Wistar rats. We observed that vasopressin release from the SCN decreases the temperature just before light onset, whereas α-melanocyte stimulating hormone release, especially at the end of the dark period, maintains high temperature. Both peptides have opposite effects on the brown adipose tissue activity through thermoregulatory nuclei such as the dorsomedial nucleus of the hypothalamus and the dorsal raphe nucleus. The present study indicates that the coordination between circadian and metabolic signaling within the hypothalamus is essential for an adequate temperature control.When circadian and metabolic systems are not well synchronized, individuals may develop metabolic diseases. The underlying mechanisms are unknown. Here, we demonstrate that the balance between the releases of neuropeptides derived from the biological clock and from a metabolic sensory organ as the arcuate nucleus, are essential for an adequate temperature control. These observations show that brain areas involved in circadian and metabolic functions of the body need to interact to produce a coherent arrangement of physiological processes associated with temperature control.	
26586468	mRNA poly(A) tails are important for mRNA stability and translation, and enzymes that regulate the poly(A) tail length significantly impact protein profiles. There are eleven putative deadenylases in mammals, and it is thought that each targets specific transcripts, although this has not been clearly demonstrated. Nocturnin (NOC) is a unique deadenylase with robustly rhythmic expression and loss of Noc in mice (Noc KO) results in resistance to diet-induced obesity. In an attempt to identify target transcripts of NOC, we performed "poly(A)denylome" analysis, a method that measures poly(A) tail length of transcripts in a global manner, and identified 213 transcripts that have extended poly(A) tails in Noc KO liver. These transcripts share unexpected characteristics: they are short in length, have long half-lives, are actively translated, and gene ontology analyses revealed that they are enriched in functions in ribosome and oxidative phosphorylation pathways. However, most of these transcripts do not exhibit rhythmicity in poly(A) tail length or steady-state mRNA level, despite Noc's robust rhythmicity. Therefore, even though the poly(A) tail length dynamics seen between genotypes may not result from direct NOC deadenylase activity, these data suggest that NOC exerts strong effects on physiology through direct and indirect control of target mRNAs. 


26584570	A variety of environmental factors contribute to progressive development of osteoarthritis (OA). Environmental factors that upset circadian rhythms have been linked to various diseases. Our recent work establishes chronic environmental circadian disruption - analogous to rotating shiftwork-associated disruption of circadian rhythms in humans - as a novel risk factor for the development of OA. Evidence suggests shift workers are prone to obesity and also show altered eating habits (i.e., increased preference for high-fat containing food). In the present study, we investigated the impact of chronic circadian rhythm disruption in combination with a high-fat diet (HFD) on progression of OA in a mouse model. Our study demonstrates that when mice with chronically circadian rhythms were fed a HFD, there was a significant proteoglycan (PG) loss and fibrillation in knee joint as well as increased activation of the expression of the catabolic mediators involved in cartilage homeostasis. Our results, for the first time, provide the evidence that environmental disruption of circadian rhythms plus HFD potentiate OA-like pathological changes in the mouse joints. Thus, our findings may open new perspectives on the interactions of chronic circadian rhythms disruption with diet in the development of OA and may have potential clinical implications. 
26584071	The distribution and intensity of artificial light at night, commonly referred to as light pollution, is consequently rising and progressively also ecological implications come to light. Low intensity light is known to suppress nocturnal melatonin production in several fish species. This study aims to examine the least suppressive light colour for melatonin excreted into the holding water and the influence of different light qualities and quantities in the night on gene expression of gonadotropins in fish. European perch (Perca fluviatilis) were exposed to light of different wavelengths during the night (blue, green, and red). Melatonin concentrations were measured from water samples every 3h during a 24h period. Gene expression of gonadotropins was measured in perch exposed to different light colours and was additionally examined for perch subjected to different intensities of white light (0 lx, 1 lx, 10 lx, 100 lx) during the night. All different light colours caused a significant drop of melatonin concentration; however, blue light was least suppressive. Gene expression of gonadotropins was not influenced by nocturnal light of different light colours, but in female perch gonadotropin expression was significantly reduced by white light already at the lowest level (1 lx). We conclude that artificial light with shorter wavelengths at night is less effective in disturbing biological rhythms of perch than longer wavelengths, coinciding with the light situation in freshwater habitats inhabited by perch. Different light colours in the night showed no significant effect on gonadotropin expression, but white light in the night can disturb reproductive traits already at very low light intensities. These findings indicate that light pollution has not only the potential to disturb the melatonin cycle but also the reproductive rhythm and may therefore have implications on whole species communities.
26584039	Shift workers, particularly night workers, are prone to disrupted circadian rhythms and sleep deprivation resulting in fatigue and sleepiness, thereby endangering patient safety. Little is known about the sleep patterns of emergency nurses who work highly variable around-the-clock schedules to meet the demands of fluctuating patient census and acuities throughout the 24-hour period.The purpose of this pilot study was to determine whether there are shift-related sleep pattern differences in emergency department nurses over seven consecutive 24-hour periods that include both workdays and days off.	A New Jersey mailing list (1514 members) was rented from the Emergency Nurses' Association. Three hundred on this list were systematically sampled and invited by mail to participate. The final sample consisted of 35 emergency nurses. Participants wore actigraphs for 24 hours each day for 7 days and completed sleep diaries upon awakening from their daily main sleep periods. Queries included caffeine and hypnotics usage. The nurses also completed the Standard Shiftwork Index General Biographical Information Section for demographic and scheduling data. Participants received a $50 honorarium upon completion of the protocol. The actigraph data were downloaded into a personal computer using Act Millennium and analyzed with Action W software (Ambulatory Monitoring, Inc., Ardsley, NY, USA).	Sleep durations ranged from 6.6 to 8.1 hours on workdays and from 6.2 to 8.1 hours on days off. There were no significant shift- or workday-related differences in sleep patterns. However, trends indicated that, regardless of shift, workday sleep became more disturbed and less efficient toward the end of the week. Daily caffeine usage was reported by 85.9% of the sample.	Shift working nurses need to obtain adequate and consistent sleep on workdays and days off throughout the work week to reduce fatigue and to provide safe patient care. Understanding the sleep patterns of emergency nurses and their schedules is critical to facilitating the development of shift-specific sleep promotion interventions to enhance sleep and thereby counteract fatigue.	
26583060	The human Circadian Locomotor Output Cycle protein Kaput (CLOCK) gene was originally discovered as a regulator of essential human daily rhythms. This seemingly innocuous gene was then found to be associated with a multitude of human malignancies, via several biochemical pathways. We aimed to further investigate the role of hCLOCK in the hypoxia-oxidative stress response system at the biochemical level.Expression levels of Rho GTPases were measured in normoxic and hypoxic states. The effect of hCLOCK on the hypoxic response was evaluated with the use of a retroviral shRNA vector system, a Rho inhibitor, and a ROS scavenger by analyzing expression levels of hCLOCK, Rho GTPases, and NF-κB pathway effectors. Finally, in vitro ROS production and tube formation in HUVECs were assessed.	Hypoxia induces ROS production via hCLOCK. hCLOCK activates the RhoA and NF-κB signaling pathways. Conversely, inhibition of hCLOCK deactivates these pathways. Furthermore, inhibition of RhoA or decreased levels of ROS attenuate these pathways, but inhibition of RhoA does not lead to decreased levels of ROS. Overall findings show that hypoxia increases the expression of hCLOCK, which leads to ROS production, which then activates the RhoA and NF-κB pathways.	Our findings suggest that hypoxic states induce vascular oxidative damage and inflammation via hCLOCK-mediated production of ROS, with subsequent activation of the RhoA and NF-κB pathways.	
26582653	The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after ≥1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD.Twenty patients (19 naïve and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks.	Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end.	At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study.	Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.	
26581865	Circadian rhythms coordinate cyclical behavioral and physiological changes in most organisms. In humans, this biological clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and consists of a heterogeneous neuron population characterized by their enriched expression of various neuropeptides. As highlighted here, Fan et al. (J Neurosci 35: 1905-1029, 2015) developed an elegant experimental system to investigate the synaptic properties of vasoactive intestinal peptide (VIP)-expressing neurons between day and night, and further delineate their broader architecture and function within the SCN. 

26580580	Alcohol abuse is often associated with disrupted circadian rhythms and sleep, and the link seems to be bidirectional. In addition, it has been shown that exposure to constant illumination may increase lipid peroxidation in tissues. In this study, we investigated the effects of circadian rhythm disruption (CRD) and chronic alcohol intake (A) alone and in combination (CRD+A), on the oxidative stress in total rat brain homogenate. Our results demonstrated that lipid peroxidation was increased in the brain samples of all experimental animals compared with the control ones. The oxidative stress levels increased in the order: C<CRD<A<(CRD+A). Furthermore, xanthine oxidase activity changed in the order: C<CRD<A=CRD+A. It was proposed that chronic alcohol intake, if accompanied with CRD, might lead to significantly higher lipid peroxidation in the brain, than if present alone. Our data suggest that ethanol metabolites may be involved in the increase of the brain xanthine oxidase activity in rats with chronic alcohol intake.
26580236	Shift work, which imposes a habitual disruption in the circadian system, has been linked to increased incidence of cardiometabolic diseases, and acute circadian misalignment alters various metabolic processes. However, it remains unclear whether day-to-day circadian dysregulation contributes to these risks beyond poor sleep and other behavioral characteristics.Individuals differ in circadian phase preference, known as chronotype, but may be constrained by modern work obligations to specific sleep schedules. Individuals experience social jetlag (SJL) due to a habitual discrepancy between their endogenous circadian rhythm and actual sleep times imposed by social obligations. Here, we examined whether chronotype and/or SJL associate with components of cardiovascular disease risk beyond the known effects of sleep disturbances, poor health behaviors, and depressive symptomatology.	Participants were healthy, midlife adults who worked part- or full-time day shifts (n = 447; mean age, 42.7 [range, 30-54] y; 53% female; 83% white). Chronotype was assessed with the Composite Scale of Morningness. SJL was quantified as the difference (in minutes) between the midpoints of actigraphy-derived sleep intervals before work vs non-workdays.	Multiple regression analyses showed that SJL related to a lower high-density lipoprotein-cholesterol level, higher triglycerides, higher fasting plasma insulin, insulin resistance, and adiposity (P < .05), even after adjustment for subjective sleep quality, actigraphy-derived sleep characteristics, depressive symptomatology, and health behaviors. Evening chronotype associated with lower high-density lipoprotein-cholesterol after adjustment for covariates.	Our findings suggest that a misalignment of sleep timing is associated with metabolic risk factors that predispose to diabetes and atherosclerotic cardiovascular disease.	
26580016	Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels. 

26579570	Melatonin is an indoleamine with multiple functions in both plant and animal species. In addition to data in literature describing many other important roles for melatonin, such as antioxidant, circadian rhythm controlling, anti-aging, antiproliferative or immunomodulatory activities, our group recently reported that thyroid C-cells synthesize melatonin and suggested a paracrine role for this molecule in the regulation of thyroid activity. To discern the role played by melatonin at thyroid level and its involvement in the hypothalamic-pituitary-thyroid axis, in the present study we have analyzed the effect of thyrotropin in the regulation of the enzymatic machinery for melatonin biosynthesis in C cells as well as the effect of melatonin in the regulation of thyroid hormone biosynthesis in thyrocytes. Our results show that the key enzymes for melatonin biosynthesis (AANAT and ASMT) are regulated by thyroid-stimulating hormone. Furthermore, exogenous melatonin increases thyroglobulin expression at mRNA and protein levels on cultured thyrocytes and this effect is not strictly mediated by the upregulation of TTF1 or, noteworthy, PAX8 transcription factors. The present data show that thyroid C-cells synthesize melatonin under thyroid-stimulating hormone control and, consistently with previous data, support the hypothesis of a paracrine role for C-cell-synthesised melatonin within the thyroid gland. Additionally, in the present study we show evidence for the involvement of melatonin in thyroid function by directly-regulating thyroglobulin gene expression in follicular cells. 
26579436	Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. 
26578695	The cyanobacterial circadian-related protein, Pex, accumulates in the dark period of the diurnal light-dark cycle. After the diurnal cycle, an approximately 3 h advance in the phase of the circadian bioluminescence rhythm is observed in pex-deficient mutants, as compared with the wild type. However, it is unclear what type of photosensing mechanism regulates the accumulation and the phase change. In monochromatic light irradiation experiments, Pex accumulation was strongly repressed under blue light conditions; however, only small reductions in Pex accumulation were observed under red or green light conditions. After the diurnal cycle of 12 h of white fluorescent light and 12 h of blue light, the phase advance was repressed more than that of the cycle of 12 h red (or green) light. The phase advance also occurred after 16 h light/8 h dark cycles (long-day cycles) but did not occur after 8 h light/16 h dark cycles (short-day cycles). While Pex is a unique winged helix transcription factor harboring secondary structures (α0 and α4 helices), the importance of the structures is not understood. In in vivo experiments with site-directed mutations in the α0 helix, the obtained mutants, in which Pex was missing the hydrophobic side chain at the 28th or 32nd amino acid residue, exhibited no phase delay after the light/dark cycle. In in vitro DNA binding assays, the mutant proteins showed no binding to the promoter region of the clock gene kaiA. From these results, we propose a molecular model which describes the phase delay in cyanobacteria.
26578474	Bipolar disorder is a disabling disease that involves a significant economic costs to the health system, making it is essential to investigate possible early predictors such as changes in sleep-wake cycle in high-risk populations.To review the available literature on alterations in the sleep-wake cycle and circadian rhythm in patients with bipolar disorder and their first degree relatives.	A literature search was performed in the data bases, Access Medicine, ClinicalKey, EMBASE, JAMA, Lilacs, OVID, Oxford Journals, ScienceDirect, SciELO, APA y PsycNET. Articles in both English and Spanish were reviewed, without limits by study type.	Actigraphy is a non-invasive, useful method for assessing sleep-wake cycle disturbances in the active phases of bipolar disorder, and during euthymia periods. Actigraphy showed good sensitivity to predict true sleep, but low specificity, compared with polysomnography. Although studies in bipolar offspring and relatives are scarce, they show sleep changes similar to bipolar patients.	Actigraphy may be a good screening tool of sleep/wake cycle in patients with bipolar disorders, because it is economic, non-invasive and sensitive. Longitudinal studies are required to evaluate its potential use as a risk marker.	
26578037	Cerebral autoregulation is a complex homeostatic process which ensures constant brain blood supply, despite continuous blood pressure fluctuations. Recent evidence suggests that in Parkinson's disease (PD) and multiple system atrophy (MSA) this process is maintained in a broadened range of blood pressure values, consistent with an adaptive mechanism to increase tolerance to orthostatic hypotension. In PD and MSA orthostatic hypotension may be accompanied by supine hypertension which has been recently linked with cerebral white matter lesions in these conditions. We hypothesize that cerebral autoregulation adaptation to chronic orthostatic hypotension may be directly related with an increase susceptibility to hypertensive peaks. Evaluation of cerebral autoregulatory behavior may thus represent a novel approach to simultaneously target orthostatic symptoms and silent end-organ damage in alpha-synucleinopathies, with a beneficial impact on cerebrovascular and cognitive outcome. 
26576661	As adequate food intake is crucial to survival, organisms have evolved endogenous circadian clocks to generate optimal temporal patterns of food-related behavior and physiology. The gastric ghrelin-secreting cell is thought to be part of this network of peripheral food-entrainable oscillators (FEOs), regulating the circadian release of this orexigenic peptide. This study aimed to determine the role of the core clock gene Bmal1 and the gastric ghrelin-secreting cell as an FEO in the circadian rhythmicity of ghrelin expression and secretion in vivo and in vitro. Bmal1-deficient mice not only lacked circadian rhythmicity in plasma ghrelin levels and food intake, but also showed decreased gastric mRNA expression of ghrelin and ghrelin O-acyltransferase (GOAT), the ghrelin activating enzyme. Furthermore, in the absence of the hypothalamic master clock, food-related stimuli entrained the molecular clock of gastric ghrelinoma cells to regulate the rhythmic release of ghrelin. Divergent responses in octanoyl and total ghrelin release towards different food cues were observed, suggesting that the FEO also regulates the circadian rhythmicity of GOAT. Collectively, these findings indicate that circadian rhythmicity of ghrelin signaling requires Bmal1 and is driven by a food-responsive clock in the gastric ghrelin-secreting cell that not only regulates ghrelin, but also GOAT activity. 
26576534	Most physiological processes in mammals are temporally regulated by means of a master circadian clock in the brain and peripheral oscillators in most other tissues. A transcriptional-translation feedback network of clock genes produces near 24 h oscillations in clock gene and protein expression. Here, we aim to identify novel additions to the clock network using a meta-analysis of public chromatin immunoprecipitation sequencing (ChIP-seq), proteomics and protein-protein interaction data starting from a published list of 1000 genes with robust transcriptional rhythms and circadian phenotypes of knockdowns.We identified 20 candidate genes including nine known clock genes that received significantly high scores and were also robust to the relative weights assigned to different data types. Our scoring was consistent with the original ranking of the 1000 genes, but also provided novel complementary insights. Candidate genes were enriched for genes expressed in a circadian manner in multiple tissues with regulation driven mainly by transcription factors BMAL1 and REV-ERB α,β. Moreover, peak transcription of candidate genes was remarkably consistent across tissues. While peaks of the 1000 genes were distributed uniformly throughout the day, candidate gene peaks were strongly concentrated around dusk. Finally, we showed that binding of specific transcription factors to a gene promoter was predictive of peak transcription at a certain time of day and discuss combinatorial phase regulation.	Combining complementary publicly-available data targeting different levels of regulation within the circadian network, we filtered the original list and found 11 novel robust candidate clock genes. Using the criteria of circadian proteomic expression, circadian expression in multiple tissues and independent gene knockdown data, we propose six genes (Por, Mtss1, Dgat2, Pim3, Ppp1r3b, Upp2) involved in metabolism and cancer for further experimental investigation. The availability of public high-throughput databases makes such meta-analysis a promising approach to test consistency between sources and tap their entire potential.	
26576055	Sleep disturbance is associated with the development of obesity, diabetes and hepatic steatosis in murine models. Hepatic triglyceride accumulation oscillates in a circadian rhythm regulated by clock genes, light-dark cycle and feeding time in mice. The role of the sleep-wake cycle in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD) is indeterminate. We sought to detail sleep characteristics, daytime sleepiness and meal times in relation to disease severity in patients with NAFLD.Basic Sleep duration and latency, daytime sleepiness (Epworth sleepiness scale), Pittsburgh sleep quality index, positive and negative affect scale, Munich Chronotype Questionnaire and an eating habit questionnaire were assessed in 46 patients with biopsy-proven NAFLD and 22 healthy controls, and correlated with biochemical and histological parameters.	In NAFLD compared to healthy controls, time to fall asleep was vastly prolonged (26.9 vs. 9.8 min., p = 0.0176) and sleep duration was shortened (6.3 vs. 7.2 hours, p = 0.0149). Sleep quality was poor (Pittsburgh sleep quality index 8.2 vs. 4.7, p = 0.0074) and correlated with changes in affect. Meal frequency was shifted towards night-times (p = 0.001). In NAFLD but not controls, daytime sleepiness significantly correlated with liver enzymes (ALAT [r = 0.44, p = 0.0029], ASAT [r = 0.46, p = 0.0017]) and insulin resistance (HOMA-IR [r = 0.5, p = 0.0009]) independent of cirrhosis. In patients with fibrosis, daytime sleepiness correlated with the degree of fibrosis (r = 0.364, p = 0.019).	In NAFLD sleep duration was shortened, sleep onset was delayed and sleep quality poor. Food-intake was shifted towards the night. Daytime sleepiness was positively linked to biochemical and histologic surrogates of disease severity. The data may indicate a role for sleep-wake cycle regulation and timing of food-intake in the pathogenesis of human NAFLD as suggested from murine models.	
26574119	The aim of this study was to compare the quantity/quality of sleep obtained by people living on split and consolidated sleep-wake schedules. The study had a between-groups design, with 13 participants in a consolidated condition (all males, mean age of 22.5yr) and 16 participants in a split condition (all males, mean age of 22.6yr). Both conditions employed forced desynchrony protocols with the activity:rest ratio set at 2:1, but the consolidated condition had one sleep-wake cycle every 28h (9.33+18.67), while the split condition had one sleep-wake cycle every 14h (4.67+9.33). Sleep was assessed using polysomnography. Participants in the split and consolidated conditions obtained 4.0h of sleep per 14h and 7.6h of sleep per 28h, respectively. Some differences between the groups indicated that sleep quality was lower in the split condition than the consolidated condition: the split sleeps had longer sleep onset latency (9.7 vs. 4.3min), more arousals (7.4 vs. 5.7 per hour in bed), and a greater percentage of stage 1 sleep (4.1% vs. 3.1%), than the consolidated sleeps. Other differences between the groups indicated that sleep quality was higher in the split condition than the consolidated condition: the split sleeps had a lower percentage of wake after sleep onset sleep (11.7% vs. 17.6%), and a greater percentage of slow wave sleep (30.2% vs. 23.8%), than the consolidated sleeps. These results indicate that the split schedule was not particularly harmful, and may have actually been beneficial, to sleep. Split work-rest schedules can be socially disruptive, but their use may be warranted in work settings where shiftworkers are separated from their normal family/social lives (e.g., fly-in fly-out mining) or where the need for family/social time is secondary to the task (e.g., emergency response to natural disasters).
26572977	The number of people around the world suffering from depression has dramatically increased in last few decades. It has been predicted that by 2020 depression will become the second most common cause of disability. Furthermore, depression is often misdiagnosed and confused with other psychiatric disorders showing similar symptoms, i.e., anxiety and bipolar disorder, due to the fact that diagnosing is often carried out by medical workers who are not psychiatrically trained. These facts prompt us to prepare this review which focuses on alterations in gene expression in depression. We believe that an in-depth knowledge of molecular bases of behavior in depression and other mood disorders would be of a great benefit for the correct diagnosing of these disorders, as well as for prescribing a treatment that best suits each individual depending on expression alterations in depression-related genes. Therefore, the main aim of this review is to promote further translational research on the biochemistry of mood disorders and take the results further for the design of new targeted therapeutics that can be used for personalized treatment with minimal adverse effects.
26572605	In cervical spinal cord injury (CSCI), afferent and efferent circuits that influence the basal production of melatonin and cortisol may be disrupted and hence disrupt the basal functions of human physiology. Therefore, the aim of this study was to assess circadian changes, if any, in serum cortisol and melatonin in patients with CSCI.Serum levels of cortisol and melatonin were measured at 6-h intervals of the day (0600, 1200, 1800 and 0000 hours) in 22 CSCI patients, as well as 22 healthy controls.	Significantly higher melatonin levels were observed in the patient group in morning hours, whereas a significantly lower level of melatonin was found during the night time in the patient group than in the control group. Moreover, significantly higher values were obtained in the evening and night time serum cortisol levels among the patients compared with controls. Further, when the mean values of cortisol throughout the day were tested among patient and control groups similar circadian rhythm was found. The only difference being that serum cortisol declined much more in controls in evening and night samples as compared with CSCI patients.	We conclude that circadian variations exist in the circulating levels of serum cortisol and melatonin in patients with CSCI. Low levels of melatonin secretion during night may contribute to the pervasive sleep disruption and increased pain perception.	
26569124	The circadian clock is a critical regulator of plant physiology and development, controlling key agricultural traits in crop plants. In addition, natural variation in circadian rhythms is important for local adaptation. However, quantitative modulation of circadian rhythms due to artificial selection has not yet been reported. Here we show that the circadian clock of cultivated tomato (Solanum lycopersicum) has slowed during domestication. Allelic variation of the tomato homolog of the Arabidopsis gene EID1 is responsible for a phase delay. Notably, the genomic region harboring EID1 shows signatures of a selective sweep. We find that the EID1 allele in cultivated tomatoes enhances plant performance specifically under long day photoperiods, suggesting that humans selected slower circadian rhythms to adapt the cultivated species to the long summer days it encountered as it was moved away from the equator. 
26568862	Shift work is a well-recognized occupational health hazard in both industrialized and industrially developing countries. Prolonged working time, day/night shift rotation, circadian rhythm and sleep disorders, family and social problems are the most important features of shift working, which have serious complications.The present study evaluated the fatigue and psychological distress and their relationship among shift workers, in a petrochemical plant (Southern Pars gas field) in Southwest Iran.	In this cross-sectional field study, 400 shift workers from a plant were involved, with participation rate of 72.5% (290 persons). The multidimensional fatigue inventory (MFI-20) and general health questionnaire (GHQ-28) were used to evaluate the level of fatigue and psychological distress, respectively.	The results showed that the fatigue and psychological distress (particularly social dysfunction, anxiety and insomnia) are frequent among 12-hour shift workers (the total MFI and total GHQ scores were 42.68 ± 17.88 and 34.66 ± 18.56). A relatively strong positive correlation was found between fatigue and psychological distress (r = 0.62). The results of the stepwise regression model indicated that the psychological distress was significantly related only to general fatigue, mental fatigue and reduced motivation, whereas it was not to the physical fatigue and reduced activity.	The study findings highlight the importance of the mental aspect of fatigue in this working group. These results have possible implications for workers' health and well-being and for the design of shift work systems, for industrial workers.	
26568596	To compare 24-h ambulatory blood pressure (BP) monitoring (ABPM) values and patterns in women with systemic lupus erythematosus (SLE) with those of a matched control group and their relationship with the presence of subclinical atherosclerosis.ABPM was assessed in 70 women with SLE and in 65 sex- and age-matched controls without a history of clinic cardiovascular disease (CVD). Carotid-femoral pulse wave velocity (PWV), which is a marker of subclinical atherosclerosis and a predictor of future CVD, was measured. Multivariate logistic analysis was used to determine which explanatory variables were independently associated with the non-dipper pattern and the presence of nocturnal hypertension (HTN) in women with SLE.	No differences in PWV were found between patients and controls [median 7.3, interquartile range (IQR) 6.5-8.1 m/s vs median 7.1, IQR 6.5-7.8 m/s, p = 0.474]. The frequency of nondipper pattern (p = 0.025) and nocturnal HTN (p = 0.004) was significantly higher in women with SLE than in controls. White-coat and masked HTN were present in 10% and 11% of patients and in 20% and 8% of controls, respectively (p > 0.05 in all cases). The concordance between office and ambulatory HTN in the SLE and control groups was modest (κ = 0.325 and κ = 0.451, respectively). PWV and chronic kidney disease, and PWV and the Systemic Lupus Erythematosus Disease Activity Index were found to be independently associated with nocturnal HTN and nondipper pattern, respectively.	Women with SLE were more likely to have an altered nighttime BP pattern than controls. In women with SLE, nondipper pattern and nocturnal HTN were independently associated with increased subclinical atherosclerosis measured by PWV.	
26568127	Jet lag and shift work disorder are circadian rhythm sleep-wake disorders resulting from behaviorally altering the sleep-wake schedule in relation to the external environment. Not everyone who experiences trans-meridian travel or performs shift work has a disorder. The prevalence of jet lag disorder is unclear, approximately 5%-10% of shift workers have shift work disorder. Treatment aims to realign the internal circadian clock with the external environment. Behavioral therapies include sleep hygiene and management of the light-dark and sleep schedule. Pharmacologic agents are used to treat insomnia and excessive sleepiness, and melatonin is used to facilitate sleep and circadian realignment. 
26568126	Irregular sleep-wake rhythm disorder is a circadian rhythm disorder characterized by multiple bouts of sleep within a 24-hour period. Patients present with symptoms of insomnia, including difficulty either falling or staying asleep, and daytime excessive sleepiness. The disorder is seen in a variety of individuals, ranging from children with neurodevelopmental disorders, to patients with psychiatric disorders, and most commonly in older adults with neurodegenerative disorders. Treatment of irregular sleep-wake rhythm disorder requires a multimodal approach aimed at strengthening circadian synchronizing agents, such as daytime exposure to bright light, and structured social and physical activities. In addition, melatonin may be useful in some patients. 
26568125	Non-24-hour sleep-wake rhythm disorder (N24SWD) is a cyclic debilitating circadian rhythm sleep disorder characterized by an inability to sleep on a 24-hour schedule. Individuals isolated from a 24-hour light-dark cycle exhibit sleep-wake cycles different from 24 hours. Relatively rare in sighted patients, it may be associated with delayed sleep-wake rhythm disorder or psychiatric disorders. It is more common in totally blind individuals owing to the lack of light information reaching the circadian pacemaker in the hypothalamus. We review the clinical characteristics of patients with N24SWD, discuss the biological mechanisms that may underlie its development, and describe treatment strategies. 
26568124	Evidence suggests that abnormalities in circadian rhythms might prove causally or pathophysiologically significant in psychiatric illness. The circadian regulation of hormonal and behavioral timekeeping processes is often altered in patients with major depression, bipolar disorder, and schizophrenia, and a susceptibility to rhythm instability may contribute to the functional impairment. For some patients, interventions that stabilize or resynchronize circadian rhythms prove therapeutically effective. Circadian disruption in the clinical profiles of most psychiatric illnesses and the treatment efficacy of chronobiological interventions suggest that attention to circadian phenotypes in a range of psychiatric disorders may help to uncover shared pathophysiologic mechanisms. 
26568123	Circadian rhythms have a major role in physiology and behavior. Circadian disruption has negative consequences for physiologic homeostasis at molecular, cellular, organ-system, and whole-organism levels. The onset of many cerebrovascular insults shows circadian temporal trends. Impaired sleep-wake cycle, the most robust output rhythms of the circadian system, is significantly affected by neurodegenerative disorders, may precede them by decades, and may also affect their progression. Emerging evidence suggests that circadian disruption may be a risk factor for these neurologic disorders. This article discusses the implications of circadian rhythms in brain disorders, with an emphasis on cerebrovascular and neurodegenerative disorders. 
26568122	Cardiovascular disease, diabetes and obesity are highly prevalent diseases associated with reduced quality of life and life expectancy. We discuss a novel risk factor for these cardiometabolic diseases: circadian disruption. Circadian disruption occurs when the internal circadian (∼24-hour) rhythms are not in synchrony with the environment or each other. This paper reviews (1) cardiometabolic health of shift work, which often leads to circadian disruption, (2) effects of experimentally disrupted circadian rhythms on cardiometabolic function, (3) observational studies of sleep timing and behavioral chronotype, and (4) potential mediators linking chronotype and shift work to circadian disruption and cardiometabolic health. 
26568121	Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin, and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment. 
26568120	Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. This article reviews key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. 
26568119	Nearly all organisms exhibit time-dependent behavior and physiology across a 24-hour day known as circadian rhythms. These outputs are manifestations of endogenous cyclic gene expression patterns driven by the activity of a core transcription/translation feedback loop. Cyclic gene expression determines highly tissue-specific functional activity regulating such processes as metabolic state, endocrine activity, and neural excitability. Entrainment of these cellular clocks is achieved through exogenous daily inputs, such as light and food. Dysregulation of the transcription/translation feedback loop has been shown to result in a wide range of disorders and diseases driving increased interest in circadian therapies. 
26568118	Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes. The maintenance of proper coordination within this network of cellular- and tissue-level clocks is essential for health and well-being. 
26567532	The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to synchronize the tissue-specific rhythms of the peripheral clocks with the environmental day/night changes via neural, humoral and/or behavioral connections. The feeding rhythm is considered an important Zeitgeber for peripheral clocks, as daytime feeding reverses (clock) gene rhythms in the periphery, but not in the SCN. In this study, we investigated the necessity of a daily feeding rhythm for maintaining gene expression rhythms in epididymal white adipose tissue (eWAT). We showed that 7 of 9 rhythmic metabolic/adipokine genes, but not clock genes, lost their rhythmicity upon exposure to 6-meals-a-day feeding. Previously, we showed comparable effects of adrenalectomy on eWAT; therefore, subsequently we investigated the effect of simultaneous disruption of these humoral and behavioral signaling pathways, by exposing adrenalectomized animals to 6-meals-a-day feeding. Interestingly, under these conditions, all the clock genes and 10 of 11 rhythmic metabolic/adipokine genes lost their rhythmicity. These data indicate that adrenal hormones and feeding rhythm are indispensable for maintaining daily rhythms in metabolic/adipokine gene, but not clock gene, expression in eWAT. In contrast, at least one of these two signals should be present in order for eWAT clock gene rhythms to be maintained. 
26567212	Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. 
26566981	The effect of circadian rhythm (CR) disruption on immune function depends on the method by which CRs are disrupted. Behavioral and thermoregulatory responses induced by lipopolysaccharide (LPS) treatment were assessed in female Siberian hamsters in which circadian locomotor activity (LMA) rhythms were eliminated by exposure to a disruptive phase-shifting protocol (DPS) that sustains arrhythmicity even when hamsters are housed in a light-dark cycle. This noninvasive treatment avoids genome manipulations and neurological damage associated with other models of CR disruption. Circadian rhythmic (RHYTH) and arrhythmic (ARR) hamsters housed in a 16L:8D photocycle were injected with bacterial LPS near the onset of the light (zeitgeber time 1; ZT1) or dark (ZT16) phase. LPS injections at ZT16 and ZT1 elicited febrile responses in both RHYTH and ARR hamsters, but the effect was attenuated in the arrhythmic females. In ZT16, LPS inhibited LMA in the dark phase immediately after injection but not on subsequent nights in both chronotypes; in contrast, LPS at ZT1 elicited more enduring (~4 day) locomotor hypoactivity in ARR than in RHYTH hamsters. Power and period of dark-phase ultradian rhythms (URs) in LMA and Tb were markedly altered by LPS treatment, as was the power in the circadian waveform. Disrupted circadian rhythms in this model system attenuated responses to LPS in a trait- and ZT-specific manner; changes in UR period and power are novel components of the acute-phase response to infection that may affect energy conservation.
26565891	Crop biomass production is a function of the efficiencies with which sunlight can be intercepted by the canopy and then converted into biomass. Conversion efficiency has been identified as a target for improvement to enhance crop biomass and yield. Greater conversion efficiency in modern soybean [Glycine max (L.) Merr.] cultivars was documented in recent field trials, and this study explored the physiological basis for this observation. In replicated field trials conducted over three successive years, diurnal leaf gas exchange and photosynthetic CO2 response curves were measured in 24 soybean cultivars with year of release dates (YOR) from 1923 to 2007. Maximum photosynthetic capacity, mesophyll conductance and nighttime respiration have not changed consistently with cultivar release date. However, daily carbon gain was periodically greater in more recently released cultivars compared with older cultivars. Our analysis suggests that this difference in daily carbon gain primarily occurred when stomatal conductance and soil water content were high. There was also evidence for greater chlorophyll content and greater sink capacity late in the growing season in more recently released soybean varieties. Better understanding of the mechanisms that have improved conversion efficiency in the past may help identify new, promising targets for the future. 
26565299	We articulate an adaptive and reference-free framework based on the principle of random switching to detect and control unstable steady states in high-dimensional nonlinear dynamical systems, without requiring any a priori information about the system or about the target steady state. Starting from an arbitrary initial condition, a proper control signal finds the nearest unstable steady state adaptively and drives the system to it in finite time, regardless of the type of the steady state. We develop a mathematical analysis based on fast-slow manifold separation and Markov chain theory to validate the framework. Numerical demonstration of the control and detection principle using both classic chaotic systems and models of biological and physical significance is provided. 
26564741	To investigate the expression and circadian rhythm variation of biological clock gene Per1 and cell cycle genes p53, CyclinD1, cyclin-dependent kinases (CDK1), CyclinB1 in different stages of carcinogenesis in buccal mucosa and its relationship with the development of buccal mucosa carcinoma.Ninety golden hamsters were housed under 12 hours light-12 hours dark cycles, and the model of buccal squamous cell carcinoma was established by using the dimethylbenzanthracene (DMBA) to smear the golden hamster buccal mucosa. Before the DMBA was used and after DMBA was used 6 weeks and 14 weeks respectively, the golden hamsters were sacrificed at 6 different time points (5 rats per time point) within 24 hour, including 4, 8, 12, 16, 20 and 24 hour after lights onset (HALO), and the normal buccal mucosa, precancerous lesions and cancer tissue were obtained, respectively. HE stained sections were prepared to observe the canceration of each tissue. Real time RT-PCR was used to detect the mRNA expression of Per1, p53, CyclinD1, CDK1 and CyclinB1, and a cosine analysis method was applied to determine the circadian rhythm variation of Per1, p53, CyclinD1, CDK1 and CyclinB1 mRNA expression, which were characterized by median, amplitude and acrophase.	The expression of Per1, p53, CDK1 and CyclinD1 mRNA in 6 different time points within 24 hours in the tissues of three different stages of carcinogenesis had circadian rhythm, respectively. However, the CyclinB1 mRNA was expressed with circadian rhythm just in normal and cancer tissue (P < 0.05), while in precancerous lesions the circadian rhythm was in disorder (P > 0.05). As the development of carcinoma, the median of Per1 and p53 mRNA expression were significantly decreased (P < 0.05), yet the median of CDK1, CyclinB1 and CyclinD1 mRNA expression were significantly increased (P < 0.05). The amplitude of Per1, p53 and CyclinD1 mRNA expression was significantly decreased as the development of carcinoma (P < 0.05), however the amplitude of CDK1 mRNA expression was significantly increased (P < 0.05). In addition, there was no significant difference in the amplitude of CyclinB1 mRNA expression. The time that the peak expression value of Per1 and CDK1 mRNA appeared (Acrophase) in precancerous lesions was remarkably earlier than that in normal tissues, but the acrophase of p53 and CyclinD1 mRNA expression was remarkably delayed. Moreover, the acrophase of CDK1 and CyclinB1 mRNA expression in cancer tissues was obviously earlier than that in normal tissues, yet there was no significant variation in acrophase of Per1, p53, CyclinD1 mRNA expression between normal tissues and cancer tissues.	The circadian rhythm of clock gene Per1 and cell cycle genes p53, CyclinD1, CDK1, CyclinB1 expression remarkably varied with the occurrence and development of carcinoma. Further research into the interaction between circadian and cell cycle of two cycle activity and relationship with the carcinogenesis may providenew ideas and methods of individual treatment and the mechanism of carcinogenesis.	
26564677	Air traffic controllers (ATC) work shifts and their work schedules vary according to the characteristics of each airport. The human body adapts to shiftwork differently. These adjustments affect the health-disease process, predisposing ATC to risk conditions associated with sleep deprivation and lack of night sleep, which can lead to conditions such as cardiovascular diseases, mood disorders, anxiety, and obesity. This study investigated the characteristics of health, sleep, and quality of life of ATC exposed to 8-h alternate work shifts and 6-h rotational work shifts.The study was cross-sectional with convenience samples consisting of 84 ATC from two international airports in Brazil. We applied questionnaires to collect data about socioeconomic conditions, quality of life, sleep, and physical activity levels. We also collected health data regarding nutritional status, body composition, and blood pressure. We analyzed the differences between ATC from the two airports considering the variables of sleep, quality of life, and health.	Differences were found between the groups in terms of body fat percentage (30.7% and 27.8%), scores of overall quality of life (56.2 and 68), concentration (3.37 and 3.96), energy (3.12 and 3.62), and sleep time on working days (5:20 h and 6:15 h).	ATC under 8-h alternate shifts showed lower scores for quality of life, higher body fat, and less sleep time on working days, which characterizes inadequate shiftwork for this population.	
26564225	This study was designed to investigate the association of circadian gene single nucleotide polymorphisms (SNPs) with the risk of osteoporosis. We found that the rs3781638 GG genotype was positively associated with osteoporosis prevalence in females, whereas the rs2292910 AC genotype was negatively associated with osteoporosis prevalence in a geriatric cohort.Studies have shown that disruption of endogenous circadian rhythms may increase the risk of developing type II diabetes and obesity, which are reportedly associated with osteoporosis (OP). Thus, abnormalities of circadian genes may indirectly induce OP. Here, we investigated the association of OP with 14 SNPs located in seven circadian genes.	The research subjects, geriatric residents of Shanghai Minhang, China, diagnosed with OP (N = 171) or osteopenia (N = 226) or without specific diseases (N = 200), were genotyped for 14 genetic variants of circadian genes by competitive allele-specific polymerase chain reaction. The prevalence of polymorphisms among the subject groups and the association between the SNPs and osteoporosis were investigated.	Among the 14 genotyped SNPs, we found an association between the CRY2 gene rs2292910 SNP and osteoporosis (r = -0.082, p = 0.045) in the geriatric cohort. We found a decreased risk between cryptochrome 2 rs2292910 and OP (A/C odds ratio = 0.647, p = 0.044) but an increased risk between MTNR1B rs3781638 and OP (G/G odds ratio = 2.058, p = 0.044).	For the first time, we show that Cry 2 rs2292910 and MTNR1B rs3781638 are associated with osteoporosis in a Chinese geriatric cohort. Therefore, targeting the abnormalities of the CRY2 and MTNR1B genes may be a potential strategy to treat and/or to prevent osteoporosis.	
26564192	This study successfully applied an improved valvometry technique to measure waterborne copper (Cu), based on valve activity dynamics of the freshwater clam Corbicula fluminea. The improved valvometry technique allows the use of free-range bivalves and avoids causing stresses from experimental artifacts. The proposed daily valve rhythm models and a toxicodynamics-based Hill model were linked to predict valve dynamic responses under different Cu exposures with a circadian valve rhythm endpoint. Cu-specific detection threshold was 5.6 (95 % CI 2.1-9.3) and 19.5 (14.6-24.3) μg L(-1) for C. fluminea, based on response times of 300 and 30 min, respectively. Upon exposure to Cu concentrations in excess of 50 μg L(-1), the alteration of valve rhythm behavior was correlated with Cu concentration within 30 min, indicating notable sensing ability. This study outlines the feasibility of an in situ early warning dynamic biomonitoring system for detection of waterborne Cu based on circadian valve activities of C. fluminea.
26564180	As one of the key adipokines, retinol binding protein 4 (RBP4) is suggested to positively correlate with insulin resistance; however, not all clinical studies support this association. Although some explanations are proposed for this discrepancy, the temporal aspect of RBP4 secretion has not been considered. Aryl hydrocarbon receptor nuclear translocator-like (also known as BMAL1) and its target D site-binding protein (DBP) are both pivotal transcription factors of the circadian core clock. Given the overwhelming presence of circadian control in metabolism and the principal role of the liver in RBP4 secretion, we hypothesised that RBP4 may oscillate under the control of BMAL1 and act as a hepatokine, participating in the maintenance of glucose homeostasis by the circadian clock.We used liver-specific Bmal1 (also known as Arntl)-knockout mice and recombinant adenoviruses expressing short-hairpin RNA (shRNA) specific for Dbp or Rbp4 in the liver.	RBP4 displayed diurnal oscillations in the liver and plasma, which were dampened in liver-specific-Bmal1-knockout mice. BMAL1 regulated hepatic RBP4 expression via its direct target, DBP. Hepatic knockdown of RBP4 or DBP increased whole-body insulin sensitivity in mice in a time-of-day-dependent manner. Conversely, hepatic overexpression of RBP4 reversed the insulin-sensitising effects of liver-specific depletion of BMAL1.	Our results not only provide a novel mechanism for circadian regulation of RBP4, but also unveil a critical role of RBP4, acting as a hepatokine in the regulation of glucose metabolism by the circadian clock.	

26564131	A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.
26564125	Investigate whether retirement transitions are associated with changes in sleep duration and sleep timing, and whether these associations are modified by age, sex, mental health, or circadian preference.The Retirement and Sleep Trajectories (REST) study is a longitudinal study consisting of four annual mailed surveys that collected information about employment, sleep, and health. Differences in reported sleep duration, bedtime and wake time between successive surveys were calculated to estimate change over 1, 2, and 3 y. Linear regression models were used to estimate changes in these sleep parameters associated with retirement 1, 2, and 3 y posttransition.	Retiring from full-time work was associated with bedtimes that were 30, 31, and 36 min later 1, 2, and 3 y postretirement; wake times that were 63, 69, and 78 min later; and sleep durations that were 15, 16, and 22 min longer 1, 2, and 3 y postretirement. These associations did not differ by sex or mental health status. Age and circadian preference modified the associations between retirement and change in sleep parameters; the increase in sleep duration was shorter and the wake time extension was lesser with advancing retirement age; those with evening preference had longer wake time extensions than those with morning preference.	Transitioning to retirement is associated with longer sleep duration, later bedtimes, and later wake times. These changes were detectable about 1 y postwork transition and were persistent up to 3 y later.	
26564124	The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep.EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline.	Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1-4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain.	Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context.	
26563993	Climate variability is changing on multiple temporal scales, and little is known of the consequences of increases in short-term variability, particularly in endotherms. Using mortality data with high temporal resolution of zebra finches living in large outdoor aviaries (5 years, 359.220 bird-days), we show that mortality rate increases almost two-fold per 1°C increase in diurnal temperature range (DTR). Interestingly, the DTR effect differed between two groups with low versus high experimentally manipulated foraging costs, reflecting a typical laboratory 'easy' foraging environment and a 'hard' semi-natural environment respectively. DTR increased mortality on days with low minimum temperature in the easy foraging environment, but on days with high minimum temperature in the semi-natural environment. Thus, in a natural environment DTR effects will become increasingly important in a warming world, something not detectable in an 'easy' laboratory environment. These effects were particularly apparent at young ages. Critical time window analyses showed that the effect of DTR on mortality is delayed up to three months, while effects of minimum temperature occurred within a week. These results show that daily temperature variability can substantially impact the population viability of endothermic species. 
26563991	The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.
26563802	Sleep deprivation due to shift work is related to perturbation of the sleep/wake cycle, associated with the modified activity/rest pattern. This may cause a significant disruption of circadian rhythms of biologic functions, driven by the body clock located in the suprachiasmatic nuclei of the hypothalamus. Shift and night workers have to change sleep times and strategies according to their duty periods; consequently, both sleep length and quality can be considerably affected depending on the variable start and finish times on different shifts. About 10% of night and rotating shift workers, aged between 18 and 65 years, have been estimated to have a diagnosable "shift-work sleep disorder," according to the International Classification of Sleep Disorders, version 2 (ICSD-2). In the long run, this may lead to persistent and severe disturbances of sleep, chronic fatigue and psychoneurotic syndromes, besides being a risk or aggravating factor for accidents, gastrointestinal, cardiovascular, and reproductive disorders, as well as, probably, for cancer. Preventive and corrective actions deal with the organization of shift schedules according to ergonomic criteria, careful health surveillance, appropriate education and training on effective countermeasures, in particular, sleep hygiene and napping. 
26563739	There is some evidence that short interstimulus intervals (ISIs) on the Psychomotor Vigilance Test (PVT) are associated with longer and more varied reaction times (RTs). Preparation processes may impede RT following short ISIs, resulting in additional unexplained variance. The aims of this study were to investigate whether there is an effect of ISI on RT and errors within the PVT, and whether such an effect changes with three elements of fatigue: time of day, prior wake and time on task. Twelve male participants completed 49 PVTs across 7× 28h periods of forced desynchrony. For analysis, RTs, reciprocal reaction times (1/RT), false starts and lapse responses within each 10min session were assigned to a 1-s ISI group, a 2-min time of task group, a 2.5-h PW level and a 60° phase of the circadian rhythm of core body temperature (as a measure of time of day). Responses following short ISIs (2-5s) were significantly slower and more varied than responses following longer ISIs (5-10s). The likelihood of a lapse was also higher for short ISIs, while the probability of a false start increased as a function of ISI. These effects were independent of the influences of time of day, prior wake and time on task. Hence, mixed model ANOVAs comprising only long ISIs (5-10s) contained stronger effect sizes for fatigue than a model of all ISIs (2-10s). Including an ISI variable in a model improved the model fit and explained more variance associated with fatigue. Short ISIs resulted in long RTs both in the presence and absence of fatigue, possibly due to preparation processes or ISI conditioning. Hence, omitting short ISI trials from RT means or including an ISI variable in analysis can reduce unwanted variance in PVT data, improving the sensitivity of the PVT to fatigue.
26563660	To evaluate intraocular pressure (IOP) fluctuation during office hours and its predictive factors in untreated primary angle-closure suspects (PACS); post-iridotomy primary angle closure (PAC) and primary angle-closure glaucoma (PACG) eyes with or without IOP-lowering medication(s) as appropriate and medically treated primary open-angle glaucoma (POAG) eyes.One-hundred seventeen eyes (29 PACS, 30 PAC, 28 PACG, and 30 POAG) of 117 patients were included in this cross-sectional study. The subjects underwent hourly IOP measurements with Goldmann tonometer from 0800 to 1700 hours. Subjects with PAC and PACG had laser peripheral iridotomy at least 2 weeks prior to the inclusion. SD of office-hour IOP readings was the main outcome measure.	IOP fluctuation differed between the groups (P=0.01; Kruskal-Wallis Test). Post hoc Mann-Whitney U-tests showed significantly less IOP fluctuation in PACS compared with PACG (P<0.01). Peak office-hour IOP was observed in the morning in untreated subjects and in the early afternoon in treated subjects. A stepwise linear regression model identified the presence of peripheral anterior synechiae (PAS), thickness of lens, large vertical cup-to-disc ratio (VCDR), and PAC category as significant predictive factors associated with office-hour IOP fluctuation.	Diurnal IOP fluctuation in asymptomatic PACSs was less than that in treated PACG subjects and was at least comparable to that in treated PAC and POAG subjects. The greater the amount of PAS, the thicker the lens, the larger the VCDR, the greater was the IOP fluctuation during office hours.	
26562472	A continuation of the gradual weight gain necessary for the onset of puberty may be responsible for obesity later in life. Hypothetically, a group of brain nuclei form components of a single pubertal clock mechanism that drives pre-pubertal weight gain and governs the onset of puberty and fertility. No mechanism evolved to shut off pre-pubertal and pubertal weight and body fat gain after puberty. The weight gain continues unabated throughout life. A better understanding of the mechanism of puberty and pre-pubertal weight gain could provide new insights into obesity and diseases associated with obesity such as type 2 diabetes, dyslipidemia, hypertension, heart disease, depression, etc. 
26562417	Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation.Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR.	Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes.	Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing.	
26560973	Hormone signalling during critical periods organises the adult circadian timekeeping system by altering adult hormone sensitivity and shaping fundamental properties of circadian rhythmicity. However, the timing of when developmental oestrogens modify the timekeeping system is poorly understood. To test the hypothesis that alterations in postnatal oestrogenic signalling organise adult daily activity rhythms, we utilised aromatase knockout mice (ArKO), which lack the enzyme required for oestradiol synthesis. ArKO and wild-type (WT) males and females were administered either oestradiol (E) or oil (OIL) daily for the first 5 postnatal days (p1-5E and p1-5OIL , respectively) because this time encompasses the emergence of clock gene rhythmicity and light responsiveness in the suprachiasmatic nucleus, a bilateral hypothalamic structure regarded as the 'master oscillator'. After sexual maturation, gonadectomy and exogenous oestradiol supplementation, locomotor parameters were assessed. We determined that altered oestrogenic signalling in early life exerts organisational control over the expression of daily and circadian activity rhythms in adult mice. Specifically, p1-5E reduced total wheel running activity in male and female ArKO and female WT mice but had no effect on WT male activity levels. In females, wheel running was consolidated by p1-5E to the early versus late evening, a phenomenon characteristic of male mice. The time of peak activity was advanced by p1-5E in WT and ArKO females but not males. P1-5E shortened the length of the active phase (alpha) in WT males but had no effect on ArKO males or females of either genotypes. Finally, p1-5E altered the magnitude of photic-induced shifts, suggesting that developmental oestrogenic signalling impacts adult circadian functions. In the present study, we further define both a critical period of development of the adult timekeeping system and the role that oestrogenic signalling plays in the expression of daily and circadian activity rhythms throughout life. 
26560521	Aging of the world population is a major contributor to the growing prevalence of the metabolic syndrome, as older persons are frequently affected by the constellation of cardiovascular and metabolic risk factors that constitute the syndrome. The metabolic syndrome has been related to the increasing prevalence of obesity, which is escalating even among older age groups. The present review covers data on the novel proposed biological mediators of the metabolic syndrome, which are as well linked to the aging process.Relevant biological mediators of metabolic syndrome and unhealthy aging include sarcopenic obesity, insulin resistance with ectopic fat accumulation, magnesium metabolism alterations, systemic and hypothalamic inflammation, shortening of telomeres length, epigenetics, and circadian rhythm disturbances.	Metabolic syndrome is related to increased accumulation of central adiposity and ectopic fat infiltration in the skeletal muscle and the liver, linked to overeating and sedentarism with deleterious consequences in late life. Obesity may be complicated with sarcopenia, which refers to loss of muscle mass, strength, and quality in older populations. Prevention of obesity and metabolic syndrome is a priority through the promotion of healthier lifestyles and policies for sugar and saturated fats, which might be widely implemented.	


26559889	Pelagic longliners targeting swordfish and tunas in oceanic waters regularly capture sharks as bycatch, including currently protected species as the bigeye thresher, Alopias superciliosus. Fifteen bigeye threshers were tagged with pop-up satellite archival tags (PSATs) in 2012-2014 in the tropical northeast Atlantic, with successful transmissions received from 12 tags for a total of 907 tracking days. Marked diel vertical movements were recorded on all specimens, with most of the daytime spent in deeper colder water (mean depth = 353 m, SD = 73; mean temperature = 10.7 °C, SD = 1.8) and nighttime spent in warmer water closer to the surface (mean depth = 72 m, SD = 54; mean temperature = 21.9 °C, SD = 3.7). The operating depth of the pelagic longline gear was measured with Minilog Temperature and Depth Recorders (TDRs), and the overlap with habitat utilization was calculated. Overlap is taking place mainly during the night and is higher for juveniles. The results presented herein can be used as inputs for Ecological Risk Assessments for bigeye threshers captured in oceanic tuna fisheries, and serve as a basis for efficient management and conservation of this vulnerable shark species. 
26559496	A physician's fatigue raises significant concerns regarding personal and patient safety. Effects of sleep deprivation on clinical performance and the quality of patient care are major considerations of today's health care environment.To evaluate the impact of partial sleep deprivation after a 17-h overnight call (3 pm-7 am) on the mood status and cognitive skills of anesthesiologists in an academic clinical hospital setting, as compared to these parameters during regular working hours.	Taking circadian rhythm into account, the following measures were assessed in 21 pediatric anesthesiologists at two time points over the course of the study; (i) between 7 and 8 am on a regular non call day, and (ii) between 7 and 8 am after a 17-h in-house call (3 pm-7 am). Six mood states were assessed using the Profile of Mood States. A Total Mood Disturbance (TMD) score was obtained as the sum of all mood scores minus vigor. The total score provides a global estimate of affective state. Simple cognitive tests were similarly administered to assess cognitive skills. A two-tailed paired t-test was used to compare data between regular and post call days. A P < 0.05 was used.	The study cohort included 21 pediatric anesthesiologists at a tertiary care children's hospital. Tension, anger, fatigue, confusion, TMD, irritability, feeling jittery, and sleepiness were significantly affected (P < 0.05). A decrease in vigor, energy, and confidence was observed after a night call shift (P < 0.05). There was also a decrease in being "talkative" after the call shift (P < 0.05).	Partial sleep deprivation affects the total mood status of anesthesiologists and impacts their cognitive skills. These findings are particularly relevant in a context of increased work expectation, particularly on clinical performance in our modern medical system. Such observations suggest that there may be changes that impact the safety of our patients and the quality of health care that is provided.	
26559218	The Département de psychiatrie de l'Université de Montréal houses one of the first sleep centers founded 40 years ago. This center contributed to virtually every aspect of sleep medicine. It grew considerably over time to become one of the largest sleep centers worldwide. It is now called the Center for Advanced Research in Sleep Medicine (CARSM). Fourteen researchers and more than 30 research PhDs and postdoctoral fellows are working together in a 1,500 square-meter facility that includes separate units for fundamental and clinical studies and for the sleep disorders clinic. It has 10 polysomnographic recording rooms, 3 isolated units devoted to chronobiological studies, a high resolution SPECT imaging laboratory specifically devoted to sleep research, a high-density EEG unit and a psychophysiological laboratory to study the interaction between pain and sleep. This article relates the history of the CARSM and also presents a personal sleep odyssey.The CARSM has been very active in the description of clinical features and definitions of the phenotype of most sleep disorders. It contributed specifically to the development of diagnostic tools in narcolepsy (the multiple sleep latency test in different age groups), in nocturnal epilepsy (development of a method to localize the primary focus using in-depth electrodes recording during rapid eye movement sleep), in sleep bruxism (a method for scoring masticatory muscle activity during sleep and definition of cut-off values), in the restless legs syndrome (RLS: the suggested immobilisation test), in sleepwalking (sleep deprivation and experimental awakenings) and REM sleep behaviour disorder (RBD: development of the first polygraphic method to diagnose RBD).The CARSM also contributed to the knowledge on the epidemiology of sleep disorders, conducting the first population-based prevalence study of RLS and of sleep bruxism. Researchers at the CARMS also looked at the impact of sleep disorders like narcolepsy, RLS, sleep apnea and the parasomnias on daytime cognitive functions and cardiovascular health. The CARSM collaborates with researchers throughout the world to elucidate the genetic bases of several disorders, especially narcolepsy, RLS, RBD and parasomnias in children and adults, through large well-defined cohorts of patients and normal subjects.Finally, the CARSM has made original contributions to the development of new treatments of sleep disorders, especially the dopaminergic treatments of RLS (first with levodopa and then with pramipexole). Current research also involves the identification of prodromal markers of Parkinson disease and dementia in patients with RBD as to build a ready-to trial cohort to test the efficacy of neuroprotective agents.In summary, the CARSM is a center dedicated to basic and clinical research on sleep and circadian rhythms. It is located at the Hôpital du Sacré-Coeur de Montréal but involves several other researchers at the Université de Montréal and at other universities in Canada and in the world. 
26558932	Everything in nature and life is occurring in a rhythmic manner. The major “Zeitgeber” is the change of light and dark during a 24 h day. This circadian rhythm is besides others reflected in circadian rhythms of behaviors or different biochemical parameters. A disruption of the circadian rhythm has a high pathophysiological potential. In this article a few basic issues about the role of circadian rhythms and the pathophysiological importance of desynchronisation are reviewed.
26558819	High nighttime and early morning blood pressure (BP) have been associated with greater risk for cardiovascular events than high clinic or daytime BP. BP is typically highest in the rising hours, when morning activities typically begin. We examined the effect of renal denervation on morning (6:00-8:59 AM), daytime (9:00 AM-8:59 PM), and nighttime (1:00-5:59 AM) ambulatory BP. Patient data from 2 prospective, randomized controlled trials of patients with treatment-resistant, uncontrolled hypertension, one conducted in a US population (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]) and the other in a Japanese population (SYMPLICITY HTN-Japan [HTN-Japan]), were analyzed. Patients in SYMPLICITY HTN-3 and HTN-Japan were prescribed a similar number of baseline antihypertensive medications (5.2±1.4 versus 4.9±1.6, P=0.28), but the classes prescribed and changes in prescription varied by study. Among patients treated with renal denervation, although the number of ablation treatments were similar in both studies (11.2±2.8 versus 11.5±1.9, P=0.55), patients in SYMPLICITY HTN-3 were less likely to receive at least 1 four-quadrant ablation treatment (25% versus 82%, P<0.001). In SYMPLICITY HTN-3, compared with controls (n=159), patients treated with renal denervation (n=325) experienced a significantly greater change in morning (-7.3±19.8 mm Hg, P<0.001) and nighttime (-6.1±18.2 versus -1.6±19.7 mm Hg, P=0.02) but not daytime systolic BP (-7.2±16.2 versus -6.4±18.6 mm Hg, P=0.67). This same trend was observed in the pooled analysis with HTN-Japan. Reduction of BP during these high-risk periods might provide cardiovascular protection in drug-resistant hypertensive patients, although this will need to be proved in future randomized trials.
26558771	The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson's disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (∼70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. l-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson's disease and related disorders.Dopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson's disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson's disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to l-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson's disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson's disease and potentially other basal-ganglia-related disorders.	
26558769	Melatonin supplementation has been used as a therapeutic agent for several diseases, yet little is known about the underlying mechanisms by which melatonin synchronizes circadian rhythms. G-protein signaling plays a large role in melatonin-induced phase shifts of locomotor behavior and melatonin receptors activate G-protein-coupled inwardly rectifying potassium (GIRK) channels in Xenopus oocytes. The present study tested the hypothesis that melatonin influences circadian phase and electrical activity within the central clock in the suprachiasmatic nucleus (SCN) through GIRK channel activation. Unlike wild-type littermates, GIRK2 knock-out (KO) mice failed to phase advance wheel-running behavior in response to 3 d subcutaneous injections of melatonin in the late day. Moreover, in vitro phase resetting of the SCN circadian clock by melatonin was blocked by coadministration of a GIRK channel antagonist tertiapin-q (TPQ). Loose-patch electrophysiological recordings of SCN neurons revealed a significant reduction in the average action potential rate in response to melatonin. This effect was lost in SCN slices treated with TPQ and SCN slices from GIRK2 KO mice. The melatonin-induced suppression of firing rate corresponded with an increased inward current that was blocked by TPQ. Finally, application of ramelteon, a potent melatonin receptor agonist, significantly decreased firing rate and increased inward current within SCN neurons in a GIRK-dependent manner. These results are the first to show that GIRK channels are necessary for the effects of melatonin and ramelteon within the SCN. This study suggests that GIRK channels may be an alternative therapeutic target for diseases with evidence of circadian disruption, including aberrant melatonin signaling.Despite the widespread use of melatonin supplementation for the treatment of sleep disruption and other neurological diseases such as epilepsy and depression, no studies have elucidated the molecular mechanisms linking melatonin-induced changes in neuronal activity to its therapeutic effects. Here, we used behavioral and electrophysiological techniques to address this scientific gap. Our results show that melatonin and ramelteon, a potent and clinically relevant melatonin receptor agonist, significantly affect the neurophysiological function of suprachiasmatic nucleus neurons through activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Given the importance of GIRK channels for neuronal excitability (with >600 publications on these channels to date), our study should generate broad interest from neuroscientists in fields such as epilepsy, addiction, and cognition.	
26556345	In Arabidopsis, CONSTITUTIVE PHOTOMORPHOGENIC/DE-ETIOLATED/FUSCA (COP/DET/FUS) genes act in repression of photomorphogenesis in darkness, and recent reports revealed that some of these genes, such as COP1 and DET1, also have important roles in controlling flowering time and circadian rhythm. The COP/DET/FUS protein COP10 interacts with DET1 and DNA DAMAGE-BINDING PROTEIN 1 (DDB1) to form a CDD complex and represses photomorphogenesis in darkness. The cop10-4 mutants flower normally in inductive long days (LD) but early in non-inductive short days (SD) compared with wild type (WT); however, the role of COP10 remains unknown. Here, we investigate the role of COP10 in SD-dependent floral repression. Reverse transcription-quantitative PCR revealed that in SD, expression of the LD-dependent floral inducers GI, FKF1, and FT significantly increased in cop10-4 mutants, compared with WT. This suggests that COP10 mainly regulates FT expression in a CO-independent manner. We also show that COP10 interacts with GI in vitro and in vivo, suggesting that COP10 could also affect GI function at the posttranslational level. Moreover, FLC expression was repressed drastically in cop10-4 mutants and COP10 interacts with MULTICOPY SUPPRESSOR OF IRA1 4 (MSI4)/FVE (MSI4/FVE), which epigenetically inhibits FLC expression. These data suggest that COP10 contributes to delaying flowering in the photoperiod and autonomous pathways by downregulating FT expression under SD. 
26555051	Light regulates major plant developmental transitions by orchestrating a series of nuclear events. This study uncovers the molecular function of the natural variant, TZP (Tandem Zinc-finger-Plus3), as a signal integrator of light and photoperiodic pathways in transcriptional nuclear foci. We report that TZP acts as a positive regulator of photoperiodic flowering via physical interactions with the red-light receptor phytochrome B (phyB). We demonstrate that TZP localizes in dynamic nuclear domains regulated by light quality and photoperiod. This study shows that phyB is indispensable not only for localizing TZP to transcriptionally active nuclear photobodies, but also for recruiting TZP on the promoter of the floral inducer FLOWERING LOCUS T (FT). Our findings signify a unique transcriptional regulatory role to the highly enigmatic plant nuclear photobodies, where TZP directly activates FT gene expression and promotes flowering. 
26554819	Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyltransferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor-mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5-deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide-binding protein-coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins. 
26554795	In current health examination setting, people frequently undergo heart rate variability (HRV) analysis and colonoscopy on the same day. However, it remains unclear whether the bowel preparation before colonoscopy affects HRV. This study aimed to evaluate the association between HRV and bowel preparation.We conducted a cross-sectional observational study of 1755 people from January 2012 to December 2013 in Taipei, Taiwan. The participants, aged 45 to 65 years, received health examinations that included a physical examination, blood tests, and an HRV analysis. Among these people, 1099 additionally received a colonoscopy on the same day and underwent bowel preparation 1 day before the colonoscopy. The association between HRV and bowel preparation was derived by a multivariable linear regression with adjusted confounding factors.Bowel preparation was associated with a lower standard deviation of the normal-to-normal intervals (SDNN), the root mean square of the successive differences (RMSSD), low-frequency power (LF), and high-frequency power (HF) (all P < 0.0001). After adjusting confounding factors, bowel preparation remained correlated with lower SDNN, RMSSD, LF, and HF (all P < 0.0001). Higher serum phosphorus and lower serum potassium levels were noted in the bowel preparation group (P < 0.0001), and an association between lower HRV and higher serum phosphorus and lower serum potassium levels was only noted in the bowel preparation group.Bowel preparation was significantly associated with lower HRV. The underlying mechanism may be related to an electrolyte imbalance. Cautions may be needed when interpreting HRV reports for people receiving bowel preparations before colonoscopy. 
26554521	This study investigates whether the intestinal toxicity of the immunosuppressive agent "mycophenolate mofetil (MMF)" varied according to the circadian dosing-time in rats. MMF (300 mg/kg) was acutely administered by i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). The results obtained showed that MMF-induced intestinal toxicity depends on circadian dosing-time in rats. A severe toxicity in the duodenum and jejunum was observed when the drug was administered at 7 HALO compared to controls and to other circadian times. This toxicity appeared in the form of villous and Liberkhun gland atrophy and nodular inflammation. At this dosing-time, MMF induced a significant increase of phosphatase alkaline activity and a significant decrease of gut mucosa weight, protein content and disaccharidases activities. Conversely, MMF dosing at 19 HALO induced lower gut toxicity, irrespective of type of toxicity explored. These data suggest the existence of a circadian rhythm of gut toxicity for this immunosuppressive agent and the best time of gastrointestinal tolerance (chronotolerance) of this agent was observed in the middle of the dark-activity span of rats. 
26554301	Light intensity, spectrum and pattern may affect laying hen behaviors and production performance. However, requirements of these lighting parameters from the hens' standpoint are not fully understood. This study was conducted to investigate hens' needs for light intensity and circadian rhythm using a light tunnel with five identical compartments each at a different fluorescent light intensity of <1, 5, 15, 30 or 100 lux. The hens were able to move freely among the respective compartments. A group of four W-36 laying hens (23 to 30 weeks of age) were tested each time, and six groups or replicates were conducted. Behaviors of the hens were continuously recorded, yielding data on daily time spent, daily feed intake, daily feeding time, and eggs laid under each light intensity and daily inter-compartment movement. The results show that the hens generally spent more time in lower light intensities. Specifically, the hens spent 6.4 h (45.4%) at 5 lux, 3.0 h (22.1%) at 15 lux, 3.1 h (22.2%) at 30 lux and 1.5 h (10.3%) at 100 lux under light condition; and an accumulation of 10.0 h in darkness (<1 lux) per day. The 10-h dark period was distributed intermittently throughout the day, averaging 25.0±0.4 min per hour. This hourly light-dark rhythm differs from the typical commercial practice of providing continuous dark period for certain part of the day (e.g. 8 h at night). Distributions of daily feed intake (87.3 g/hen) among the different light conditions mirrored the trend of time spent in the respective light intensity, that is, highest at 5 lux (28.4 g/hen, 32.5% daily total) and lowest at 100 lux (5.8 g/hen, 6.7%). Hen-day egg production rate was 96.0%. Most of the eggs were laid in <1 lux (61.9% of total) which was significantly higher than under other light intensities (P<0.05). Findings from this study offer insights into preference of fluorescent light intensity by the laying hens. Further studies to assess or verify welfare and performance responses of the hens to the preferred lighting conditions and rhythm over extended periods are recommended. 
26554135	Purpose of the work was to test the concept about existence of a heliobiological relation in the Earth's middle-latitude region for which to analyze, as an example, frequency of circulatory disease exacerbation, mental and behavior disorders, and respiratory diseases (bronchial asthma). The subject and object of the experimental statistic survey have been dwellers of city of Murom (Vladimir region) located in middle-latitude geomagnetic region Φ ≈ 53 degrees. The source material in the investigation was medical data of the Murom ambulance service and geophysical data of the Borok geomagnetic observatory (Yaroslavl region). The survey went on 3 years from February, 1985 till December, 1987 and coincided with the rise of the 11th solar cycle. The largest number of calls to the ambulance service due to acute circulatory condition, mental or behavior disorders, respiratory diseases (bronchial asthma particularly) and their fatal outcome fell on periods of long absence of high-frequency geomagnetic pulsation within the frequency range of human biorhythms.

26554015	Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation. 
26553998	In large regions of the open ocean, iron is a limiting resource for phytoplankton. The reduction of iron quota and the recycling of internal iron pools are among the diverse strategies that phytoplankton have evolved to allow them to grow under chronically low ambient iron levels. Phytoplankton species also have evolved strategies to cope with sporadic iron supply such as long-term storage of iron in ferritin. In the picophytoplanktonic species Ostreococcus we report evidence from observations both in the field and in laboratory cultures that ferritin and the main iron-binding proteins involved in photosynthesis and nitrate assimilation pathways show opposite diurnal expression patterns, with ferritin being maximally expressed during the night. Biochemical and physiological experiments using a ferritin knock-out line subsequently revealed that this protein plays a central role in the diel regulation of iron uptake and recycling and that this regulation of iron homeostasis is essential for cell survival under iron limitation. 
26553914	Many hormones, including stress hormones, are intermittently secreted as pulses. The pulsatile location process, describing times when pulses occur, is a regulator of the entire stress system. Characterizing the pulse location process is particularly difficult because the pulse locations are latent; only hormone concentration at sampled times is observed. In addition, for stress hormones the process may change both over the day and relative to common external stimuli. This potentially results in clustering in pulse locations across subjects. Current approaches to characterizing the pulse location process do not capture subject-to-subject clustering in locations. Here we show how a Bayesian Cox cluster process may be adapted as a model of the pulse location process. We show that this novel model of pulse locations is capable of detecting circadian rhythms in pulse locations, clustering of pulse locations between subjects, and identifying exogenous controllers of pulse events. We integrate our pulse location process into a model of hormone concentration, the observed data. A spatial birth-and-death Markov chain Monte Carlo algorithm is used for estimation. We exhibit the strengths of this model on simulated data and adrenocorticotropic and cortisol data collected to study the stress axis in depressed and non-depressed women. 
26553726	The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca(2+)]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca(2+)]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca(2+)]i-activated channel is one of the targets. 
26553482	The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM(®) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p < 0.001; ΔOFV = -204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p < 0.001, ΔOFV = -15.6, and p < 0.001, ΔOFV = -47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall. 
26552565	Juvenile myoclonic epilepsy (JME) is a heterogeneous syndrome with seizures presenting typical fluctuation in diurnal cycle and relation with awakening. Few publications have approached clinical expressions of praxis induction (PI) in the nosology of JME as well as its impact on outcome. The aim of this study is to characterize PI as the only reflex trait in JME and its relation with prognosis.JME with PI reported on a questionnaire and confirmed by video-EEG testing (Group 1, 20 patients) were compared with JME without any reflex epileptic trait (Group 2, 25 patients) and followed for a mean of 7.82 years (SD=3.98). Circadian distribution and frequency of seizures were assessed in a diary. Patients also had psychiatric evaluation.	Prevalence of PI was 20/133 (15%) JME patients, and was predominant in males (1.5 male: 1 female; OR 13; p=0.042). Among Group 1 patients, only 2/20 presented seizures exclusively in the morning (p=0.013), and none, exclusively on awakening (p<0.001). PI patients had worse prognosis regarding control of myocloni (p=0.02) and absences (p=0.01); only 7/20 (35.0%) could be treated with VPA in monotherapy (p=0.01). At the last follow-up, 2/20 (10.0%) of Group 1 and 10 (40.0%) of Group 2 patients were free of all three seizure types (p=0.02). Even though relative risk of stress as a precipitant of seizures increased 3.82 times in Group 1, psychiatric comorbidities were not different between groups.	PI reflex trait in JME is related to seizures without preferential circadian occurrence and reduced response to antiepileptic drugs.	
26552502	The immediate effect within minutes to hours of personal exposure to ambient fine particulate matter (PM2.5) on cardiac autonomic function is limited, particularly at night. Our study aimed to assess the lagged association between personal exposure to PM2.5 and nocturnal heart rate variability. Repeated measures panel study among 21 community adults recruited from a local health clinic during the period of March 1, 2004, to August 31, 2004, in Boston, Massachusetts, in the United States. Ambulatory electrocardiogram and continuous monitoring of personal exposure to PM2.5 and were measured for up to 2 consecutive days. We calculated 5-minute time-specific average PM2.5 exposure for each participant. Mixed-effects models were fit for 5-minute SD of normal-to-normal intervals (SDNN) and 5-minute heart rate in relation to 5-minute PM2.5 exposure lagged in 5-minute intervals up to 4 hours. We found an 8.4% decrease in nocturnal SDNN (95% confidence interval [CI] -11.3% to -5.5%) and a 1.9% increase in nighttime heart rate (95% CI 1.1% to 2.7%) for an interquartile range increase in PM2.5 (13.6 μg/m(3)), after adjusting for confounders. Significant decreases in nocturnal SDNN associated with PM2.5 exposure occurred within 2.5 hours. The largest decrease in nocturnal SDNN of -12.8% (95% CI -16.4 to -9.1%) that was associated with PM2.5 exposure was found with a lag of 25 minutes. Rapid changes in nocturnal heart rate variability associated with personal PM2.5 exposure occurred within the previous 2.5 hours, with the largest effects at 25 minutes, suggesting immediate cardiac autonomic effects of fine particulate exposure.
26550081	Ventricular fibrillation (VF) in Brugada syndrome (BrS) is known to occur more frequently during nighttime and from spring to early summer. In this study, we investigated whether early repolarization syndrome (ERS) has the same seasonal, weekly, and circadian distribution of VF events as BrS using data from the "J-wave associated with prior cardiac event" (J-PREVENT) registry.The study included 90 consecutive patients with BrS and 31 patients with ERS during a mean follow-up of 49±37 months. Follow-up data from implantable cardioverter-defibrillators were evaluated in all cases.	In patients with ERS, the circadian distribution of VF episodes differed among the four 6-h periods, with a significant peak from midnight to 6:00 am (p<0.01) similar to that observed in BrS patients. However, VF occurred more frequently on weekends in patients with ERS, whereas on weekdays in patients with BrS (p<0.01). The months of peak VF occurrence also differed between the groups, with the frequency of VF episodes at peak between December and March in ERS patients and between March and June in BrS patients. In ERS patients, VF events had an inverse correlation with air temperature (r=-0.726, p<0.01).	ERS and BrS patients show similar nighttime increases in the occurrence of VF, but different seasonal and weekly distributions, suggesting a pathophysiological difference between the two syndromes.	
26549869	This study compared the impact of split and consolidated sleep/wake schedules on subjective sleepiness during the biological day and biological night. This was achieved using a between-group design involving two forced desynchrony protocols: consolidated sleep/wake and split sleep/wake. Both protocols included 7×28-h days with 9.33h in bed and 18.67h of wake each day. While the consolidated sleep/wake protocol had 1×9.33-h sleep opportunity and 1×18.67-h wake period each day, the split sleep/wake protocol had 2×4.67-h sleep opportunities and 2×9.33-h wake periods each day. For both protocols, subjective sleepiness was measured using the Karolinska Sleepiness Scale every 2.5h during wake. A total of 29 healthy adult males participated, with 13 in the consolidated sleep/wake group (mean age=22.5 yrs) and 16 in the split sleep/wake group (mean age=22.6 yrs). On average, subjective sleepiness during wake periods of the split condition was significantly higher than that during the first half of wake periods of the consolidated condition, but was similar to the level during the second half. These findings were observed for wake periods that occurred during both the biological day and biological night. Previous data have shown that cognitive impairment at night is lower for split schedules than consolidated schedules, but the current data indicate that feelings of sleepiness are greater for split schedules than consolidated schedules for at least half of the time awake. Thus, it should be explained to people operating split sleep/wake schedules that although they may perform well, they are likely to feel sleepy.
26549833	Even though shift work has been suspected to be a risk factor for cardiovascular disease, little research has been done to determine the logical underlying inflammation mechanisms. This study investigated the association between shift work and circulating total and differential leukocyte counts among Chinese steel workers.The subjects were 1,654 line workers in a steel plant, who responded to a cross-sectional survey with a questionnaire on basic attributes, life style, and sleep. All workers in the plant received a periodic health checkup. Total and differential leukocytes counts were also examined in the checkup.	Shift workers had higher rates of alcohol use, smoking, poor sleep, poor physical exercise, and obesity than daytime workers. In further analysis, we found that the peripheral total WBC, monocyte, neutrophil, and lymphocyte counts were also greater in shift workers than in daytime workers. When subjects were divided into quartiles according to total WBC, neutrophil, monocyte, and lymphocyte counts, increased leukocyte count was associated with shift work. Using stepwise linear regression analysis, smoking, obesity, and shift work were independently associated with total WBC, monocyte, neutrophil, and lymphocyte counts.	This study indicates that peripheral total and differential leukocyte counts are significantly higher in shift workers, which suggests that shift work may be a risk factor of cardiovascular disease. Applicable intervention strategies are needed for prevention of cardiovascular disease for shift workers.	
26549635	Children with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD. 
26549257	Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform, we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure.
26549253	Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration.
26549156	Morningness-eveningness (M-E) is typically considered to be a trait-like construct. However, M-E could plausibly shift in concert with changes in circadian or homeostatic processes. We examined M-E changes across three studies employing behavioral or pharmacological sleep treatments. Baseline and posttreatment M-E scores were strongly correlated across all three samples. M-E showed small but systematic changes toward morningness in sleep-disturbed military veterans receiving behavioral interventions. No systematic M-E changes were observed in the two pharmacological studies (sleep-disturbed military veterans and adults with primary insomnia, respectively). In the behavioral study, M-E changes correlated with changes in depression, positive affect, and sleep quality. M-E changes also correlated with changes in positive affect in the adult insomnia group. M-E appears to exhibit state-like aspects in addition to trait-like aspects. 
26549008	Sleep-wake and circadian rhythm disturbances are common in remitted bipolar disorder. These disturbances include difficulty initiating and maintaining sleep, daytime sleepiness, sleep irregularity, and a circadian tendency toward eveningness. To date, few studies have examined the impact of eveningness on impairments in remitted bipolar disorder. Ninety-eight adults diagnosed with bipolar disorder I, II, or not otherwise specified were evaluated. Hierarchical linear regression analyses showed that eveningness was associated with greater sleep-wake disturbances, more unhealthy dietary habits, worse quality of life, more impaired interpersonal relationships, and more dysfunctional sleep-related cognitions and behaviors, controlling for age, gender, and years of education. Targeted intervention on dysfunctional sleep-related cognitions and behaviors may reverse eveningness and improve functioning in bipolar disorder. 
26547141	Solar ultraviolet (UV) radiation varies with latitude, time of day, and season. Both spectral UV composition and ambient UV dose lead to different health outcomes at different latitudes. Finding the optimal time for sun exposure, whereby the positive effects of UV exposure (vitamin D) are facilitated and the negative effects (skin cancer, photoimmunosuppression) avoided are the most important consideration in modern skin cancer prevention programs.This paper focuses on the latitude dependency of UVB, UVA, vitamin D production, and skin cancer risk in Caucasians.	Biologically effective UVB (280-315 nm) and UVA (315-400 nm) doses were calculated using radiative transfer models with appropriate climatologic data for selected locations. Incidences of squamous cell carcinoma (SCC) and cutaneous melanoma (CM) were retrieved from cancer registries and published articles.	Annual doses of UVA radiation decrease much less with increasing latitude than annual doses of UVB. Incidences of CM also decrease less steeply with increasing latitude than incidences of SCC. As SCC is caused mainly by UVB, these observations support the assumption that UVA plays an important role in the development of CM. The variations in UVA (relevant to CM) and UVB (relevant to vitamin D production) over 1 day differ: the UVB : UVA ratio is maximal at noon.	The best way to obtain a given dose of vitamin D with minimal carcinogenic risk is through a non-burning exposure in the middle of the day, rather than in the afternoon or morning.	
26547053	Although age-related hypofunction of Leydig cells is well illustrated across species, its circadian nature has not been analyzed. Here we describe changes in circadian behavior in Leydig cells isolated from adult (3-month) and aged (18- and 24-month) rats. The results showed reduced circadian pattern of testosterone secretion in both groups of aged rats despite unchanged LH circadian secretion. Although arrhythmic, the expression of Insl3, another secretory product of Leydig cells, was decreased in both groups. Intracellular cAMP and most important steroidogenic genes (Star, Cyp11a1 and Cyp17a1), together with positive steroidogenic regulator (Nur77), showed preserved circadian rhythm in aging although rhythm robustness and expression level were attenuated in both aged groups. Aging compromised cholesterol mobilization and uptake by Leydig cells: the oscillatory transcription pattern of genes encoding HDL-receptor (Scarb1), hormone sensitive lipase (Lipe, enzyme that converts cholesterol esters from lipid droplets into free cholesterol) and protein responsible for forming the cholesterol esters (Soat2) were flattened in 24-month group. The majority of examined clock genes displayed circadian behavior in expression but only a few of them (Bmal1, Per1, Per2, Per3 and Rev-Erba) were reduced in 24-month-old group. Furthermore, aging reduced oscillatory expression pattern of Sirt1 and Nampt, genes encoding key enzymes that connect cellular metabolism and circadian network. Altogether circadian amplitude of Leydig cell's endocrine function decreased during aging. The results suggest that clock genes are more resistant to aging than genes involved in steroidogenesis supporting the hypothesis about peripheral clock involvement in rhythm maintenance during aging. 
26546785	Depressive disorders in older persons are associated with an altered functioning of the Hypothalamic-Pituitary-Adrenal (HPA)-axis. In adults, a lower cortisol awakening response is a predictor of a worse prognosis of depression, but to date longitudinal studies in older depressed persons are lacking. We hypothesised that a lower cortisol awakening response is also associated with poorer course of depression in later life.Data were derived from the Netherlands Study of Depression in Older Persons (NESDO). Participants with a 6-month Major Depressive Disorder (MDD), who provided 2-year follow-up data, were included (n=246). Logistic regression analyses were conducted to examine the association between diurnal cortisol levels and depressive status at 2-year follow-up.	Both lower (OR=3.54; 95% CI=1.59-7.89) and higher evening cortisol levels (OR=2.41; 95% CI=1.09-5.35) at baseline were associated with poorer prognosis of MDD. Low dexamethasone suppression was associated with poorer course (OR=2.37; 95% CI=1.09-5.16), but failed to reach significance after additional adjustment for severity and chronicity of MDD (OR=1.98; 95% CI=0.89-4.42). Cortisol awakening response was not significantly associated with course. Since smoking has a great impact on cortisol levels, we conducted post-hoc analyses including non-smokers only, indicating that lower evening cortisol levels (OR=2.83, 95% CI=1.31-6.13) predicted unfavourable course.	This first longitudinal study on cortisol and prognosis of depression in older persons demonstrates that in particular lower evening cortisol levels may predict poorer course in MDD. This finding may have clinical implications. Evening cortisol values may serve as a marker to identify persons at risk for an unfavourable course.	
26546267	We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N).We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The phenotype was detectable from six weeks on and was preserved after cross-fostering. RNA-seq data of liver provided evidence for higher biosynthesis and elongation of fatty acids (p = 0.00635) in obese male offspring of a BFMI mother versus lean offspring of a BFMI father. Furthermore, fatty acid degradation (p = 0.00198) and the peroxisome pathway were impaired (p = 0.00094). The circadian rhythm was affected as well (p = 0.00087). Among the highest up-regulated protein coding genes in obese males were Acot4 (1.82 fold, p = 0.022), Cyp4a10 (1.35 fold, p = 0.026) and Cyp4a14 (1.32 fold, p = 0.012), which hydroxylize fatty acids and which are known to be increased in liver steatosis. Obese males showed lower expression of the genetically imprinted and paternally expressed 3 (Peg3) gene (0.31 fold, p = 0.046) and higher expression of the androgen receptor (Ar) gene (2.38 fold, p = 0.068). Allelic imbalance was found for expression of ATP-binding cassette transporter gene Abca8b. Several of the differentially expressed genes contain estrogen response elements.	Parent-of-origin effects during gametogenesis and/or fetal development in an obese mother epigenetically modify the transcription of genes that lead to enhanced fatty acid synthesis and impair β-oxidation in the liver of male, but not female F1 offspring. Down-regulation of Peg3 could contribute to trigger this metabolic setting. At puberty, higher amounts of the androgen receptor and altered access to estrogen response elements in affected genes are likely responsible for male specific expression of genes that were epigenetically triggered. A suggestive lack of estrogen binding motifs was found for highly down-regulated genes in adult hepatocytes of obese F1 males (p = 0.074).	
26545401	Many species possess an endogenous circadian clock to synchronize internal physiology with an oscillating external environment. In plants, the circadian clock coordinates growth, metabolism and development over daily and seasonal time scales. Many proteins in the circadian network form oscillating complexes that temporally regulate myriad processes, including signal transduction, transcription, protein degradation and post-translational modification. In Arabidopsis thaliana, a tripartite complex composed of EARLY FLOWERING 4 (ELF4), EARLY FLOWERING 3 (ELF3), and LUX ARRHYTHMO (LUX), named the evening complex, modulates daily rhythms in gene expression and growth through transcriptional regulation. However, little is known about the physical interactions that connect the circadian system to other pathways. We used affinity purification and mass spectrometry (AP-MS) methods to identify proteins that associate with the evening complex in A. thaliana. New connections within the circadian network as well as to light signaling pathways were identified, including linkages between the evening complex, TIMING OF CAB EXPRESSION1 (TOC1), TIME FOR COFFEE (TIC), all phytochromes and TANDEM ZINC KNUCKLE/PLUS3 (TZP). Coupling genetic mutation with affinity purifications tested the roles of phytochrome B (phyB), EARLY FLOWERING 4, and EARLY FLOWERING 3 as nodes connecting the evening complex to clock and light signaling pathways. These experiments establish a hierarchical association between pathways and indicate direct and indirect interactions. Specifically, the results suggested that EARLY FLOWERING 3 and phytochrome B act as hubs connecting the clock and red light signaling pathways. Finally, we characterized a clade of associated nuclear kinases that regulate circadian rhythms, growth, and flowering in A. thaliana. Coupling mass spectrometry and genetics is a powerful method to rapidly and directly identify novel components and connections within and between complex signaling pathways. 
26545247	Sleep changes across the lifespan, with a delay in sleep timing and a reduction in slow wave sleep seen in adolescence, followed by further reductions in slow wave sleep but a gradual drift to earlier timing during healthy ageing. The mechanisms underlying changes in sleep timing are unclear: are they primarily related to changes in circadian processes, or to a reduction in the neural activity dependent build up of homeostatic sleep pressure during wake, or both? We review existing studies of age-related changes to sleep and explore how mathematical models can explain observed changes. Model simulations show that typical changes in sleep timing and duration, from adolesence to old age, can be understood in two ways: either as a consequence of a simultaneous reduction in the amplitude of the circadian wake-propensity rhythm and the neural activity dependent build-up of homeostatic sleep pressure during wake; or as a consequence of reduced homeostatic sleep pressure alone. A reduction in the homeostatic pressure also explains greater vulnerability of sleep to disruption and reduced daytime sleep-propensity in healthy ageing. This review highlights the important role of sleep homeostasis in sleep timing. It shows that the same phenotypic response may have multiple underlying causes, and identifies aspects of sleep to target to correct delayed sleep in adolescents and advanced sleep in later life. 
26545246	Many schools have instituted later morning start times to improve sleep, academic, and other outcomes in response to the mismatch between youth circadian rhythms and early morning start times. However, there has been no systematic synthesis of the evidence on the effects of this practice. To examine the impact of delayed school start time on students' sleep, health, and academic outcomes, electronic databases were systematically searched and data were extracted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Six studies satisfied selection criteria and used pre-post, no control (n = 3), randomized controlled trial (n = 2), and quasi-experimental (n = 1) designs. School start times were delayed 25-60 min, and correspondingly, total sleep time increased from 25 to 77 min per weeknight. Some studies revealed reduced daytime sleepiness, depression, caffeine use, tardiness to class, and trouble staying awake. Overall, the evidence supports recent non-experimental study findings and calls for policy that advocates for delayed school start time to improve sleep. This presents a potential long-term solution to chronic sleep restriction during adolescence. However, there is a need for rigorous randomized study designs and reporting of consistent outcomes, including objective sleep measures and consistent measures of health and academic performance. 
26544867	Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects. 
26544624	We previously reported that dietary methylselenocysteine (MSC) inhibits N-methyl-N-nitrosourea (NMU)-induced mammary tumorigenesis by resetting circadian gene expression disrupted by the carcinogen at the early stage of tumorigenesis. To investigate the underlying mechanism, we developed a circadian reporter system comprised of human mammary epithelial cells with a luciferase reporter driven by the promoter of human PERIOD 2 (PER2), a core circadian gene. In this in vitro model, NMU disrupted cellular circadian rhythm in a pattern similar to that observed with SIRT1-specific inhibitors; in contrast, MSC restored the circadian rhythms disrupted by NMU and protected against SIRT1 inhibitors. Moreover, NMU inhibited intracellular NAD+/NADH ratio and reduced NAD+-dependent SIRT1 activity in a dose-dependent manner, while MSC restored NAD+/NADH and SIRT1 activity in the NMU-treated cells, indicating that the NAD+-SIRT1 pathway was targeted by NMU and MSC. In rat mammary tissue, a carcinogenic dose of NMU also disrupted NAD+/NADH oscillations and decreased SIRT1 activity; dietary MSC restored NAD+/NADH oscillations and increased SIRT1 activity in the mammary glands of NMU-treated rats. MSC-induced SIRT1 activity was correlated with decreased acetylation of BMAL1 and increased acetylation of histone 3 lysine 9 at the Per2 promoter E-Box in mammary tissue. Changes in SIRT1 activity were temporally correlated with loss or restoration of rhythmic Per2 mRNA expression in NMU-treated or MSC-rescued rat mammary glands, respectively. Together with our previous findings, these results suggest that enhancement of NAD+-dependent SIRT1 activity contributes to the chemopreventive efficacy of MSC by restoring epigenetic regulation of circadian gene expression at early stages of mammary tumorigenesis. 
26544506	Recent research in major depressive disorder suggests that dysregulation of the circadian system may be a core pathophysiological component. In pregnancy, women often experience significant disruptions in their daily rhythms, including changes in day-to-day schedule and sleep habits. Current evidence suggests that these disruptions in daily rhythms may adversely affect underlying circadian rhythmicity. The purpose of our study was to examine whether subjectively rated daily rhythm disruptions were associated with a greater incidence of depressive symptoms during the third trimester.Our study was a cross-sectional design, assessing sleep quality, symptoms of depression, and daily rhythm disruptions in 51 pregnant women in their third trimester.	We observed a significant relationship between mild depressive symptoms and disruptions in daily rhythms. While we initially observed a strong correlation between subjective sleep quality and depressive symptoms, this was attenuated after accounting for daily rhythm disruptions. Disruptions in daily social rhythms, eating patterns, and general activity were all significantly associated with depressive symptomatology.	Our findings point to a strong correlation between daily rhythm disruptions and prenatal depressive symptoms. Given that these daily rhythms are known to act as zeitgebers, longitudinal studies examining the directionality of this relationship between circadian rhythms and depressive symptoms during pregnancy are warranted.	
26544192	We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM).In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL).	The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL∙h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL∙h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL∙h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL∙h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects.	We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime.	
26542995	Melatonin has been described as a protective agent against cell death and oxidative stress in different tissues, including in the reproductive system. However, the information on the action of this hormone in rat uterine apoptosis is low. Our objective was to evaluate the effects of melatonin on mechanisms of cell death in uterus of rats exposed to continuous light stress. Twenty adult Wistar rats were divided into two groups: GContr (vehicle control) and GExp which were treated with melatonin (0.4 mg/mL), both were exposed to continuous light for 90 days. The uterus was removed and processed for quantitative real time PCR (qRT-PCR), using PCR-array plates of the apoptosis pathway; for immunohistochemistry and TUNEL. The results of qRT-PCR of GEXP group showed up-regulation of 13 and 7, pro-apoptotic and anti-apoptotic genes, respectively, compared to GContr group. No difference in pro-apoptotic proteins (Bax, Fas and Faslg) expression was observed by immunohistochemistry, although the number of TUNEL-positive cells was lower in the group treated with melatonin compared to the group not treated with this hormone. Our data suggest that melatonin influences the mechanism and decreases the apoptosis in uterus of rats exposed to continuous light.
26542934	Biological rhythms are widespread, allowing organisms to temporally organize their behavior and metabolism in advantageous ways. Such proper timing of molecular and cellular events is critical to their development and health. This is best understood in the case of the circadian clock that orchestrates the daily sleep/wake cycle of organisms. Temporal rhythms can also be used for spatial organization, if information from an oscillating system can be recorded within the tissue in a manner that leaves a permanent periodic pattern. One example of this is the "segmentation clock" used by the vertebrate embryo to rhythmically and sequentially subdivide its elongating body axis. The segmentation clock moves with the elongation of the embryo, such that its period sets the segment length as the tissue grows outward. Although the study of this system is still relatively young compared to the circadian clock, outlines of molecular, cellular, and tissue-level regulatory mechanisms of timing have emerged. The question remains, however, is it truly a clock? Here we seek to introduce the segmentation clock to a wider audience of chronobiologists, focusing on the role and control of timing in the system. We compare and contrast the segmentation clock with the circadian clock, and propose that the segmentation clock is actually an oscillatory ruler, with a primary function to measure embryonic space. 
26542802	Major depressive disorder (MDD) is a common psychiatric disorder effecting approximately 121 million people worldwide and recent reports from the World Health Organization (WHO) suggest that it will be the leading contributor to the global burden of diseases. At present, the most commonly used treatment strategies are still based on the monoamine hypothesis that has been the predominant theory in the last 60 years. Clinical observations show that only a subset of depressed patients exhibits full remission when treated with classical monoamine-based antidepressants together with the fact that patients exhibit multiple symptoms suggest that the pathophysiology leading to mood disorders may differ between patients. Accumulating evidence indicates that depression is a neural circuit disorder and that onset of depression may be located at different regions of the brain involving different transmitter systems and molecular mechanisms. This review synthesises findings from rodent studies from which emerges a role for different, yet interconnected, molecular systems and associated neural circuits to the aetiology of depression.
26542738	The circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for controlling behavioral activity rhythms, such as a free running rhythm in constant darkness. Rodents have several circadian oscillators in other brain regions including the arcuate nucleus (ARC). In specific conditions such as food anticipatory activity rhythms in the context of timed restricted feeding, an alternative circadian pace-making system has been assumed by means of circadian oscillators like the SCN. Despite extensive lesion studies, the anatomic locations of extra-SCN circadian pacemakers responsible for regulating behavioral rhythms have not been found. In the present study, we investigated circadian rhythms in the SCN and extra-SCN region of the arcuate nucleus (ARC) by analyzing PER2::LUCIFERASE expression in specific regions from wild-type C57BL/6, Cry1(-/-), and Cry2(-/-) mice. Compared to wild-type animals, we observed period shortening in both the SCN and ARC of Cry1(-/-) mice and period lengthening in Cry2(-/-) mice. Interestingly, the periods in the ARC of both genotypes were identical to those in the SCN. Moreover, the amplitudes of PER2::LUC rhythms in the ARC of all animals were decreased compared to those in the SCN. These data suggest that the ARC is a candidate circadian pacemaker outside the SCN. 
26542580	The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic β cell function, we examined pancreatic islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that β cell clock ablation in adult mice caused severe glucose intolerance. Thus, cell type-specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes. 

26541531	Previous findings on the association of obstructive sleep apnoea (OSA) and the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, partly due to the confounding effect of obesity and infrequent sampling. Our goal was to examine whether in a relatively nonobese population, OSA is associated with elevated cortisol levels and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (sham-CPAP) use.72 subjects (35 middle-aged males and post-menopausal females with OSA, and 37 male and female controls) were studied in the sleep laboratory for four nights. 24-h blood sampling was performed every hour on the fourth day and night in the sleep laboratory at baseline, after sham-CPAP and after CPAP treatment.In both apnoeic men and women, OSA was associated with significantly higher 24-h cortisol levels compared with controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.These results suggest that OSA in nonobese men and slightly obese women is associated with HPA axis activation, similar albeit stronger compared with obese individuals with sleep apnoea. Short-term CPAP use decreased cortisol levels significantly compared with baseline, indicating that CPAP may have a protective effect against comorbidities frequently associated with chronic activation of the HPA axis, e.g. hypertension. 
26541085	Light is the visible part of the electromagnetic radiation within a range of 380-780 nm; (400-700 on primates retina). In vertebrates, the retina is adapted to capturing light photons and transmitting this information to other structures in the central nervous system. In mammals, light acts directly on the retina to fulfill two important roles: (1) the visual function through rod and cone photoreceptor cells and (2) non-image forming tasks, such as the synchronization of circadian rhythms to a 24 h solar cycle, pineal melatonin suppression and pupil light reflexes. However, the excess of illumination may cause retinal degeneration or accelerate genetic retinal diseases. In the last century human society has increased its exposure to artificial illumination, producing changes in the Light/Dark cycle, as well as in light wavelengths and intensities. Although, the consequences of unnatural illumination or light pollution have been underestimated by modern society in its way of life, light pollution may have a strong impact on people's health. The effects of artificial light sources could have direct consequences on retinal health. Constant exposure to different wavelengths and intensities of light promoted by light pollution may produce retinal degeneration as a consequence of photoreceptor or retinal pigment epithelium cells death. In this review we summarize the different mechanisms of retinal damage related to the light exposure, which generates light pollution. 

26540994	Shift work has become more and more common for the last thirty years. By definition, shift work disturbs the circadian rhythm and the internal clock. Even if the pathophysiological mechanisms are not well understood, a greater cardiovascular risk has been attributed to shift work. Cross-sectional and cohort studies have identified an association between shift work and an elevated blood pressure. Shift workers also present a higher incidence of hypertension and progression than day workers. Unfortunately, the heterogeneity of the studies, the multiple confounding factors, as well as the complexity to achieve a suitable comparison group make it impossible to draw firm clinical evidence. Nevertheless, this population needs a medical follow-up focused on the cardiovascular risks and blood pressure.
26540634	Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms. 
26540575	The individual's chronotype is regarded as rather stable trait with substantial heritability and normal distribution of the "morningness-eveningness" dimension in the general population. Eveningness has been related to the risk of developing affective, particularly depressive, disorders. However, age and other sociobiological factors may influence chronotypes. The present study investigated the distribution, stability, and clinical correlates of chronotype and morningness-eveningness in hospitalized patients with affective disorder. Chronotype was assessed with the morningness-eveningness questionnaire (MEQ) in 93 patients with nonseasonal depressive syndrome (85% major depression; 15% depressive adjustment disorder) after admission, and in 19 patients again before discharge. Distribution, stability and correlations of MEQ scores with clinical variables were calculated. Additionally, a literature analysis of chronotype distributions in samples of nondepressed persons and patients with nonseasonal depression was carried out. MEQ scores (mean 49 ± 11, range 23-75, higher scores indicate morningness) in 93 acutely depressed inpatients (age 41 ± 14 years, range 18-75 years; 63% women; hospitalization 48 ± 22 days; BDI-II 32 ± 11) were normally distributed (Shapiro-Wilk test; W = 0.993, p = 0.920) with 59.1% intermediate types, 19.4% evening types, and 21.5% morning types. MEQ change scores from admission to discharge were nonsignificant (-1.3 ± 5.0; paired t-test, t18 = -1.09; p = 0.29) despite significantly improved depression scores (-19.4 ± 7.6; paired t-test, t18 = 11.2, p < 0.001). Age (r = 0.24), and depression scores (r = -0.21) correlated significantly (p < 0.05) with MEQ scores; associations with sex and hospitalization duration were nonsignificant. The present study and literature findings revealed that the frequency of evening types is not clearly elevated in depression, but morning types are less frequent compared to healthy samples (p < 0.001). Morningness-eveningness scores were normally distributed and stable in depressive inpatients. In line with previous findings, but contrary to theoretical assumptions, evening types were not overrepresented in depressed patients. Additionally, relatively less morning types and more intermediate types were found in depressed patients. Future studies should focus on transitions from morning to intermediate types as a tentative risk or correlate of emerging depression. 
26540469	The aim of this study was to investigate whether different shift work schedules were associated with nonrapid eye movement (NREM)- and/or REM-related parasomnias. A total of 2198 nurses with different work schedules participated in a longitudinal cohort study. The parasomnia questions were included in the fourth wave of the data collection, with a response rate of 74.1%. Logistic regression analyses with the different parasomnias as dependent variables were conducted. Nurses working two shift (day and evening) and nurses working three shift (day, evening and night) rotational schedules had increased risk of confusional arousal, a NREM-related parasomnia, compared to nurses working daytime only (odds ratios = 2.10 and 1.71, respectively). Similarly, nurses working two and three shift rotational schedules had increased risk of nightmares, a REM-related parasomnia (odds ratios = 1.64 and 1.57, respectively). The other parasomnias were not significantly associated with work schedule. Working night shifts only was not associated with any of the parasomnias. In conclusion, confusional arousal and nightmares were more commonly reported by nurses working rotational shift work schedules compared to nurses working daytime only. This is likely related to the circadian rhythm misalignment and sleep deprivation caused by such shift schedules. 
26539967	Hypothalamic-pituitary-adrenal (HPA) axis irregularities have been associated with several psychological disorders. Hence, the identification of individual difference variables that predict variations in HPA-axis activity represents an important challenge for psychiatric research. We investigated whether self-reported attentional control in emotionally demanding situations prospectively predicted changes in diurnal salivary cortisol secretion following exposure to a prolonged psychosocial stressor. Low ability to voluntarily control attention has previously been associated with anxiety and depressive symptomatology. Attentional control was assessed using the Emotional Attentional Control Scale. In students who were preparing for academic examination, salivary cortisol was assessed before (time 1) and after (time 2) examination. Results showed that lower levels of self-reported emotional attentional control at time 1 (N=90) predicted higher absolute diurnal cortisol secretion and a slower decline in cortisol throughout the day at time 2 (N=71). Difficulty controlling attention during emotional experiences may lead to chronic HPA-axis hyperactivity after prolonged exposure to stress. These results indicate that screening for individual differences may foster prediction of HPA-axis disturbances, paving the way for targeted disorder prevention. 
26539966	Sex differences in stress hormone functions are presumed to depend on sex hormones. And yet, surprisingly few psychoneuroendocrine studies actually assess within-sex variations of testosterone, estradiol, and progesterone when investigating sex-specific activities of the hypothalamic-pituitary-adrenal axis. In this methodological study of 204 healthy adults (60 men), we assessed whether cortisol profiles would differ between the sexes when unadjusted or adjusted for basal sex hormones among both sexes. Reactive cortisol was sampled using 6 saliva samples measured every 10-min as part of the Trier Social Stress Test that generally activates cortisol among men more than women. Diurnal cortisol was sampled over two days at (1) awakening, (2) 30-min thereafter, (3) 1400 h, (4) 1600 h, and (5) bedtime. Sex hormones were collected at baseline before the psychosocial stressor and on two occasions during diurnal cortisol assessment. Repeated-measures analysis of covariance controlled for key covariates in analyses unadjusted or adjusted for sex hormones. Results revealed that men had higher reactive cortisol than women in unadjusted analysis, but this sex difference was attenuated when adjusting for sex hormones. While diurnal cortisol showed no sex differences in unadjusted models, adjusting for sex hormones revealed that women have higher morning cortisol. Correlations using area under the curve formulae revealed intriguing sex-specific associations with progesterone in men and testosterone in women that we propose have implications for social and affective neuroscience. In summary, our results reveal that adjusting for sex hormones alters "sex-specific" reactive and diurnal cortisol profiles.
26539689	Previous studies linked heavy computer use to disturbed sleep. This study investigates the association between computer use during work and leisure and sleep problems in working adults. From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners on daytime schedule (N = 7883) replied to the Bergen insomnia scale and questions on weekly duration of computer use. Results showed that sleep problems for three or more days per week (average of six questions) were experienced by 14.9% of the respondents. Logistic regression analyses, controlled for gender, age, physical and psychosocial work factors, lifestyle, chronic disease and mental health showed that computer use during leisure for 30 or more hours per week (reference 0-10 hours per week) was associated with increased odds of sleep problems (OR 1.83 [95% CI 1.06-3.17]). Computer use during work and shorter duration of computer use during leisure were not associated with sleep problems. In conclusion, excessive computer use during leisure - but not work - is associated with sleep problems in adults working on daytime schedule. 
26539161	Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei (SCN) as an indicator of the time of the day. Herein, we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the SCN, arginine vasopressin, and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition, we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis [kisspeptin (Kp) neurons, gonadotropin-releasing hormone neurons, gonadotropic cells, the ovary, and the uterus]. This review will point to the critical position of the Kp neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift-work conditions on female reproductive performance and fertility in both animal model and humans. 
26538282	The composition of flower scent and the timing of emission are crucial for chemical communication between plants and their pollinators; hence, they are key traits for the characterization of pollination syndromes. In many plants, however, plants are assigned to a syndrome based on inexpensive to measure flower traits, such as color, time of flower opening, and shape. We compared day and night scents from 31 Sileneae species and tested for quantitative and semi-quantitative differences in scent among species classified a priori as diurnal or nocturnal. As most Sileneae species are not only visited by either diurnal or nocturnal animals as predicted by their syndrome, we hypothesized that, even if flower scent were preferentially emitted during the day or at night, most species also would emit some scents during the opposing periods of the day. This phenomenon would contribute to the generalized assemblage of flower visitors usually observed in Sileneae species. We found that diel variations of scent often were not congruent with the syndrome definition, but could partially be explained by taxonomy and sampling times. Most species emitted compounds with attractive potential to insects during both the night and day. Our results highlight the current opinion that syndromes are not watertight compartments evolved to exclude some flower visitors. Thus, important information may be lost when scents are collected either during day- or night-time, depending on the a priori classification of the species as diurnal or nocturnal. 
26537429	Animal personality and coping styles are basic concepts for evaluating animal welfare. Struggling response of piglets in so-called backtests early in life reflects their coping strategy. Behavioral reactions of piglets in backtests have a moderate heritability, but their genetic basis largely remains unknown. Here, latency, duration and frequency of struggling attempts during one-minute backtests were repeatedly recorded of piglets at days 5, 12, 19, and 26. A genome-wide association study for backtest traits revealed 465 significant SNPs (FDR ≤ 0.05) mostly located in QTL (quantitative trait locus) regions on chromosome 3, 5, 12 and 16. In order to capture genes in these regions, 37 transcripts with significant SNPs were selected for expressionQTL analysis in the hypothalamus. Eight genes (ASGR1, CPAMD8, CTC1, FBXO39, IL19, LOC100511790, RAD51B, UBOX5) had cis- and five (RANGRF, PER1, PDZRN3, SH2D4B, LONP2) had trans-expressionQTL. In particular, for PER1, with known physiological implications for maintenance of circadian rhythms, a role in coping behavior was evidenced by confirmed association in an independent population. For CTC1 a cis-expression QTL and the consistent relationship of gene polymorphism, mRNA expression level and backtest traits promoted its link to coping style. GWAS and eQTL analyses uncovered positional and functional gene candidates for coping behavior. 
26537049	To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI).Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (<10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver.	Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate.	Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.	


26536485	In this issue of Cell Metabolism, Zwighaft and colleagues (Zwighaft et al., 2015) describe a novel mechanism through which intracellular polyamines regulate circadian rhythms. These findings are significant, as they add yet another layer of complexity to the interplay between environmental, dietary, and organismal factors in the molecular control of daily behavioral oscillations. 
26536406	Living organisms follow a circadian rhythm in which physiological processes such as hormonal secretion, metabolism, heart rate, and renal output are affected by the time of day. Chronotherapy coordinates drug delivery with the circadian rhythm to enhance effectiveness and mitigate adverse effects and is achieved by delivering a drug when the system is most susceptible. Cancer is a chronotherapeutic disorder. Cancer treatment requires high doses of intravenous medication to kill cancerous cells; however, normal cells are also killed, creating intolerable side effects. This review shows that chronotherapy can play a vital role in the quality of life and survival rate for oncology patients. 
26535595	Morning stiffness, a common patient reported symptom in rheumatoid arthritis, is associated with an increase in early morning inflammatory cytokines and significant disability. Little is known about categorical morning stiffness responses to glucocorticoid use in rheumatoid arthritis patients. Chronic pain threshold models have indicated previously that response rates of 15% to 30% indicate minimally important relief, 40% to 50% indicate substantial pain relief, and greater than 70% represents extensive pain relief. The objective of the present analysis was to assess differences in the percentages of patients achieving 25%(minimally important change), 50% (substantial change), and 75% (extensive change) reduction in the duration of patient-reported morning stiffness between patients receiving DR- and IR-prednisone in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial.The CAPRA-1 trial was a 12-week, double-blind study followed by an additional 9-month open-label extension. Patients in the CAPRA-1 trial were randomized to IR-prednisone in the morning or DR-prednisone at bedtime in addition to stable disease modifying antirheumatic drug therapy. After the double-blind phase, patients randomized to IR-prednisone (N =110) were switched to DR-prednisone and followed at 3, 6, and 9 months in an open-label extension phase. Patients originally randomized to DR-prednisone (N = 97) continued that therapy in the open-label extension. Patient morning stiffness diary entries from 4 weeks before and 4 weeks after each scheduled visit were analyzed over 1 year for threshold response. The number of patients reaching threshold response (25%, 50%, and 75% improvement) and time to morning stiffness response were examined.	The DR-prednisone arm had significantly more responders in all three morning stiffness threshold response categories at the end of the double-blind period compared with IR-prednisone (p ≤ 0.05). Patients who switched from IR- to DR-prednisone in the open-label extension had comparable responses in all categories within 3 months and significantly shorter time to response versus patients already receiving DR-prednisone.	DR-prednisone produced significantly higher morning stiffness response rates compared with IR prednisone, as defined by 25%, 50%, and 75% improvement thresholds, at week 12. The time to reach these thresholds was quicker with DR-prednisone, and patients who switched to DR-prednisone from IR-prednisone achieved responses comparable to the continuous DR-prednisone group over 9 months of therapy. This analysis is the first to assess time-to-event and percentage threshold morning stiffness responses to differently timed glucocorticoid therapy and propose clinically meaningful response rates in RA patients.	
26534845	Fatigue is a significant contributor to motor-vehicle accidents and fatalities. Shift workers are particularly susceptible to fatigue-related risks as they are often sleep-restricted and required to commute around the clock. Simple assays of performance could provide useful indications of risk in fatigue management, but their effectiveness may be influenced by changes in their sensitivity to sleep loss across the day. The aim of this study was to evaluate the sensitivity of several neurobehavioral and subjective tasks to sleep restriction (SR) at different circadian phases and their efficacy as predictors of performance during a simulated driving task. Thirty-two volunteers (M±SD; 22.8±2.9 years) were time-isolated for 13-days and participated in one of two 14-h forced desynchrony protocols with sleep opportunities equivalent to 8h/24h (control) or 4h/24h (SR). At regular intervals during wake periods, participants completed a simulated driving task, several neurobehavioral tasks, including the psychomotor vigilance task (PVT), and subjective ratings, including a self-assessment measure of ability to perform. Scores transformed into standardized units relative to baseline were folded into circadian phase bins based on core body temperature. Sleep dose and circadian phase effect sizes were derived via mixed models analyses. Predictors of driving were identified with regressions. Performance was most sensitive to sleep restriction around the circadian nadir. The effects of sleep restriction around the circadian nadir were larger for simulated driving and neurobehavioral tasks than for subjective ratings. Tasks did not significantly predict driving performance during the control condition or around the acrophase during the SR condition. The PVT and self-assessed ability were the best predictors of simulated driving across circadian phases during SR. These results show that simple performance measures and self-monitoring explain a large proportion of the variance in driving when fatigue-risk is high.
26530153	The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. 
26529643	Serotonin plays an important role in the central regulation of circadian clock function. Serotonin levels are generally higher in the brain during periods of high activity, and these periods are in turn heavily regulated by the circadian clock located in the suprachiasmatic nucleus. However, the role of serotonin as a regulator of circadian rhythms elsewhere in the brain has not been extensively examined. In this study, we examined circadian rhythms of clock gene expression in the cerebellum in mice lacking the Pet-1 transcription factor, which results in a developed brain that is deficient in serotonin neurons. If serotonin helps to synchronize rhythms in brain regions other than the suprachiasmatic nucleus, we would expect to see differences in clock gene expression in these serotonin deficient mice. We found minor differences in the expression of Per1 and Per2 in the knockout mice as compared to wild type, but these differences were small and of questionable functional importance. We also measured the response of cerebellar clocks to injections of the serotonin agonist 8-OH-DPAT during the early part of the night. No effect on clock genes was observed, though the immediate-early gene Fos showed increased expression in wild type mice but not the knockouts. These results suggest that serotonin is not an important mediator of circadian rhythms in the cerebellum in a way that parallels its regulation of the circadian clock in the suprachiasmatic nucleus. 
26529412	Cognitive impairment caused by traumatic brain injury (TBI) can lead to devastating consequences for both patients and their families. The underlying neurological basis for TBI-induced cognitive dysfunction remains unknown. However, many lines of research have implicated the hippocampus in the pathophysiology of TBI. In particular, past research has found that theta oscillations, long thought to be the electrophysiological basis of learning and memory, are decreased in the hippocampus post-TBI. Here, we recorded in vivo electrophysiological activity in the hippocampi of 16 mice, 8 of which had previously undergone a TBI. Consistent with previous data, we found that theta power in the hippocampus was decreased in TBI animals compared to sham controls; however, this effect was driven by changes in broadband power and not theta oscillations. This result suggests that broadband fluctuations in the hippocampal local field potential can be used as an electrophysiological surrogate of abnormal neurological activity post-TBI. 
26528813	Coupling between cyclically varying external light and an endogenous biochemical oscillator known as the circadian clock, modulates a rhythmic pattern with two prominent peaks in the locomotion of Drosophila melanogaster. A morning peak appears around the time lights turn on and an evening peak appears just before lights turn off. The close association between the peaks and the external 12:12 hour light/dark photoperiod means that respective morning and evening peaks of individual flies are well-synchronized in time and, consequently, feature prominently in population-averaged data. Here, we report on a brief but strong stochastic burst in fly activity that, in contrast to morning and evening peaks, is detectable only in single fly recordings. This burst was observed across 3 wild-type strains of Drosophila melanogaster. In a single fly recording, the burst is likely to appear once randomly within 0.5-5 hours after lights turn on, last for only 2-3 minutes and yet show 5 times greater activity compared to the maximum of morning peak with data binned in 3 minutes. Owing to its variable timing and short duration, the burst is virtually undetectable in population-averaged data. We use a locally-built illumination system to study the burst and find that its incidence in a population correlates with light intensity, with ~85% of control flies showing the behavior at 8000 lux (1942 μW/cm2). Consistent with that finding, several mutant flies with impaired vision show substantially reduced frequency of the burst. Additionally, we find that genetic ablation of the clock has insignificant effect on burst frequency. Together, these data suggest that the pronounced burst is likely generated by a light-activated circuit that is independent of the circadian clock. 
26527095	The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings. 
26527094	Since the kidney is integral to maintenance of fluid and ion homeostasis, and therefore blood pressure regulation, its proper function is paramount. Circadian fluctuations in blood pressure, renal blood flow, glomerular filtration rate, and sodium and water excretion have been documented for decades, if not longer. Recent studies on the role of circadian clock proteins in the regulation of a variety of renal transport genes suggest that the molecular clock in the kidney controls circadian fluctuations in renal function. The circadian clock appears to be a critical regulator of renal function with important implications for the treatment of renal pathologies, which include chronic kidney disease and hypertension. The development, regulation, and mechanism of the kidney clock are reviewed here.
26526738	Glucocorticoids are indispensable anti-inflammatory and decongestant drugs with high prevalence of use at (~)0.9% of the adult population. Better holistic insights into glucocorticoid-induced changes are crucial for effective use as concurrent medication and management of adverse effects. The profiles of 214 metabolites from plasma of 20 male healthy volunteers were recorded prior to and after ingestion of a single dose of 4 mg dexamethasone (+20 mg pantoprazole). Samples were drawn at three predefined time points per day: seven untreated (day 1 midday - day 3 midday) and four treated (day 3 evening - day 4 evening) per volunteer. Statistical analysis revealed tremendous impact of dexamethasone on the metabolome with 150 of 214 metabolites being significantly deregulated on at least one time point after treatment (ANOVA, Benjamini-Hochberg corrected, q < 0.05). Inter-person variability was high and remained uninfluenced by treatment. The clearly visible circadian rhythm prior to treatment was almost completely suppressed and deregulated by dexamethasone. The results draw a holistic picture of the severe metabolic deregulation induced by single-dose, short-term glucocorticoid application. The observed metabolic changes suggest a potential for early detection of severe side effects, raising hope for personalized early countermeasures increasing quality of life and reducing health care costs. 
26526372	Sleep is thought to be controlled by two main processes: a circadian clock that primarily regulates sleep timing and a homeostatic mechanism that detects and responds to sleep need. Whereas abundant experimental evidence suggests that sleep need increases with time spent awake, the contributions of different brain arousal systems have not been assessed independently of each other to determine whether certain neural circuits, rather than waking per se, selectively contribute to sleep homeostasis. Using the fruit fly, Drosophila melanogaster, we found that sustained thermogenetic activation of three independent neurotransmitter systems promoted nighttime wakefulness. However, only sleep deprivation resulting from activation of cholinergic neurons was sufficient to elicit subsequent homeostatic recovery sleep, as assessed by multiple behavioral criteria. In contrast, sleep deprivation resulting from activation of octopaminergic neurons suppressed homeostatic recovery sleep, indicating that wakefulness can be dissociated from accrual of sleep need. Neurons that promote sleep homeostasis were found to innervate the central brain and motor control regions of the thoracic ganglion. Blocking activity of these neurons suppressed recovery sleep but did not alter baseline sleep, further differentiating between neural control of sleep homeostasis and daily fluctuations in the sleep/wake cycle. Importantly, selective activation of wake-promoting neurons without engaging the sleep homeostat impaired subsequent short-term memory, thus providing evidence that neural circuits that regulate sleep homeostasis are important for behavioral plasticity. Together, our data suggest a neural circuit model involving distinct populations of wake-promoting neurons, some of which are involved in homeostatic control of sleep and cognition.
26526321	Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) have a high prevalence of obesity. This is the first study to investigate whether circadian rhythm disruption is a mechanism linking ADHD symptoms to obesity.ADHD symptoms and two manifestations of circadian rhythm disruption: sleep problems and an unstable eating pattern (skipping breakfast and binge eating later in the day) were assessed in participants with obesity (n= 114), controls (n= 154), and adult ADHD patients (n= 202).	Participants with obesity had a higher prevalence of ADHD symptoms and short sleep on free days as compared to controls, but a lower prevalence of ADHD symptoms, short sleep on free days, and an unstable eating pattern as compared to ADHD patients.We found that participants with obesity had a similar prevalence rate of an unstable eating pattern when compared to controls. Moreover, mediation analyses showed that both sleep duration and an unstable eating pattern mediated the association between ADHD symptoms and body mass index (BMI).	Our study supports the hypothesis that circadian rhythm disruption is a mechanism linking ADHD symptoms to obesity. Further research is needed to determine if treatment of ADHD and circadian rhythm disruption is effective in the prevention and treatment of obesity in patients with obesity and/or ADHD.	
26526320	This study aims to investigate whether incident workplace bullying and its dicontinuance is related to subsequent change in morning and evening saliva cortisol concentrations.Participants came from two Danish cohort studies, the PRISME cohort (n=4489) and the Workplace Bullying and Harassment Cohort (n=3707). At baseline and follow-up exposure to bullying was measured by a single question on bullying (preceded by a definition). Two saliva samples to measure cortisol were collected during a work-day (30 min after awakening and at 8 p.m.). All participants responding to the item on workplace bullying, giving saliva samples and participated at both baseline and follow-up were included. The reference group consisted of non-bullied respondents at both baseline and follow-up. Multilevel mixed-effects linear regressions were used to test for changes in salivary cortisol after newly onset of and discontinuance of workplace bullying. All analyses were adjusted for the potentially confounding effect of differences from baseline to follow-up in education, smoking, alcohol consumption, body mass index, cohort, sampling waves, time of awakening, and time of sampling.	We found no indication of statistically significant difference in saliva cortisol, neither when participants changed their self-labelling from not bullied at baseline to being bullied at follow-up, nor when they at follow-up two years later reported discontinuance of bullying.	This longitudinal study on the impact of changes in bullying status on change in cortisol levels showed consistent lack of associations with onset and discontinuance of workplace bullying.	
26526317	The stress hormone cortisol exhibits a diurnal rhythm throughout the day, as well as within person variability. Recent statistical approaches allow for the estimation of intraindividual cortisol variability ("ICV") and a greater ICV has been observed in some mood disorders (major depression, remitted bipolar disorder); however, ICV has not been examined following stress management. In this secondary analyses of an efficacious randomized clinical trial, we examine how ICV may change after cognitive behavioral stress management (CBSM) among healthy stressed women at risk for breast cancer. Second, we concurrently compare other calculations of cortisol that may change following CBSM.Multilevel modeling (MLM) was applied to estimate ICV and to test for a group by time interaction from baseline, post-intervention, to 1 month following CBSM. Forty-four women were randomized to the CBSM; 47 to the comparison group; mean age of the entire group was 44.2 (SD=10.27).	After controlling for relevant covariates, a significant time by group interaction emerged (β estimate=-.070; p<.05), such that CBSM participants demonstrated a lower ICV following CBSM compared to the comparison group. The interaction for cortisol slope and cortisol output (area under the curve) approached significance (β estimates=-.10 and -.062, respectively; p's<.08), while other cortisol outcomes tested were not significantly changed following CBSM.	ICV may represent a novel index of cortisol dysregulation that is impacted by CBSM and may represent a more malleable within-person calculation than other, widely applied cortisol outcomes. Future research should examine these relationships in larger samples, and examine ICV and health outcomes.	
26525960	To characterize the changes in urine composition associated with increasing severity of diabetes, we analyzed urine composition relative to glycated hemoglobin (HbA1c) and treatment strategy in a largely minority population.Patients treated for kidney stones between 2001 and 2013 at a single tertiary institution and had 24-hour urine collections were included in the study. Patients with type 1 diabetes or taking either thiazide diuretics or alkalinizing agents were excluded. Analysis was performed in IBM SPSS Statistics version 20 using multivariate regression, and Kruskal-Wallis testing was used.	Nine hundred fifty-five patients were included in this study-268 (28%) with type 2 diabetes mellitus, of whom 53 (19.8%) used insulin. Patients with diabetes had lower urine pH, calcium, and phosphate when compared with the control group, but no significant differences were found between the diabetes groups. Multivariate analysis found that HbA1c had a positive correlation with citrate (P = .008), creatinine (P = .037), urine volume (P = .044), and a trend toward a positive association with urinary calcium calcium (P = .064). Insulin use did not have a significant relationship with urinary parameters but trended toward an inverse relationship with calcium (P = .051). pH was not a significant predictor of any urine constituent.	In an ethnically diverse inner city patient population, patients with diabetes mellitus type 2 who use insulin have no significant differences in urine parameters when compared with those on oral hypoglycemics. Worsening glucose control as measured by HbA1c levels predicts increased urine citrate and volume.	
26524465	Modulation of biological oscillations by stimuli lies at the root of many phenomena, including maintenance of circadian rhythms, propagation of neural signals, and somitogenesis. While it is well established that regular periodic modulation can entrain an oscillator, an aperiodic (noisy) modulation can also robustly entrain oscillations. This latter scenario may describe, for instance, the effect of irregular weather patterns on circadian rhythms, or why irregular neural stimuli can still reliably transmit information. A synthetic gene oscillator approach has already proven to be useful in understanding the entrainment of biological oscillators by periodic signaling, mimicking the entrainment of a number of noisy oscillating systems. We similarly seek to use synthetic biology as a platform to understand how aperiodic signals can strongly correlate the behavior of cells. This study should lead to a deeper understanding of how fluctuations in our environment and even within our body may promote substantial synchrony among our cells. Specifically, we investigate experimentally and theoretically the entrainment of a synthetic gene oscillator in E. coli by a noisy stimulus. This phenomenon was experimentally studied and verified by a combination of microfluidics and microscopy using the real synthetic circuit. Stochastic simulation of an associated model further supports that the synthetic gene oscillator can be strongly entrained by aperiodic signals, especially telegraph noise. Finally, widespread applicability of aperiodic entrainment beyond the synthetic gene oscillator is supported by results derived from both a model for a natural oscillator in D. discoideum and a model for predator-prey oscillations. 
26524198	The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h) governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12-12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions) obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50) was equal to 1796 (light) and 2055 (darkness). We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI) with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79%) and Macrobrachium rosenbergii (clock: 100%). We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster. 
26523393	The mammalian suprachiasmatic nucleus (SCN) drives daily rhythmic behavior and physiology, yet a detailed understanding of its coordinated transcriptional programmes is lacking. To reveal the finer details of circadian variation in the mammalian SCN transcriptome we combined laser-capture microdissection (LCM) and RNA-seq over a 24 hr light / dark cycle. We show that 7-times more genes exhibited a classic sinusoidal expression signature than previously observed in the SCN. Another group of 766 genes unexpectedly peaked twice, near both the start and end of the dark phase; this twin-peaking group is significantly enriched for synaptic transmission genes that are crucial for light-induced phase shifting of the circadian clock. 341 intergenic non-coding RNAs, together with novel exons of annotated protein-coding genes, including Cry1, also show specific circadian expression variation. Overall, our data provide an important chronobiological resource (www.wgpembroke.com/shiny/SCNseq/) and allow us to propose that transcriptional timing in the SCN is gating clock resetting mechanisms.
26522272	To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes. 
26521875	The endogenous circadian clock drives robust oscillations in physiology and behavior, such as hormone secretions and sleep/wake cycles, with a period of about 24 h. We are rarely aware of this internal clock system because it is usually synchronized with environmental light-dark cycles. However, travelling rapidly across multiple time zones in a jet airplane suddenly makes us aware of the desynchrony between the body clock and external time, causing sleep disturbances and gastrointestinal problems. Although jet lag is recognized as a chronobiological problem, its specific molecular and neural mechanisms are poorly understood. To address this issue, we identified genes highly expressed in the suprachiasmatic nucleus of the anterior hypothalamus (SCN), the mammalian master clock that controls rhythmic behavior, then analyzed the behavior of knock-out mice for these genes under jet lag condition. We found that the circadian rhythms of locomotor activity and clock gene expression rapidly re-entrained to phase-shifted light-dark cycles in mice genetically deficient in V1a and V1b receptors. Real-time imaging of cellular rhythms in the SCN suggested that interneuronal communication through V1a and V1b confers on the SCN an intrinsic resistance to external perturbation, enhancing the robustness of the SCN clockwork. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice accelerated their recovery from jet lag symptoms, suggesting vasopressin signaling as a potential pharmaceutical intervention for the management of circadian rhythm misalignment.
26521744	To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes.Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT-PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NFкB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms.	Exposure to IL-1β severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1β was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFкB signalling was involved in the effect of IL-1β on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFα had little impact on the circadian rhythm and clock gene expression in cartilage.	In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1β (but not TNFα) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA).	

26519778	Facebook(©) is changing the way people interact and socialize. Despite great interest in psychology and sociology, little is known about Facebook behaviors in relation to physiological markers of stress. Given that the brain undergoes important development during adolescence and that glucocorticoids--a major class of stress hormones-are known to modulate its development, it is important to study psychosocial factors that may influence secretion of stress hormones during adolescence. The goal of the present study was to explore the associations between Facebook behaviors (use frequency, network size, self-presentation and peer-interaction) and basal levels of cortisol among adolescent boys and girls. Eighty-eight adolescents (41 boys, 47 girls) aged between 12 and 17 (14.5 ± 1.8) were recruited. Participants provided four cortisol samples per day for two non-consecutive weekdays. Facebook behaviors were assessed in accordance with the existing literature. Well-validated measures of perceived stress, perceived social support, self-esteem, and depressive symptoms were also included. A hierarchical regression showed that after controlling for sex, age, time of awakening, perceived stress, and perceived social support, cortisol systemic output (area under the curve with respect to ground) was positively associated with the number of Facebook friends and negatively associated with Facebook peer-interaction. No associations were found among depressive symptoms, self-esteem, and cortisol. These results provide preliminary evidence that Facebook behaviors are associated with diurnal cortisol concentrations in adolescents.
26519752	Sleep plays an important role in memory processing. However, its role in anesthesia-induced cognitive dysfunction was not revealed. Our study sought to investigate the connection between the cognition decline and sleep-wake rhythm disorders after long-term isoflurane anesthesia in mice. Also, we examined the effect of exogenous melatonin pretreatment on both cognitive function and circadian rhythm. Furthermore, we discussed whether NR2B (N-methyl-D-aspartate receptor 2B subunit)-CREB (cAMP-response element binding protein) signaling pathway was involved in this course.2-month-old male C57/BL-6J mice were submitted to long-term anesthesia using 1% isoflurane from CT (Circadian Time) 14 to CT20. Melatonin pretreatment were conducted before anesthesia for 7 Days. Intellicage for mice and Mini-Mitter were applied to monitor spatial memory and gross motor activity which can reflect cognition and sleep-wake rhythm. Messenger RNA and protein expression of right hippocampus NR2B and CREB were examined by RT-PCR and Western blot.	6h isoflurane anesthesia led to impaired spatial memory from Day 3 to Day 10 in mice accompanied by the disruption of sleep-wake rhythm. Meanwhile, the hippocampus CREB and NR2B expression declined in step. Melatonin pretreatment ameliorated disturbed sleep-wake cycle, improved isoflurane-induced cognitive dysfunction, and reversed the down-regulation of CREB and NR2B expression.	Our data demonstrate that sleep-wake rhythm is involved in the isoflurane-induced cognition impairment and pretreatment of melatonin has a positive effect on circadian normalization and cognition reversal. Also, NR2B-CREB signaling pathway has a critical role in this process. This study provides us a new strategy for anesthesia-induced cognitive dysfunction therapy.	
26519636	Sleep disturbance in bipolar disorder (BD) is common during and between mood episodes. In recovered (euthymic at least two months) BD patients, we assessed sleep compared to controls and its relationships with residual mood symptoms and mood episode recurrence.Recovered Stanford University BD Clinic patients diagnosed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and monitored with the STEP-BD Clinical Monitoring Form (CMF) for >1 year and healthy controls completed the Pittsburgh Sleep Quality Index (PSQI). PSQI parameters were compared in BD patients versus controls, and the most robustly differentiating PSQI parameter was assessed in relationship to residual mood symptoms, and time to mood episode recurrence in BD patients.	Eighty nine recovered BD patients compared to 56 healthy controls had significantly worse PSQI global score, more sleep medication use, longer sleep latency, and worse daytime dysfunction. PSQI global score had the greatest BD patient versus control effect size, and among BD patients, correlated significantly with residual mood symptoms and predicted earlier mood episode recurrence, even after covarying for residual mood symptoms.	Use of subjective (PSQI) rather objective (polysomnography) sleep metric. Statistical power limited by small sample size. Potential psychotropic medication confound. Northern California tertiary BD clinic referral sample.	Further research is needed to confirm that in recovered BD patients, poor sleep quality correlates with residual mood symptoms, and independently predicts mood episode recurrence. If confirmed, these observations suggest potential mood benefit for focusing on sleep quality in interventions for recovered BD patients.	
26519517	Courtship vibratory signals can be air-borne or substrate-borne. They convey distinct and species-specific information from one individual to its prospective partner. Here, we study the substrate-borne vibratory signals generated by the abdominal quivers of the Drosophila male during courtship; these vibrations travel through the ground towards courted females and coincide with female immobility. It is not known which physical parameters of the vibrations encode the information that is received by the females and induces them to pause. We examined the intervals between each vibratory pulse, a feature that was reported to carry information for animal communication. We were unable to find evidence of periodic variations in the lengths of these intervals, as has been reported for fly acoustical signals. Because it was suggested that the genes involved in the circadian clock may also regulate shorter rhythms, we search for effects of period on the interval lengths. Males that are mutant for the period gene produced vibrations with significantly altered interpulse intervals; also, treating wild type males with constant light results in similar alterations to the interpulse intervals. Our results suggest that both the clock and light/dark cycles have input into the interpulse intervals of these vibrations. We wondered if we could alter the interpulse intervals by other means, and found that ambient temperature also had a strong effect. However, behavioural analysis suggests that only extreme ambient temperatures can affect the strong correlation between female immobility and substrate-borne vibrations. 
26519507	The mechanisms of rhythmic motor pattern generation have been studied in detail in vitro, but the long-term stability and sources of variability in vivo are often not well described. The crab stomatogastric ganglion contains the well-characterized gastric mill (chewing) and pyloric (filtering of food) central pattern generators. In vitro, the pyloric rhythm is stereotyped with little variation, but inter-circuit interactions and neuromodulation can alter both rhythm cycle frequency and structure. The range of variation of activity in vivo is, with few exceptions, unknown. Curiously, although the pattern-generating circuits in vivo are constantly exposed to hormonal and neural modulation, the majority of published data show only the unperturbed canonical motor patterns typically observed in vitro. Using long-term extracellular recordings (N=27 animals), we identified the range and sources of variability of the pyloric and gastric mill rhythms recorded continuously over 4 days in freely behaving Jonah crabs (Cancer borealis). Although there was no evidence of innate daily rhythmicity, a 12 h light-driven cycle did manifest. The frequency of both rhythms increased modestly, albeit consistently, during the 3 h before and 3 h after the lights changed. This cycle was occluded by sensory stimulation (feeding), which significantly influenced both pyloric cycle frequency and structure. This was the only instance where the structure of the rhythm changed. In unfed animals the structure remained stable, even when the frequency varied substantially. So, although central pattern generating circuits are capable of producing many patterns, in vivo outputs typically remain stable in the absence of sensory stimulation.
26519279	We studied the effect of melatonin and epithalon on age-related changes in proteolytic digestive enzyme activity in the pancreas and gastric mucosa of rats kept under different lighting conditions. In rats kept under standard illumination, pepsin activity and the total proteolytic activity in the stomach and pancreas increased by the age of 12 months, but then decreased. Constant and natural lighting disturbed the age dynamics of proteolytic digestive enzyme activity. Administration of melatonin and epithalon to animals exposed to constant lighting restored age dynamics of pepsin activity and little affected total proteolytic activity. 
26518594	Historically, mathematical models of human neurobehavioral performance developed on data from one sleep study were limited to predicting performance in similar studies, restricting their practical utility. We recently developed a unified model of performance (UMP) to predict the effects of the continuum of sleep loss-from chronic sleep restriction (CSR) to total sleep deprivation (TSD) challenges-and validated it using data from two studies of one laboratory. Here, we significantly extended this effort by validating the UMP predictions across a wide range of sleep/wake schedules from different studies and laboratories.We developed the UMP on psychomotor vigilance task (PVT) lapse data from one study encompassing four different CSR conditions (7 d of 3, 5, 7, and 9 h of sleep/night), and predicted performance in five other studies (from four laboratories), including different combinations of TSD (40 to 88 h), CSR (2 to 6 h of sleep/night), control (8 to 10 h of sleep/night), and nap (nocturnal and diurnal) schedules.	The UMP accurately predicted PVT performance trends across 14 different sleep/wake conditions, yielding average prediction errors between 7% and 36%, with the predictions lying within 2 standard errors of the measured data 87% of the time. In addition, the UMP accurately predicted performance impairment (average error of 15%) for schedules (TSD and naps) not used in model development.	The unified model of performance can be used as a tool to help design sleep/wake schedules to optimize the extent and duration of neurobehavioral performance and to accelerate recovery after sleep loss.	
26518503	Circadian rhythm provides organisms with an internal system to maintain temporal order in a dynamic environment. This is typified by a 24-h cycle for a number of physiological processes, including immunity. The present study characterized the humoral and mucosal defense molecules and their dynamics during a light-dark (LD) cycle in juvenile permit, Trachinotus falcatus. All studied defense molecules were constitutively identified in serum and skin mucus. Serum generally exhibited higher levels of these defenses than skin mucus, with the exception of anti-protease (ANTIPRO). The difference in ANTIPRO, lysozyme (LYZ), esterase (ESA) and catalase (CAT) levels between serum and skin mucus was not affected by the phase of the daily cycle. However, a clear phase-dependent difference was observed in protease (PRO), globulin (GLOB), myeloperoxidase (MPO), alkaline phosphatase (ALP) and glutathione peroxidase (GPX) levels. Activities of ALP and GPX displayed significant daily rhythmicity in both serum and skin mucus. Circadian profile of ALP was identical in both biofluids, but an antiphasic feature was exhibited by GPX. GLOB and MPO levels also exhibited significant daily oscillation but only in serum with acrophases registered at ZT 14.5 and 6.15, respectively. Mucus PRO and serum ANTIPRO demonstrated significant temporal variations during a daily cycle albeit not rhythmic. Cluster analysis of the defense molecules in serum and skin mucus revealed two different daily profiles suggesting a possibility of distinct circadian control between humoral and mucosal immunity. These observations indicate that LD cycle had a remarkable impact in the defense molecules characterizing the humoral and mucosal immunity in permit. Daily rhythmic patterns of these defense molecules contribute to our understanding of the barely explored interplay of immunity and circadian rhythm in teleost fish. Lastly, the results could be useful in developing aquaculture practices aiming at modifying the immune functions of permit for improved health.
26518256	Acromegaly is a rare hormonal disease related to excessive growth hormone secretion. It can result in a range of complications, including cardiovascular, respiratory, metabolic, articular and neoplastic disorders. Among patients with the condition, obstructive sleep apnea syndrome occurs frequently and the effect of treatment is inconstant: improvement, statu quo or deterioration can be observed. We here report three clinical cases, which illustrate the unpredictable evolution of this condition. 
26518222	RF-(Arg-Phe) related peptides (RFRP-1 and -3) are considered to play a role in the seasonal regulation of reproduction; however, the effect of the peptides depends on species and gender. This study aimed at comparing the RFRP system in male and female Syrian hamsters over long and short photoperiods to investigate the neuroanatomical basis of these differential effects. The neuroanatomical distribution of RFRP neurons and fibers, revealed using an antiserum recognizing RFRP-1 and -3, as well as GPR147 mRNA, are similar in male and female Syrian hamsters. RFRP neurons are mainly found in the medial hypothalamus, whereas RFRP projections and GPR147 mRNA are observed in the preoptic area, anteroventral-periventricular nucleus, suprachiasmatic nucleus, paraventricular nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamus, habenular nucleus, and arcuate nucleus. The number of RFRP neurons is higher in females than in males, and in both sexes, the number of RFRP neurons is reduced in short photoperiods. GPR147 mRNA levels are higher in females than in males and are downregulated in short photoperiods, particularly in females. Interestingly, the number of RFRP-positive fibers in the anteroventral-periventricular nucleus is higher only in females adjusted to a short photoperiod. Our results suggest that the RFRP system, which is strongly regulated by photoperiod in both male and female Syrian hamsters, is particularly important in females, with a distinct role in the anteroventral-periventricular nucleus, possibly in the regulation of the preovulatory luteinizing hormone surge via kisspeptin neurons.
26518084	Current medical therapy of glaucoma aims to attain a meaningful and consistent reduction of intraocular pressure (IOP) to a predetermined level of target IOP, which will commensurate with either stability, or delayed progression of visual loss. Glaucoma is a 24-h disease and the damaging effect of elevated IOP is continuous. Therefore, it is reasonable that we should endeavor to identify the true efficacy of currently available and future antiglaucoma medications throughout the 24-h period. This review chapter deals first with the concept and value of diurnal and 24-h pressure monitoring. It then evaluates existing evidence on the 24-h efficacy of medical therapy options. Unfortunately, significant gaps exist in our present understanding of the short-term and particularly the long-term 24-h efficacy of most antiglaucoma medications. More long-term controlled evidence is needed in the future to improve our understanding of the 24-h efficacy of current medical glaucoma therapy, the ideal 24-h target pressure and the precise impact of IOP characteristics upon the different stages of the various forms of glaucoma. 
26517605	The purpose of this study was to investigate the effect of time-of-day (morning vs. afternoon) on static and dynamic balance in recreational athletes. A total of 34 recreational athletes completed the single-leg stance test with or without eyes open, lower quarter Y-balance test, upper quarter Y-balance test, and single-leg landing balance test in a random order in the morning (7:00-10:00 am) and afternoon (3:00-6:00 pm) for two consecutive days. Compared with the morning, participants demonstrated decreased centre of pressure (COP) sway areas (p = 0.002; Cohen's d (d) = 0.28) and sway speeds (p = 0.002; d = 0.17) during the eyes-open single-leg stance test, increased stance time (p = 0.031; d = 0.16) and decreased COP sway areas (p = 0.029; d = 0.22) during the eyes-closed single-leg stance test, and increased reaching distances (p = 0.024; d = 0.10) during the upper quarter Y-balance test in the afternoon. The between-day effect (day 1 vs. day 2) was observed for several parameters. Time-of-day had a minimal effect on dynamic balance and a noticeable effect on static balance. Time-of-day may be considered as a factor in designing balance training programmes and intervention studies for recreational athletes.
26516924	The coccolithophorid unicellular alga Emiliania huxleyi is known to form large blooms, which have a strong effect on the marine carbon cycle. As a photosynthetic organism, it is subjected to a circadian rhythm due to the changing light conditions throughout the day. For a better understanding of the metabolic processes under these periodically-changing environmental conditions, a genome-scale model based on a genome reconstruction of the E. huxleyi strain CCMP 1516 was created. It comprises 410 reactions and 363 metabolites. Biomass composition is variable based on the differentiation into functional biomass components and storage metabolites. The model is analyzed with a flux balance analysis approach called diurnal flux balance analysis (diuFBA) that was designed for organisms with a circadian rhythm. It allows storage metabolites to accumulate or be consumed over the diurnal cycle, while keeping the structure of a classical FBA problem. A feature of this approach is that the production and consumption of storage metabolites is not defined externally via the biomass composition, but the result of optimal resource management adapted to the diurnally-changing environmental conditions. The model in combination with this approach is able to simulate the variable biomass composition during the diurnal cycle in proximity to literature data. 
26516126	Copper homeostasis under deficiency is regulated by the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7) transcription factor. The daily oscillating expression of two SPL7-dependent copper deficiency markers, COPPER TRANSPORTER (COPT2) and IRON SUPEROXIDE DISMUTASE (FSD1), has been followed by quantitative PCR and in promoter:LUCIFERASE transgenic plants. Both genes showed circadian and diurnal regulation. Under copper deficiency, their expression decreased drastically in continuous darkness. Accordingly, total copper content was slightly reduced in etiolated seedlings under copper deficiency. The expression of SPL7 and its targets COPT2 and FSD1 was differently regulated in various light signalling mutants. On the other hand, increased copper levels reduced the amplitude of nuclear circadian clock components, such as GIGANTEA (GI). The alteration of copper homeostasis in the COPT1 overexpression line and spl7 mutants also modified the amplitude of a classical clock output, namely the circadian oscillation of cotyledon movements. In the spl7 mutant, the period of the oscillation remained constant. These results suggest a feedback of copper transport on the circadian clock and the integration of rhythmic copper homeostasis into the central oscillator of plants. 
26515929	The circadian clock plays an important role in several aspects of female reproductive biology. Evidence linking circadian clock-related genes to pregnancy outcomes has been inconsistent. We sought to examine whether variations in single nucleotide polymorphisms (SNPs) of circadian clock genes are associated with PA risk.Maternal blood samples were collected from 470 PA case and 473 controls. Genotyping was performed using the Illumina Cardio-MetaboChip platform. We examined 119 SNPs in 13 candidate genes known to control circadian rhythms (e.g., CRY2, ARNTL, and RORA). Univariate and penalized logistic regression models were fit to estimate odds ratios (ORs); and the combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score (wGRS).	A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of PA (P < 0.05). The odds of PA increased with increasing wGRS (Ptrend < 0.001). The corresponding ORs were 1.00, 1.83, 2.81 and 5.13 across wGRS quartiles. Participants in the highest wGRS quartile had a 5.13-fold (95% confidence interval: 3.21-8.21) higher odds of PA compared to those in the lowest quartile. Although the test for interaction was not significant, the odds of PA was substantially elevated for preeclamptics with the highest wGRS quartile (OR = 14.44, 95%CI: 6.62-31.53) compared to normotensive women in the lowest wGRS quartile.	Genetic variants in circadian rhythm genes may be associated with PA risk. Larger studies are needed to corroborate these findings and to further elucidate the pathogenesis of this important obstetrical complication.	
26515884	The use of mice in alcohol research provides an excellent model system for a better understanding of the genetics and neurobiology of alcohol addiction. Almost 60 years ago, alcohol researchers began to test strains of mice for alcohol preference and intake. In particular, various voluntary alcohol drinking paradigms in the home cage were developed. In mouse models of voluntary oral alcohol consumption, animals have concurrent access to water and either one or several concentrated alcohol solutions in their home cages. Although these models have high face validity, many experimental conditions require a more precise monitoring of alcohol consumption in mice in order to capture the role of specific strains or genes, or any other manipulation on alcohol drinking behavior. Therefore, we have developed a fully automated, highly precise monitoring system for alcohol drinking in mice in the home cage. This system is now commercially available. We show that this drinkometer system allows for detecting differences in drinking behavior (i) in transgenic mice, (ii) following alcohol deprivation, and (iii) following stress applications that are usually not detected by classical home-cage drinking paradigms. In conclusion, our drinkometer system allows disturbance-free and high resolution monitoring of alcohol drinking behavior. In particular, micro-drinking and circadian drinking patterns can be monitored in genetically modified and inbred strains of mice after environmental and pharmacological manipulation, and therefore this system represents an improvement in measuring behavioral features that are of relevance for the development of alcohol use disorders. 
26515228	To investigate thermal balance of infants in a Mongolian winter, and compare the effects of traditional swaddling with an infant sleeping-bag in apartments or traditional tents (Gers).A substudy within a randomised controlled trial.	Community in Ulaanbaatar, Mongolia.	A stratified randomly selected sample of 40 swaddled and 40 non-swaddled infants recruited within 48 h of birth.	Sleeping-bags and baby outfits of total thermal resistance equivalent to that of swaddled babies.	Digital recordings of infants' core, peripheral, environmental and microenvironmental temperatures at 30-s intervals over 24 h at ages 1 month and 3 months.	In Gers, indoor temperatures varied greatly (<0->25°C), but remained between 20°C and 22°C, in apartments. Despite this, heavy wrapping, bed sharing and partial head covering, infant core and peripheral temperatures were similar and no infants showed evidence of significant heat or cold stress whether they were swaddled or in sleeping-bags. At 3 months, infants in sleeping-bags showed the 'mature' diurnal pattern of a fall in core temperature after sleep onset, accompanied by a rise in peripheral temperature, with a reverse pattern later in the night, just before awakening. This pattern was not related to room temperature, and was absent in the swaddled infants, suggesting that the mature diurnal pattern may develop later in them.	No evidence of cold stress was found. Swaddling had no identifiable thermal advantages over sleeping-bags during the coldest times, and in centrally heated apartments could contribute to the risk of overheating during the daytime.	ISRTN01992617.	
26515173	We studied the response of the pineal gland and organs of the immune system to melatonin treatment in Wistar rats kept under conditions of abnormal illumination regimen. The animals were kept under natural light regimen or continuous illumination for 14 days and then received daily injections of melatonin (once a day in the evening) for 7 days. Administration of melatonin to rats kept at natural light cycle was followed by a decrease in percent ratio of CD4+8+ splenocytes and CD4-8+ thymocytes. In 24-h light with the following melatonin injections were accompanied by an increase in percent rate and absolute amount of CD4+8+ cells in the spleen, and a decrease in percent rate of CD11b/c and CD4-8+ splenocytes. In the thymus amount of CD4-8+ cells increased, and absolute number of CD4+25+ cells reduced. Melatonin significantly decreased lipofuscin concentration in the pineal gland during continuous light. Direction and intensity of effects of melatonin on parameters of cell immunity and state of the pineal gland were different under normal and continuous light conditions. It should be taken into account during using of this hormone for correction of immune and endocrine impairments developing during change in light/dark rhythm.
26514754	Circadian clocks have evolved independently in all three domains of life, and fitness benefits of a functional clock have been demonstrated in experimental genotypes in controlled conditions. Still, little is known about genetic variation in the clock and its fitness consequences in natural populations from heterogeneous environments. Using Wyoming populations of the Arabidopsis relative Boechera stricta as our study system, we demonstrate that genetic variation in the clock can occur at multiple levels: means of circadian period among populations sampled at different elevations differed by less than 1 h, but means among families sampled within populations varied by as much as 3.5 h. Growth traits also varied among and within populations. Within the population with the most circadian variation, we observed evidence for a positive correlation between period and growth and a negative correlation between period and root-to-shoot ratio. We then tested whether performance tradeoffs existed among families of this population across simulated seasonal settings. Growth rankings of families were similar across seasonal environments, but for root-to-shoot ratio, genotype × environment interactions contributed significantly to total variation. Therefore, further experiments are needed to identify evolutionary mechanisms that preserve substantial quantitative genetic diversity in the clock in this and other species. 
26514267	In mammals, the hormone melatonin is mainly produced by the pineal gland with nocturnal peak levels. Its peripheral and central actions rely either on its intrinsic antioxidant properties or on binding to melatonin MT1 and MT2 receptors, belonging to the G protein-coupled receptor (GPCR) super-family. Melatonin has been reported to be involved in many functions of the central nervous system such as circadian rhythm regulation, neurotransmission, synaptic plasticity, memory, sleep, and also in Alzheimer's disease and depression. However, little is known about the subcellular localization of melatonin receptors and the molecular aspects involved in neuronal functions of melatonin. Identification of protein complexes associated with GPCRs has been shown to be a valid approach to improve our understanding of their function. By combining proteomic and genomic approaches we built an interactome of MT1 and MT2 receptors, which comprises 378 individual proteins. Among the proteins interacting with MT1 , but not with MT2 , we identified several presynaptic proteins, suggesting a potential role of MT1 in neurotransmission. Presynaptic localization of MT1 receptors in the hypothalamus, striatum, and cortex was confirmed by subcellular fractionation experiments and immunofluorescence microscopy. MT1 physically interacts with the voltage-gated calcium channel Cav 2.2 and inhibits Cav 2.2-promoted Ca(2+) entry in an agonist-independent manner. In conclusion, we show that MT1 is part of the presynaptic protein network and negatively regulates Cav 2.2 activity, providing a first hint for potential synaptic functions of MT1.
26514211	The aim of this study was to evaluate individual differences in the subjective flexibility of the circadian system in a community sample, with respect to age, gender, chronotype, and sleepiness perceptions. An online questionnaire containing the Circadian Type Inventory, the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale was administered. In addition, participants performed a visuo-verbal judgment task to determine time-of-day variations in estimated sleepiness. We analyzed data of 752 participants, aged between 18 and 83 years, who reported good sleep quality, no sleep disturbances, no excessive daytime sleepiness, and no engagement in shiftwork. Our results suggest gender- and chronotype-related differences in the subjective flexibility of the circadian system. Subjective circadian flexibility was higher in men in comparison with women and was positively related to evening preference. Age was not associated with flexibility scores. Additionally, the subjective flexibility of the circadian system had an influence on estimated sleepiness profiles: individuals with a high flexibility displayed lower sleepiness estimations during the biological night in comparison to individuals with a low flexibility. These findings suggests that, next to known chronotype and other dispositional differences, subjective circadian flexibility should be taken into account when evaluating tolerance to activities associated with nighttime functioning (e.g. night shifts). 
26514204	Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents. 
26513010	Influences of starvation, re-feeding and time of food supply on daily rhythm features of melatonin (5-methoxy-N-acetyltryptamine) and its key regulator AANAT (arylalkylamine N-acetyltransferase) protein in the gut tissues were separately evaluated in carp Catla catla. The first experiment was aimed at demonstration of duration dependent effects of starvation and re-feeding after starvation on the daily profiles and rhythm features of gut melatonin and AANAT. Accordingly, juvenile carp were randomly distributed in three groups, which were (a) provided with balanced diet daily at a fixed time, that is, 10:00 clock hour or zeitgeber time (ZT) 4 (control), or (b) starved (for 2-, 4-, 6- or 8 days), or (c) initially starved for 8 days and then re-fed (for 2-, 4-, 6-, 8-, 12- or 16 days) daily with the same food and at the time (ZT4) used for control fish. The carp in each group were sampled for collection of gut tissues at six different time points at a regular interval of 4 h in a daily cycle. In another experiment, the influences of timing of food supply were separately examined in four fish groups, which were provided with a fixed amount of food once daily either at 06:00 or 12:00 or 18:00 or 24:00 clock hour corresponding to ZT0 or ZT6 or ZT12 or ZT18, respectively, for 7 days before sampling at 12 different time points with a regular interval of 2 h in a 24-h cycle. The study revealed a gradual increase in the mesor and amplitude values of melatonin and AANAT in gut with the progress of starvation till their values reached maximum at day-6 and remained steady thereafter. In contrast, re-feeding of 8-day starved fish resulted in a sharp decrease in their mesor and amplitude values after 2 days and then followed by a steady-state increase till re-attainment of their values close to control fish at the end of 16 days. The acrophase of these gut variables in each control, starved and re-fed fish was noted mostly at midday or ZT6. However, the results of another experiment demonstrated that a shift of food supply time led to a shift in their acrophase. The amount of residual food in the gut lumen in each, but not starved, fish by showing a significant positive correlation independently with the gut levels of melatonin and AANAT also indicated possible role of food as the synchronizer for their daily rhythms. Collectively, it appears reasonable to argue that daily profiles of gut melatonin and AANAT are strongly influenced by the availability of food, while their daily rhythm features seem to be dependent mostly on the time of food supply in carp. 
26512910	The circadian clock regulates many cellular processes, notably including the cell cycle, metabolism and aging. Mitochondria play essential roles in metabolism and are the major sites of reactive oxygen species (ROS) production in the cell. The clock regulates mitochondrial functions by driving daily changes in NAD(+) levels and Sirt3 activity. In addition to this central route, in the present study, we find that the expression of some mitochondrial genes is also rhythmic in the liver, and that there rhythms are disrupted by the Clock(Δ19) mutation in young mice, suggesting that they are regulated by the core circadian oscillator. Related to this observation, we also find that the regulation of oxidative stress is rhythmic in the liver. Since mitochondria and ROS play important roles in aging, and mitochondrial functions are also disturbed by aging, these related observations prompt the compelling hypothesis that circadian oscillators influence aging by regulating ROS in mitochondria. During aging, the expression rhythms of some mitochondrial genes were altered in the liver and the temporal regulation over the dynamics of mitochondrial oxidative stress was disrupted. However, the expression of clock genes was not affected. Our results suggested that mitochondrial functions are combinatorially regulated by the clock and other age-dependent mechanism(s), and that aging disrupts mitochondrial rhythms through mechanisms downstream of the clock. 
26512752	Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST, mesor, circadian quotient, 24-h autocorrelation and bed and wake times; PER3 was associated with amplitude, 24-h autocorrelation, acrophase and bed and wake times. Most of the observed associations involved a significant interaction between genotype and HIV. In this chronic illness population, polymorphisms in several circadian genes were associated with measures of sleep disruption and timing. These findings extend the evidence for an association between genetic variability in circadian regulation and sleep outcomes to include the sleep-wake patterns experienced by adults living with HIV/AIDS. These results provide direction for future intervention research related to circadian sleep-wake behavior patterns. 

26512337	One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle. Other common sleep problems in this age group, such as obstructive sleep apnea and restless leg syndrome, can also worsen the sleep quality. Exogenous melatonin use reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs (selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonists) with prolonged effects and slow-release melatonin preparations have been developed. They were found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency in insomnia patients. The purpose of this review is to give an overview on the changes in hormonal status to sleep problems among menopausal and postmenopausal women.
26511603	Most organisms have cell-autonomous circadian clocks to coordinate their activity and physiology according to 24-h environmental changes. Despite recent progress in circadian studies, it is not fully understood how the period length and the robustness of mammalian circadian rhythms are determined. In this study, we established a series of mouse embryonic stem cell (ESC) lines with single or multiplex clock gene ablations using the CRISPR/Cas9-based genome editing method. ESC-based in vitro circadian clock formation assay shows that the CRISPR-mediated clock gene disruption not only reproduces the intrinsic circadian molecular rhythms of previously reported mice tissues and cells lacking clock genes but also reveals that complexed mutations, such as CKIδ(m/m):CKIε(+/m):Cry2(m/m) mutants, exhibit an additively lengthened circadian period. By using these mutant cells, we also investigated the relation between period length alteration and temperature compensation. Although CKIδ-deficient cells slightly affected the temperature insensitivity of period length, we demonstrated that the temperature compensation property is largely maintained in all mutants. These results show that the ESC-based assay system could offer a more systematic and comprehensive approach to the genotype-chronotype analysis of the intracellular circadian clockwork in mammals. 
26510662	Though recommended for pregnant women at risk of preterm birth to improve perinatal outcomes, antenatal corticosteroid (ACS) treatment can cause maternal hyperglycemia, especially in cases of glucose intolerance. A standardized protocol for preventing hyperglycemia during ACS treatment remains to be established. We herein retrospectively investigated the time-dependent changes in insulin dose required for maternal glycemic control during ACS treatment in gestational diabetes (GDM). Twelve singleton pregnant women with GDM who received 12 mg of betamethasone intramuscularly twice 24 hours apart were included in this analysis. Of those, eight also received ritodrine hydrochloride for preterm labor. The blood glucose levels were maintained at 70-120 mg/dL with continuous intravenous infusion of insulin and nothing by mouth for 48 hours after the first betamethasone administration. After the first dose of betamethasone, the insulin dosage needed for glycemic control gradually increased and reached a maximum (6.6 ± 5.8 units/hr) at 10 hours, then, decreased to 4.1 ± 1.5 units/hr at 24 hours. Similar changes in the insulin requirement were found after the second betamethasone dose (the maximum insulin dosage: 5.5 ± 1.6 units/hr at 9 hours following the second administration). Women treated with ritodrine hydrochloride needed more insulin, than those without ritodrine hydrochloride treatment (130.8 ± 15.0 vs. 76.8 ± 15.2 units/day, respectively, p < 0.05). Our data indicated that the requirement for insulin is highest 9-10 hours after each dose of betamethasone. When GDM is treated with ACS, levels of blood glucose should be carefully monitored, especially in patients treated with ritodrine hydrochloride. 
26509470	The circadian pattern of adipokines is blunted in obese subjects, and we tested the hypothesis that bariatric surgery could normalize the 24-hr pattern of adipokines. Therefore, this study was designed to examine the early impact of the newly designed sleeve gastrectomy with transit bipartition (SGTB) surgery on the circadian pattern of leptin, adiponectin, and resistin in morbidly obese subjects.The study group included six morbidly obese women [body mass index (BMI) 41.3 ± 1.53 kg/m(2)] who underwent SGTB and four lean women (BMI 18.61 ± 0.92 kg/m(2)). Blood from all subjects was collected before and 3 months after bariatric surgery every 6 hr throughout the 24-hr period. The circadian pattern of leptin, adiponectin, and resistin was measured by enzyme-linked immunosorbent assay or Luminex techniques.	Lean women exhibited rise of plasma leptin levels at nighttime, whereas obese women had an increase in the overall plasma leptin levels throughout the 24-hr period, lacking the physiological rise of nocturnal leptin levels compared to controls. Obese women had a decrease in 24-hr adiponectin levels and similar plasma resistin levels compared to controls. Three months after SGTB, obese women lost 16.0% (P < 0.005) of their initial body weight and had a decrease in overall 24-hr leptin levels. However, there was no recovery of the nocturnal rise in leptin levels 3 months after SGTB. The 24-hr adiponectin levels were still decreased after SGTB surgery compared to controls, while resistin levels were decreased only during night time after SGTB.	These results suggested that SGTB is an efficient innovative procedure to rapidly decrease 24-hr leptin levels. However, after 3 months, SGTB was not enough to recover the physiological nocturnal rise of leptin levels present in lean subjects.	
26509110	Hematopoiesis is characterized by a lifelong balance between hematopoietic stem cell (HSC) self-renewal and differentiation into mature blood populations. Proper instruction of cell fate decisions requires tight homeostatic regulation of transcriptional programs through a combination of epigenetic modifications, management of cis-regulatory elements, and transcription factor activity. Recent work has focused on integrating biochemical, genetic, and evolutionary data sets to gain further insight into these regulatory components. Long noncoding RNA (lncRNA), post-translational modifications of transcription factors, and circadian rhythm add additional layers of complexity. These analyses have provided a wealth of information, much of which has been made available through public databases. Elucidating the regulatory processes that govern hematopoietic transcriptional programs is expected to provide useful insights into hematopoiesis that may be applied broadly across tissue types while enabling the discovery and implementation of therapeutics to treat human disease.
26508522	CONSTANS (CO) has a central role in the photoperiod response mechanism in Arabidopsis. However, the functions of legume CO genes in controlling flowering remain unknown. Here, we analyze the expression patterns of E1, E2 and GmCOL1a/1b using near-isogenic lines (NILs), and we further analyze flowering-related genes in gmcol1b mutants and GmCOL1a-overexpressing plants. Our data showed that both E3 and E4 up-regulate E1 expression, with the effect of E3 on E1 being greater than the effect of E4 on E1. E2 was up-regulated by E3 and E4 but down-regulated by E1. GmCOL1a/1b were up-regulated by E1, E2, E3 and E4. Although the spatial and temporal patterns of GmCOL1a/1b expression were more similar to those of AtCOL2 than to those of AtCO, gmcol1b mutants flowered earlier than wild-type plants under long-day (LD) conditions, and the overexpression of GmCOL1a caused late flowering under LD or natural conditions. In addition, GmFT2a/5a, E1 and E2 were down-regulated in GmCOL1a-overexpressing plants under LD conditions. Because E1/2 influences the expression of GmCOL1a, and vice versa, we conclude that these genes may function as part of a negative feedback loop, and GmCOL1a/b genes may serve as suppressors in photoperiodic flowering in soybean under LD conditions. 
26508332	Driver sleepiness is a major crash risk factor but may be underrecognized as a risky driving behavior. Sleepy driving is usually rated as less of a road safety issue than more well-known risky driving behaviors, such as drink driving and speeding. The objective of this study was to compare perception of crash risk of sleepy driving, drink driving, and speeding.Three hundred Australian drivers completed a questionnaire that assessed crash risk perceptions for sleepy driving, drink driving, and speeding. Additionally, the participants' perceptions of crash risk were assessed for 5 different contextual scenarios that included different levels of sleepiness (low, high), driving duration (short, long), and time of day/circadian influences (afternoon, nighttime) of driving.	The analysis confirmed that sleepy driving was considered a risky driving behavior but not as risky as high levels of speeding (P < .05). Yet, the risk of crashing at 4 a.m. was considered as equally risky as low levels of speeding (10 km over the limit). The comparisons of the contextual scenarios revealed driving scenarios that would arguably be perceived as quite risky because time of day/circadian influences were not reported as high risk.	The results suggest a lack of awareness or appreciation of circadian rhythm functioning, particularly the descending phase of circadian rhythm that promotes increased sleepiness in the afternoon and during the early hours of the morning. Yet, the results suggested an appreciation of the danger associated with long-distance driving and driver sleepiness. Further efforts are required to improve the community's awareness of the impairing effects from sleepiness and, in particular, knowledge regarding the human circadian rhythm and the increased sleep propensity during the circadian nadir.	
26508317	During the resettlement of 6500 persons living around the Nam Theun 2 hydroelectric project in Laos, more than 1200 pour-flush latrines were constructed. To assess the role of these latrines as productive larval habitats for mosquitoes, entomological investigations using Centers for Disease Control (CDC) light traps, visual inspection and emergence trapping were carried out in over 300 latrines during the rainy seasons of 2008-2010. Armigeres subalbatus (Diptera: Culicidae) were nine times more likely to be found in latrines (mean catch: 3.09) than in adjacent bedrooms (mean catch: 0.37) [odds ratio (OR) 9.08, 95% confidence interval (CI) 6.74-15.11] and mosquitoes were active in and around 59% of latrines at dusk. Armigeres subalbatus was strongly associated with latrines with damaged or improperly sealed septic tank covers (OR 5.44, 95% CI 2.02-14.67; P < 0.001). Armigeres subalbatus is a nuisance biter and a putative vector of Japanese encephalitis and dengue viruses. Dengue virus serotype 3 was identified from a single pool of non-blood-fed female A. subalbatus using reverse transcription polymerase chain reaction. Maintaining a good seal around septic tanks by covering them with a layer of soil is a simple intervention to block mosquito exit/entry and contribute to vector control in resettlement villages. The scale-up of this simple, cheap intervention would have global impact in preventing the colonization of septic tanks by nuisance biting and disease-transmitting mosquitoes. 
26507264	Circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response. These symptoms may contribute to PD pathogenesis, despite a lack of direct experimental evidence supporting this relationship. Clock genes are essential to drive and maintain circadian rhythm. To elucidate the possible role of circadian disruptions in PD, we investigated 132 tag variants in eight clock genes. We genotyped these tags within 1,394 Chinese cases and 1,342 controls using Illumina GoldenGate chips. We discovered that SNPs in ARNTL (rs900147, P = 3.33 × 10(-5), OR = 0.80) and PER1 (rs2253820, P = 5.30 × 10(-6), OR = 1.31) genes are significantly associated with PD risk. Moreover, the positive association of the ARNTL rs900147 variant was more robust in tremor dominant (TD) (P = 3.44 × 10(-4)) than postural instability and gait difficulty (PIGD) cases (P = 6.06 × 10(-2)). The association of the PER1 rs2253820 variant was more robust in PIGD (P = 5.42 × 10(-5)) than TD cases (P = 4.2 × 10(-2)). Haplotype analysis also showed that ARNTL and PER1 were associated with PD. Imputation analysis identified more SNPs within ARNTL and PER1 associated with PD, some of which may affect gene expression through altering the transcription factor binding site. In summary, our findings suggest that genetic polymorphisms in ARNTL and PER1 genes, as well as circadian disruptions, may contribute to PD pathogenesis.

26506922	The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-β-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p < 0.05), particularly the 24 and 32 kHz ones (both p < 0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although, even after the second week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ∼25% (p < 0.001), in the rats of the 14 than 2 HALO group (x ± S.E.: 3.22 ± 0.49 and 4.53 ± 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono) pharmacodynamic than (chrono) pharmacokinetic mechanisms. 
26506093	Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes expression in such locations, suggesting a possible connection between the ghrelinergic and circadian systems in teleosts.
26505992	Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.	We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.	We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.	
26503676	Reversible acetylation was initially described as an epigenetic mechanism regulating DNA accessibility. Since then, this process has emerged as a controller of histone and nonhistone acetylation that integrates key physiological processes such as metabolism, circadian rhythm and cell cycle, along with gene regulation in various organisms. The widespread and reversible nature of acetylation also revitalized interest in the mechanisms that regulate lysine acetyltransferases (KATs) and deacetylases (KDACs) in health and disease. Changes in protein or histone acetylation are especially relevant for many common diseases including obesity, diabetes mellitus, neurodegenerative diseases and cancer, as well as for some rare diseases such as mitochondrial diseases and lipodystrophies. In this Review, we examine the role of reversible acetylation in metabolic control and how changes in levels of metabolites or cofactors, including nicotinamide adenine dinucleotide, nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or β-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status to adaptive cellular and organismal homeostasis. 
26503235	1. The aim of this study was to develop a population pharmacokinetic (PK) model for 5-fluorouracil (5-FU) and perform simulations to identify the circadian rhythm of the PK of 5-FU and the degree of circadian effects on the 5-FU plasma concentrations. 2. 5-FU plasma concentrations in rats following administration of 5-FU at varying time points throughout the day were obtained and used to develop the population PK model incorporating a circadian rhythm. The Cosinor method was used to describe the circadian variation of 5-FU clearance. 3. Our population PK model could successfully characterize the 5-FU disposition and provide reliable PK parameter estimates. The mesor, amplitude and acrophase of Cosinor model were estimated as 1.93 L/h/kg, 0.10 L/h/kg and 2.02 h, respectively. The peak clearance levels were estimated at ∼2 Hours After Light Onset (HALO) and the trough levels at ∼14 HALO. The plasma concentration-time profile of 5-FU after continuous infusion of 5-FU in rats successfully simulated the circadian variation of steady-state plasma concentrations. 4. The population PK model with individual 5-FU plasma concentrations, dose levels and sampling time points could be valuable for estimating area under the curve (AUC) levels and determining individual 5-FU dose management.
26501383	Milk has long been known and used to promote sleep. The sleep-promoting effect of milk has been attributed to its psychological associations (i.e., the memory of a mother giving milk at bedtime) and its rich store of sleep-promoting constituents (e.g., tryptophan). Studies have shown that milk harvested at night (Night milk) contains exceptionally high amounts of tryptophan and melatonin. In the present study, we evaluated the psychopharmacological properties of Night milk, particularly its probable sleep-promoting/enhancing, and anxiolytic effects. Night milk was orally administered to ICR mice at various concentrations (100, 200, or 300 mg/kg). An hour after administration, assessment of its sedative (open-field and rotarod tests) and sedative sleep-potentiating effects (pentobarbital-induced sleeping test) was conducted. For comparison, the effects of Day milk (daytime milking) were also assessed. In addition, the effects of Night milk on anxiety behavior (elevated plus maze [EPM] test) and electroencephalographic (EEG) waves were evaluated. Night milk-treated animals exhibited decreased spontaneous locomotion (open-field test) and impaired motor balance and coordination (rotarod test). Furthermore, Night milk shortened the sleep onset and prolonged the sleep duration induced by pentobarbital sodium. These effects were comparable to that of diazepam. In addition, Night milk significantly increased the percentage of time spent and entries into the open arms of the EPM, indicating that it also has anxiolytic effects. No significant changes in EEG waves were observed. Altogether, these findings suggest that Night milk is a promising natural aid for sleep- and anxiety-related disturbances.
26501334	Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. 
26500489	Silent information regulator-1 (SIRT1) deacetylase, a sensor of intermittent energy restriction, is inextricably intertwined with circadian regulation of central and peripheral clock genes. The purpose of this study was to identify SIRT1-specific target genes that are expressed in a circadian rhythm pattern and driven, in part, by specific components of foodstuffs. Using human cells and rats fed with a resveratrol diet we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding the G protein-coupled receptor (GPR), GPR50 in the brain. GPR50 is the mammalian orthologue of the melatonin1c membrane-bound receptor which has been identified as a genetic risk factor for bipolar disorder and major depression in women. In general, our findings support and expand the notion that circadian clock signaling components and dietary interventions are adaptively linked, and suggest that the brain may be particularly sensitive to metabolic events in response to light-dark cycles. 
26500165	Melanopsin (Opn4), a member of the G-protein-coupled receptor family, is a vitamin A-based opsin in the vertebrate retina that has been shown to be involved in the synchronization of circadian rhythms, pupillary light reflexes, melatonin suppression and other light-regulated tasks. In nonmammalian vertebrates there are two Opn4 genes, Opn4m and Opn4x, the mammalian and Xenopus orthologs respectively. Opn4x is only expressed in nonmammalian vertebrates including reptiles, fish and birds, while Opn4m is found in a subset of retinal ganglion cells (RGCs), the intrinsically photosensitive (ip) RGCs of the inner retina of both mammals and nonmammalian vertebrates. All opsins described utilize retinaldehyde as chromophore, photoisomerized from 11-cis- to all-trans-retinal upon light exposure. Visual retinal photoreceptor cones and rods, responsible for day and night vision respectively, recycle retinoids through a process called the visual cycle that involves the retinal pigment epithelium or glial Müller cells. Although Opn4 has been characterized as a bistable photopigment, little is known about the mechanism/s involved in its chromophore regeneration. In this review, we will attempt to shed light on the visual cycle taking place in the inner retina and discuss the state of the art in the nonvisual photochemistry of vertebrates. 

26498978	We studied the physical and mental conditions of 8 healthy young female ambulance paramedics working 24-hour shifts during their menstrual cycle, including assessment of cardiac autonomic nervous system activity by heart rate variability power spectral analysis.The autonomic activity during the awake period of on- and off-duty days in the follicular, late luteal, and menstruation phases was measured. Questionnaires regarding fatigue and menstrual distress were administered and correlated with the autonomic profile.	While degrees of fatigue significantly increased after work, the changes in autonomic activity during the awake period on on-duty days were not significantly different from those on off-duty days (LF/HF, p=0.123; HF/(HF+LF), p=0.153). As for the sleeping period, there were no significant differences. Although the Menstrual Distress Questionnaire (MDQ) revealed the presence of mild menstrual discomfort in the late luteal and menstruation phases, no significant difference was observed in the autonomic profile of the three menstrual cycle phases. No significant correlation was observed between the degree of menstrual distress and autonomic profile, though there was a significant correlation in the late luteal phase between degree of menstrual distress and fatigue after work (p<0.01).	These results showed that, while subjects experienced menstrual discomfort and fatigue after work, their autonomic profile did not alter in the menstrual cycle. It is suggested that healthy young female ambulance paramedics may tolerate 24-hour shifts, though attention should be paid to subjective menstrual symptoms and fatigue.	
26498531	Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP-activated protein kinase (AMPK) activity plays important roles in the metabolic process and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, little is known regarding the regulatory mechanisms involved in the circadian rhythm of AMPK activity. The aim of this study is to investigate whether there is a direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased AMPK activity, whereas overexpression of DEC1 decreased it. Overexpressing the DEC1 basic mutants had little effect on the AMPK activity. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. There was an inverse relationship between DEC1 expression and AMPK activity. Our results suggest that DEC1 negatively regulates AMPK activity via LKB1. 
26498241	Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor β (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers.Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses.	The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001).	Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies.	
26498240	Night-shift work (NSW) has previously been related to incidents of breast cancer and all-cause mortality, but many published studies have reported inconclusive results. The aim of the present study was to quantify a potential dose-effect relationship between NSW and morbidity of breast cancer, and to evaluate the association between NSW and risk of all-cause mortality. The outcomes included NSW, morbidity of breast cancer, cardiovascular mortality, cancer-related mortality, and all-cause mortality. Sixteen investigations were included, involving 2,020,641 participants, 10,004 incident breast cancer cases, 7185 cancer-related deaths, 4820 cardiovascular end points, and 2480 all-cause mortalities. The summary risk ratio (RR) of incident breast cancer for an increase of NSW was 1.057 [95% confidence interval (CI) 1.014-1.102; test for heterogeneity p = 0.358, I(2) = 9.2%]. The combined RR (95% CI) of breast cancer risk for NSW vs daytime work was: 1.029 (0.969-1.093) in the <5-year subgroup, 1.019 (1.001-1.038) for 5-year incremental risk, 1.025 (1.006-1.044) for 5- to 10-year exposure times, 1.074 (1.010-1.142) in the 10- to 20-year subgroup, and 1.088 (1.012-1.169) for >20-year exposure lengths. The overall RR was 1.089 (95% CI 1.016-1.166) in a fixed-effects model (test for heterogeneity p = 0.838, I(2) = 0%) comparing rotating NSW and day work. Night-shift work was associated with an increased risk of cardiovascular death (RR 1.027, 95% CI 1.001-1.053), and all-cause death 1.253 (95% CI 0.786-1.997). In summary, NSW increased the risk of breast cancer morbidity by: 1.9% for 5 years, 2.5% for 5-10 years, 7.4% for 10-20 years, and 8.8% for >20-years of NSW. Additionally, rotating NSW enhanced the morbidity of breast cancer by 8.9%. Moreover, NSW was associated with a 2.7% increase in cardiovascular death.
26498235	A number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light-dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light-dark schedule would affect behavior-, circadian clock-, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice.Mice were subjected to an 8-hour phase delay in the light-dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus.	Locomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light-dark and inactive-active cycles. The amplitude of the day-night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light-dark-shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period.	The present results suggest that misalignment of the internal and external clocks by continuous shifting of the light-dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice.	
26498192	The regulation of metabolism by circadian systems is believed to be a key reason for the extensive representation of circadian rhythms within the tree of life. Despite this, surprisingly little work has focused on the link between metabolism and the clock in Neurospora, a key model system in circadian research. The analysis that has been performed has focused on the unidirectional control from the clock to metabolism and largely ignored the feedback from metabolism on the clock. Recent efforts to understand these links have broken new ground, revealing bidirectional control from the clock to metabolism and vise-versa, showing just how strongly interconnected these two cellular systems can be in fungi. This review describes both well understood and emerging links between the clock and metabolic output of fungi as well as the role that metabolism plays in influencing the rhythm set by the clock. 
26498045	Theoretical models on shift work fall short of describing relevant health-related pathways associated with the broader concept of nonstandard working schedules. Shift work models neither combine relevant working time characteristics applicable to nonstandard schedules nor include the role of rest periods and recovery in the development of health complaints. Therefore, this paper aimed to develop a comprehensive model on nonstandard working schedules to address these shortcomings.A literature review was conducted using a systematic search and selection process. Two searches were performed: one associating the working time characteristics time-of-day and working time duration with health and one associating recovery after work with health. Data extracted from the models were used to develop a comprehensive model on nonstandard working schedules and health.	For models on the working time characteristics, the search strategy yielded 3044 references, of which 26 met the inclusion criteria that contained 22 distinctive models. For models on recovery after work, the search strategy yielded 896 references, of which seven met the inclusion criteria containing seven distinctive models. Of the models on the working time characteristics, three combined time-of-day with working time duration, 18 were on time-of-day (i.e. shift work), and one was on working time duration. The model developed in the paper has a comprehensive approach to working hours and other work-related risk factors and proposes that they should be balanced by positive non-work factors to maintain health. Physiological processes leading to health complaints are circadian disruption, sleep deprivation, and activation that should be counterbalanced by (re-)entrainment, restorative sleep, and recovery, respectively, to maintain health.	A comprehensive model on nonstandard working schedules and health was developed. The model proposes that work and non-work as well as their associated physiological processes need to be balanced to maintain good health. The model gives researchers a useful overview over the various risk factors and pathways associated with health that should be considered when studying any form of nonstandard working schedule.	
26497961	The aim of the present study was to evaluate diurnal variations of the variability and irregularity of heart rate (HR) in patients with permanent atrial fibrillation (AF) with and without rate control drugs. Thirty-eight patients with permanent AF were part of an investigator-blind crossover study comparing diltiazem, verapamil, metoprolol, and carvedilol. We analyzed five Holter recordings per patient: at baseline (no rate control drug) and with each of the four drug regimens. HR, variability (SD; percentages of interval differences of successive RR intervals of >20, 50, and 80 ms; and root of the mean squared differences of successive RR intervals), and irregularity (approximate and sample entropy) parameters were computed in 20-min long nonoverlapping segments. Circadian rhythmicity was evaluated using cosinor analysis to each parameter series, which is characterized by the 24-h mean [midline statistic of rhythm (MESOR)] and excursion over the mean (amplitude). Arrhythmia-related symptoms were assessed by a questionnaire measuring symptom severity and frequency. HR and variability parameters showed a significant circadian variation in most patients, whereas only a small minority of the patients had circadian variations of irregularity parameters. Patients with circadian approximate entropy n at baseline had more severe symptoms (symptom severity: 9 ± 4 vs. 6 ± 5, P < 0.05, circadian vs. noncircadian variations). All drugs decreased the MESOR of HR and increased the MESOR of variability parameters. Only carvedilol and metoprolol decreased the normalized amplitude over 24 h of all parameters and HR. In conclusion, HR and RR variability parameters present a circadian variation in patients with permanent AF, whereas few patients demonstrated circadian fluctuations in irregularity parameters, suggesting different physiological mechanisms. 
26497887	Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke.
26496725	Circadian clocks synchronize organisms to the 24 h rhythms of the environment. These clocks persist under constant conditions, have their origin at the cellular level, and produce an output of rhythmic mRNA expression affecting thousands of transcripts in many mammalian cell types. Here, we review the charting of circadian output rhythms in mRNA expression, focusing on mammals. We emphasize the challenges in statistics, interpretation, and quantitative descriptions that such investigations have faced and continue to face, and outline remaining outstanding questions.
26496621	To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel(®) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study.	TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group.	Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.	
26496543	Because of the increase in the use of 24-hour-a-day 7-day-a-week real-time radiologic interpretation, radiologists more frequently perform after-hours work. The purpose of this article was to examine the challenges arising from after-hours work and describe evidence-based strategies meant to limit the adverse physical and psychologic stresses of after-hours work.Working nontraditional hours affects a radiologist's health, social life, professional productivity, and possibly interpretive accuracy. Appropriate attention to these factors and targeted countermeasures can optimize the professional development and personal well-being of radiologists working after hours.	
26494808	The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa.The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D).	The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied.	Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.	
26493868	Previous microarray analyses of RNAs from 8-cell (8C) human embryos revealed a lack of cell cycle checkpoints and overexpression of core circadian oscillators and cell cycle drivers relative to pluripotent human stem cells [human embryonic stem cells/induced pluripotent stem (hES/iPS)] and fibroblasts, suggesting growth factor independence during early cleavage stages. To explore this possibility, we queried our combined microarray database for expression of 487 growth factors and receptors. Fifty-one gene elements were overdetected on the 8C arrays relative to hES/iPS cells, including 14 detected at least 80-fold higher, which annotated to multiple pathways: six cytokine family (CSF1R, IL2RG, IL3RA, IL4, IL17B, IL23R), four transforming growth factor beta (TGFB) family (BMP6, BMP15, GDF9, ENG), one fibroblast growth factor (FGF) family [FGF14(FH4)], one epidermal growth factor member (GAB1), plus CD36, and CLEC10A. 8C-specific gene elements were enriched (73%) for reported circadian-controlled genes in mouse tissues. High-level detection of CSF1R, ENG, IL23R, and IL3RA specifically on the 8C arrays suggests the embryo plays an active role in blocking immune rejection and is poised for trophectoderm development; robust detection of NRG1, GAB1, -2, GRB7, and FGF14(FHF4) indicates novel roles in early development in addition to their known roles in later development. Forty-four gene elements were underdetected on the 8C arrays, including 11 at least 80-fold under the pluripotent cells: two cytokines (IFITM1, TNFRSF8), five TGFBs (BMP7, LEFTY1, LEFTY2, TDGF1, TDGF3), two FGFs (FGF2, FGF receptor 1), plus ING5, and WNT6. The microarray detection patterns suggest that hES/iPS cells exhibit suppressed circadian competence, underexpression of early differentiation markers, and more robust expression of generic pluripotency genes, in keeping with an artificial state of continual uncommitted cell division. In contrast, gene expression patterns of the 8C embryo suggest that it is an independent circadian rhythm-competent equivalence group poised to signal its environment, defend against maternal immune rejection, and begin the rapid commitment events of early embryogenesis.
26490070	The aim of this study was to observe the influence of interfered circadian rhythm on pregnancy of rats and growth of neonatal rats, and to explore the relationship between the interfered circadian rhythm and the changes of melatonin and progesterone. Continuous light was used to inhibit melatonin secretion and therefore the interfered circadian rhythm animal model was obtained. The influence of interfered circadian rhythm on delivery of pregnant rats was observed. Serum was collected from rats during different stages of pregnancy to measure the concentrations of melatonin and progesterone. In order to observe the embryo resorption rate, half of pregnant rats were randomly selected to undergo a laparotomy, and the remainder was used to observe delivery and assess the growth of neonatal rats after delivery. The results showed that the interfered circadian rhythm induced adverse effects on pregnancy outcomes, including an increase of embryo resorption rate and a decrease in the number of live births; inhibited the secretion of melatonin along with decreased serum progesterone level; prolonged the stage of labor, but not the duration of pregnancy; and disturbed the fetal intrauterine growth and the growth of neonatal rats. The results suggest that interfered circadian rhythm condition made by continuous light could make adverse effects on both pregnant rats and neonatal rats. The results of our study may provide a way to modulate pregnant women's circadian rhythm and a possibility of application of melatonin on pregnant women. 
26489367	The temporal order of physiology and behaviour in mammals is regulated by the coordination of the master circadian clock in the suprachiasmatic nucleus (SCN) and peripheral clocks in various tissues outside the SCN. Because the circadian oscillator(s) in the olfactory bulb (OB) is regarded as SCN independent, we examined the relationship between the SCN master clock and the circadian clock in the OB. We also examined the role of vasoactive intestinal peptide receptor 2 in the circadian organization of the OB. We continuously monitored the circadian rhythms of a clock gene product PER2 in the SCN and OB of freely moving mice by means of a bioluminescence reporter and an optical fibre implanted in the brain. Robust circadian rhythms were detected in the OB and SCN for up to 19 days. Bilateral SCN lesions abolished the circadian behaviour rhythms and disorganized the PER2 rhythms in the OB. The PER2 rhythms in the OB showed more than one oscillatory component of a similar circadian period, suggesting internal desynchronization of constituent oscillators. By contrast, significant circadian PER2 rhythms were detected in the vasoactive intestinal peptide receptor 2-deficient mice, despite the substantial deterioration or abolition of circadian behavioural rhythms. These findings indicate that the circadian clock in the OB of freely moving mice depends on the SCN master clock but not on the circadian behavioural rhythms. The circadian PER2::LUC rhythm in the cultured OB was as robust as that in the cultured SCN but reset by slice preparation, suggesting that culturing of the slice reinforces the circadian rhythm.
26487747	Cardiovascular autonomic neuropathy is one of the factors implicated in the high morbidity and mortality rate in patients with COPD. Thus, several studies and nonsystematic reviews have increasingly reported autonomic function impairment in these subjects. For a better understanding, this systematic review was performed to evaluate not only the evidence for autonomic function impairment, but also factors influencing it. The results of the studies reviewed showed a strong level of evidence to support the impairment of heart rate variability in the time domain. A similar evidence level was also found to support impairment in baroreceptor sensitivity and muscle sympathetic nerve activity. Furthermore, this review identified physical activity level, muscle function, and circadian rhythm as the major influencing factors (strong evidence) of autonomic function in subjects with COPD. However, no definite conclusion could be reached for factors such as dyspnea, anxiety, body composition, pulmonary function, age, breathing frequency, ventilatory effort, quality of life, and disease severity due to limited, conflicting, or lack of existing evidence. The results of this review highlight relevant clinical messages for clinicians and other health-care providers regarding the role autonomic function can play as an important physiological marker for prognostication and stratification. Hence, autonomic function outcomes should be identified and considered during management of patients with COPD. Moreover, this review can serve as basis for future research aimed at assessing the interventions for autonomic function abnormalities in these patients.
26486724	Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ. 
26486627	The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1(-/-) ) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity. Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1(-/-) ), a model of advanced ageing. iMSBmal1(-/-) mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing.Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1(-/-) mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone.	
26486360	The polyphagous Drosophila suzukii is a highly invasive species that causes extensive damage to a wide range of berry and stone fruit crops. A better understanding of its biology and especially its behaviour will aid the development of new control strategies. We investigated the locomotor behaviour of D. suzukii in a semi-natural environment resembling a typical summer in northern England and show that adult female D. suzukii are at least 4-fold more active during daylight hours than adult males. This result was reproduced in several laboratory environments and was shown to be a robust feature of mated, but not virgin, female flies. Both males and virgin females kept on a 12 h light:12 h dark (12LD) cycle and constant temperature displayed night-time inactivity (sleep) followed by weak activity in the morning, an afternoon period of quiescence (siesta) and then a prominent evening peak of activity. Both the siesta and the sharp evening peak at lights off were severely reduced in females after mating. Flies of either sex entrained in 12LD displayed a circadian pattern of activity in constant darkness confirming the importance of an endogenous clock in regulating adult activity. This response of females to mating is similar to that elicited in female Drosophila melanogaster by the male sex peptide (SP). We used mass spectrometry to identify a molecular ion (m/z, 5145) corresponding to the poly-hydroxylated SP of D. suzukii and to show that this molecule is transferred to the female reproductive tract during copulation. We propose that the siesta experienced by male and virgin female D. suzukii is an adaptation to avoid unnecessary exposure to the afternoon sun, but that mated females faced with the challenge of obtaining resources for egg production and finding oviposition sites take greater risks, and we suggest that the change in female behaviour is induced by the male SP. 
26485373	Endogenous long-term timing is a key component of seasonality. Where and how are such rhythms generated? Recent findings pointed to the pituitary pars tuberalis, already implicated in photoperiod responsiveness. Now, a new study provides mechanistic insights which support this hypothesis. 
26485124	Fetal cells in maternal blood may be used for noninvasive prenatal diagnostics, although their low number is a challenge. This study's objectives were to evaluate whether physical activity, transabdominal and transvaginal ultrasound scans of the uterus, as well as overnight or day-to-day variation affect the number of isolated fetal cells, more specifically the presumed endovascular trophoblast (pEVT).In each of 3 different experiments, 10 normal singleton pregnant women (gestational age 10+4-14+4 weeks) participated. The number of pEVTs was assessed in 30-36 ml blood using specific markers for enrichment and identification.	The number of pEVTs increased overnight (p = 0.001) from a median of 1.5 to 3.5 and even further to a median of 6.0 after 30 min of physical activity (p = 0.04) but was not affected by transabdominal and transvaginal ultrasound scans. Repeated sampling showed that the interindividual variation of pEVTs was higher than the intraindividual variation (p < 0.001). However, even in pregnant women with a consistently low number of pEVTs, isolation of the pEVTs for prenatal diagnoses was possible in all cases by doing 2 separate blood samplings a few days apart.	The number of pEVTs identified in maternal blood can be increased by presampling conditions or repeated sampling.	
26484767	To compare the 24-hour (24h) effects on intraocular pressure (IOP) and cardiovascular parameters of timolol 0.5% and bimatoprost 0.01% in open angle glaucoma and ocular hypertensive subjects.In this prospective, randomized, double masked, crossover, clinical trial, after washout from previous medications enrolled subjects underwent 24h IOP, blood pressure (BP) and heart rate (HR) measurements and were randomized to either topical bimatoprost 0.01% at night plus placebo in the morning or to timolol 0.5% bid. After 8 weeks of treatment a second 24h assessment of IOP, BP and HR was performed and then subjects switched to the opposite treatment for additional 8 weeks when a third 24h assessment was performed. The primary endpoint was the comparison of the mean 24h IOP after each treatment. Secondary endpoints included the comparisons of IOP at each timepoint of the 24h curve and the comparison of BP, HR, ocular perfusion pressure and tolerability.	Mean untreated 24h IOP was 20.3 mmHg (95%CI 19.0 to 21.6). Mean 24h IOP was significantly lower after 8 weeks of treatment with bimatoprost 0.01% than after 8 weeks of treatment with timolol 0.5% bid (15.7 vs 16.8 mmHg, p = 0.0003). Mean IOP during the day hours was significantly reduced from baseline by both drugs while mean IOP during the night hours was reduced by -2.3 mmHg (p = 0.0002) by bimatoprost 0.01% plus placebo and by -1.1 mmHg by timolol 0.5% bid (p = 0.06). Timolol 0.5% significantly reduced the mean 24h systolic BP from baseline, the diastolic BP during the day hours, the HR during the night hours, and the mean 24h systolic ocular perfusion pressure.	Both Bimatoprost 0.01% and Timolol 0.5% are effective in reducing the mean 24h IOP from an untreated baseline but Bimatoprost 0.01% is more effective than timolol 0.5% throughout the 24h. Timolol 0.5% effect on IOP is reduced during the night hours and is associated with reduced BP, HR and ocular perfusion pressure.	EU Clinical Trial Register and EudraCT# 2010-024272-26.	
26484727	A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia.This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model.	In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59.	Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions.	
26483921	Circadian rhythmicity in humans has been well studied using actigraphy, a method of measuring gross motor movement. As actigraphic technology continues to evolve, it is important for data analysis to keep pace with new variables and features. Our objective is to study the behavior of two variables, interdaily stability and intradaily variability, to describe rest activity rhythm. Simulated data and actigraphy data of humans, rats, and marmosets were used in this study. We modified the method of calculation for IV and IS by modifying the time intervals of analysis. For each variable, we calculated the average value (IVm and ISm) results for each time interval. Simulated data showed that (1) synchronization analysis depends on sample size, and (2) fragmentation is independent of the amplitude of the generated noise. We were able to obtain a significant difference in the fragmentation patterns of stroke patients using an IVm variable, while the variable IV60 was not identified. Rhythmic synchronization of activity and rest was significantly higher in young than adults with Parkinson׳s when using the ISM variable; however, this difference was not seen using IS60. We propose an updated format to calculate rhythmic fragmentation, including two additional optional variables. These alternative methods of nonparametric analysis aim to more precisely detect sleep-wake cycle fragmentation and synchronization. 
26483754	Team performance is a complex phenomenon involving numerous influencing factors including physiology, psychology, and management. Biological rhythms and the impact of circadian phenotype have not been studied for their contribution to this array of factors so far despite our knowledge of the circadian regulation of key physiological processes involved in physical and mental performance. This study involved 216 individuals from 12 different teams who were categorized into circadian phenotypes using the novel RBUB chronometric test. The composition of circadian phenotypes within each team was used to model predicted daily team performance profiles based on physical performance tests. Our results show that the composition of circadian phenotypes within teams is variable and unpredictable. Predicted physical peak performance ranged from 1:52 to 8:59 p.m. with performance levels fluctuating by up to 14.88% over the course of the day. The major predictor for peak performance time in the course of a day in a team is the occurrence of late circadian phenotypes. We conclude that circadian phenotype is a performance indicator in teams that allows new insight and a better understanding of team performance variation in the course of a day as often observed in different groupings of individuals. 
26483181	Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms. 
26482709	Odor discrimination behavior displays circadian fluctuations in mice, indicating that mammalian olfactory function is under control of the circadian system. This is further supported by the facts that odor discrimination rhythms depend on the presence of clock genes and that olfactory tissues contain autonomous circadian clocks. However, the molecular link between circadian function and olfactory processing is still unknown. To elucidate the molecular mechanisms underlying this link, we focused on the olfactory epithelium (OE), the primary target of odors and the site of the initial events in olfactory processing. We asked whether olfactory sensory neurons (OSNs) within the OE possess an autonomous circadian clock and whether olfactory pathways are under circadian control. Employing clock gene-driven bioluminescence reporter assays and time-dependent immunohistochemistry on OE samples, we found robust circadian rhythms of core clock genes and their proteins in OSNs, suggesting that the OE indeed contains an autonomous circadian clock. Furthermore, we performed a circadian transcriptome analysis and identified several OSN-specific components that are under circadian control, including those with putative roles in circadian olfactory processing, such as KIRREL2-an established factor involved in short-term OSN activation. The spatiotemporal expression patterns of our candidate proteins suggest that they are involved in short-term anabolic processes to rhythmically prepare the cell for peak performances and to promote circadian function of OSNs.
26481542	The hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the release of corticosterone in response to stress, exhibits large circadian variations in its activity that can also be regulated by the noradrenergic system, thereby contributing to the pathophysiology of depression. We have recently shown that mice in which glucocorticoid receptors (GR) are selectively ablated in the noradrenergic system (GR(DBHCre) mice) exhibit sex-dependent phenotype alterations, manifested as increased anxiety- and depressive-like behaviors in female but not male mutants.In this study, we investigated the regulation of circadian HPA axis activity in GR(DBHCre) transgenic mice by measuring plasma corticosterone levels.	We found that evening plasma corticosterone increase was profoundly higher in females than males, and this diversification was further augmented in mutant GR(DBHCre) mice.	Our results provide evidence of the involvement of the noradrenergic system in the regulation of the sexually dimorphic circadian activity of the HPA axis.	
26480842	How did humans sleep before the modern era? Because the tools to measure sleep under natural conditions were developed long after the invention of the electric devices suspected of delaying and reducing sleep, we investigated sleep in three preindustrial societies [1-3]. We find that all three show similar sleep organization, suggesting that they express core human sleep patterns, most likely characteristic of pre-modern era Homo sapiens. Sleep periods, the times from onset to offset, averaged 6.9-8.5 hr, with sleep durations of 5.7-7.1 hr, amounts near the low end of those industrial societies [4-7]. There was a difference of nearly 1 hr between summer and winter sleep. Daily variation in sleep duration was strongly linked to time of onset, rather than offset. None of these groups began sleep near sunset, onset occurring, on average, 3.3 hr after sunset. Awakening was usually before sunrise. The sleep period consistently occurred during the nighttime period of falling environmental temperature, was not interrupted by extended periods of waking, and terminated, with vasoconstriction, near the nadir of daily ambient temperature. The daily cycle of temperature change, largely eliminated from modern sleep environments, may be a potent natural regulator of sleep. Light exposure was maximal in the morning and greatly decreased at noon, indicating that all three groups seek shade at midday and that light activation of the suprachiasmatic nucleus is maximal in the morning. Napping occurred on <7% of days in winter and <22% of days in summer. Mimicking aspects of the natural environment might be effective in treating certain modern sleep disorders. 
26480221	The treatment of bipolar disorder is a current challenge for clinicians and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance. Particularly, relapse prevention and longterm stabilization is a major therapeutic target. Combination treatment and polypharmacy are the most common choices concerning relapse prevention. Furthermore, during maintenance phase patients often experience residual mood symptoms, cognitive deficits and functional decline, which altogether illustrate the inadequate effectiveness of existing treatments and the need for new, targeted, effective and safe treatments for bipolar disorder. This review focuses on active agents for maintenance treatment in bipolar disorder investigated during the last 5 years. The compounds under investigation have been tried or tested either as monotherapy or as an add-on treatment in clinical trials that have progressed up to phase 3 or in preclinical models of bipolar disorder. While awaiting the completion of many ongoing studies, the results so far indicate that paliperidone and pregabalin may have a position in the maintenance treatment of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA antagonist, may be an interesting compound for further study. However, results on memantine, another NMDA antagonist, were not encouraging. The effects of omega-3 fatty acids and cytidine were not superior to placebo, although they both have neurotrophic and neuroprotective properties. Eslicarbazepine, which has antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding preclinical studies in experimental models, the pharmacological agents under investigation seem to follow the neurobiological pathways related to mechanism of action of lithium, which is still the "golden standard" for preventing recurrence in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-3) and the path of phosphoinositol (IMP), both probably involved in the action of lithium. Furthermore, the role of circadian rhythms maintenance is being studied in preclinical and clinical trials investigating the efficacy and safety of compounds CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents based on epigenetic changes and gene expression modulation, as the inhibitor of histone deacetylase (HDAC). Of note, the development of valid and reliable experimental models for bipolar disorder, which currently remains quite controversial, will contribute to the understanding of the pathogenic mechanisms and the development of new effective treatments. Improving methodology aspects of clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender differences and comorbidities, may promote research. Current studies seem promising for the development of novel pharmacological agents in the near future, although there are methodological limitations in the search for the maintenance treatment in bipolar disorder. New therapeutic targets include not only the already known mechanisms of action, but also novel pathophysiological pathways, probably implicated in bipolar disorder. 
26479844	The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects. 
26479272	Captive giraffes (Giraffa camelopardalis) are known to perform oral and locomotor stereotypies. However, many studies do not consider the behavioral repertoire of these animals during the time when animals are confined to night quarters. At two zoological institutions, a total of six captive giraffes were observed via camera trap technology throughout six diurnal and nocturnal periods to record feeding, ruminating, and stereotypic behaviors. The effect of browse enrichment was assessed on alternate nights to determine how behaviors may be altered in the presence of natural forage. Results need to be interpreted with caution due to a high proportion of time when animals were out of camera range. For the observed time, stereotypical licking behavior was significantly higher at night compared to daytime at both facilities, while tongue play increased at the same time, but not significantly. The provision of browse enrichment during the night decreased the rate of tongue playing, but not significantly; however, browse did significantly reduce pacing behavior. Across treatments and institutions, observed oral stereotypies tended to correlate negatively with increased feeding behavior. Apart from a short-term effect of enrichment, this study indicates relevant differences in the frequencies of behaviors observed during the day and night, suggesting that assessing nocturnal behavior specifically may be important in many species.
26479193	Polycystic ovary syndrome (PCOS) is an endocrine disorder linked to type II diabetes and the leading cause of female infertility worldwide. Despite being considered a "lifestyle" disease, PCOS has received scant attention in the social science literature. In India, media accounts citing prominent doctors have expressed concern that the syndrome affects a growing number of urban middle-class Indian women. The general public, doctors, and afflicted women all attribute the condition to stress, lifestyle changes, "Westernization," modernization, and disrupted circadian rhythms. These factors are associated with changes in diets, gender roles, and aspirations since 1991, when the introduction of neoliberal reforms opened up the country to processes of globalization. Women with PCOS have come to be seen as living embodiments of the biosocial stresses associated with modern urban middle-class living, and discourse about PCOS serves as commentary indexing anxieties about social and political-economic shifts in the country. In this paper, based on ethnographic fieldwork in Mumbai, India, with 141 participants from 2012 to 2014, we point to local understanding of PCOS as corresponding to an ecosocial perspective that highlights the structural vulnerabilities of urban middle-class women. Whereas most research on structural vulnerabilities and health has centered on economically and otherwise disadvantaged groups, we use PCOS as a case study to draw attention to the rise of lifestyle disorders linked to the impact of globalization and the pressures of "modern" identities and aspirations among middle-class populations. 
26478783	Molecular oscillation of the circadian clock is based on E-box-mediated transcriptional feedback loop formed with clock genes and their encoding products, clock proteins. The clock proteins are regulated by post-translational modifications such as phosphorylation. We investigated the effects of a series of kinase inhibitors on gene expression rhythms in Rat-1 fibroblasts. The period of the cellular circadian rhythm in culture was lengthened by treatment with SB203580 (p38 MAPK inhibitor), SP600125 (JNK inhibitor), IC261 (CKI inhibitor) and Roscovitine (CDK inhibitor). On the other hand, the period was shortened by SB216763 (GSK-3 inhibitor) or KN93 (CaMKII inhibitor) treatment. Application of 20 μM KN93 completely abolished the rhythmic gene expression. The activity of CaMKII exhibited circadian variation in a phase close to the E-box-mediated transcriptional rhythms. In vitro kinase assay revealed that CaMKII directly phosphorylates N-terminal and Ser/Pro-rich domains of CLOCK, an activator of E-box-mediated transcription. These results indicate a phosphorylation-dependent tuning of the period length by a regulatory network of multiple kinases and reveal an essential role of CaMKII in the cellular oscillation mechanism. 
26478577	Although many studies have assessed the efficacy of yoga in older individuals, minimal research has focused on how nurses use yoga to improve sleep quality and to reduce work stress after work hours. We used the Pittsburgh Sleep Quality Index in Chinese and the Questionnaire on Medical Worker's Stress in Chinese to determine the impact of yoga on the quality of sleep and work stress of staff nurses employed by a general hospital in China.Disturbances in the circadian rhythm interrupt an individual's pattern of sleep.	Convenient sampling method.	One hundred and twenty nurses were randomised into two groups: a yoga group and a non-yoga group. The yoga group performed yoga more than two times every week for 50-60 minutes each time after work hours. The NG group did not participate in yoga. After six months, self-reported sleep quality and work stress were compared between the two groups, and then we used linear regression to confirm the independent factors related to sleep quality.	Nurses in the yoga group had better sleep quality and lower work stress compared with nurses in the non-yoga group. The linear regression model indicated that nursing experience, age and yoga intervention were significantly related to sleep quality.	Regular yoga can improve sleep quality and reduce work stress in staff nurses.	This study provides evidence that hospital management should pay attention to nurse sleep quality and work stress, thereby taking corresponding measures to reduce work pressure and improve health outcomes.	
26478197	The older patient population is growing rapidly around the world and in the USA. Almost half of seniors over age 65 who live at home are dissatisfied with their sleep, and nearly two-thirds of those residing in nursing home facilities suffer from sleep disorders. Chronic and pervasive sleep complaints and disturbances are frequently associated with excessive daytime sleepiness and may result in impaired cognition, diminished intellect, poor memory, confusion, and psychomotor retardation all of which may be misinterpreted as dementia. The key sleep disorders impacting patients with dementia include insomnia, hypersomnolence, circadian rhythm misalignment, sleep disordered breathing, motor disturbances of sleep such as periodic leg movement disorder of sleep and restless leg syndrome, and parasomnias, mostly in the form of rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a pre-clinical marker for a class of neurodegenerative diseases, the "synucleinopathies", and requires formal polysomnographic evaluation. Untreated sleep disorders may exacerbate cognitive and behavioral symptoms in patients with dementia and are a source of considerable stress for bed partners and family members. When left untreated, sleep disturbances may also increase the risk of injury at night, compromise health-related quality of life, and precipitate and accelerate social and economic burdens for caregivers. 
26476412	Besides stomatal closure, biological detoxification is an important protection mechanism for plants against ozone (O3). This study investigated the diurnal changes of ascorbate (a major detoxification agent) in the apoplast and leaf tissues of winter wheat grown under ambient air field conditions. Results showed the reduced ascorbate in the apoplast (ASCapo) exhibited a peak in late morning or midday, mismatching with either the maximum external O3 concentrations in mid-afternoon or the maximum stomatal O3 uptake between late morning and mid-afternoon. In contrast, the ASC in leaf tissues remained stable throughout the day. The investigations conducted in a Free-Air Concentration Elevation of O3 system confirmed that the diurnal variations of the ASCapo were induced more by the daily variations of O3 concentrations rather than the cumulative O3 effects. In conclusion, the O3-stress detoxification should be a dynamic variable rather than a fixed threshold as assumed in the stomatal flux-based O3 dose metrics. 
26476274	Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca(2+) changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2::luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 h in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca(2+) less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs.We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms.	
26476176	Studies have established that grown children's problems affect parental well-being, but a dearth of research has addressed daily interactions and biological systems that may underlie these associations. This study examined whether parents have different types of daily interactions with adult children who have problems and whether those interactions are associated with variations in parents' diurnal cortisol rhythms. Middle-aged parents (n=197) reported their interactions with adult children for seven consecutive days and provided saliva, analyzed for cortisol, three times a day (wake, 30 min after wake, bedtime) for four of those days. Parents were more likely to report negative encounters but not less likely to report positive interactions or contact with adult children who suffered from problems. Interactions with adult children who had physical-emotional problems had more immediate same day associations with cortisol whereas interactions with adult children who had lifestyle-behavioral problems had more delayed, or next day associations with cortisol. Daily interactions and their associations with the hypothalamic-pituitary-adrenal-axis may be important mechanisms by which adult children with problems negatively affect parental well-being.
26475937	In this study, we investigated the influence of diurnal sampling bias on the community structure of plankton by comparing the biodiversity among seawater samples (n=9) obtained every 3h for 24h by using massively parallel sequencing (MPS)-based plankton monitoring at a fixed point conducted at Himedo seaport in Yatsushiro Sea, Japan. The number of raw operational taxonomy units (OTUs) and OTUs after re-sampling was 507-658 (558 ± 104, mean ± standard deviation) and 448-544 (467 ± 81), respectively, indicating high plankton biodiversity at the sampling location. The relative abundance of the top 20 OTUs in the samples from Himedo seaport was 48.8-67.7% (58.0 ± 5.8%), and the highest-ranked OTU was Pseudo-nitzschia species (Bacillariophyta) with a relative abundance of 17.3-39.2%, followed by Oithona sp. 1 and Oithona sp. 2 (Arthropoda). During seawater sampling, the semidiurnal tidal current having an amplitude of 0.3ms(-1) was dominant, and the westward residual current driven by the northeasterly wind was continuously observed during the 24-h monitoring. Therefore, the relative abundance of plankton species apparently fluctuated among the samples, but no significant difference was noted according to G-test (p>0.05). Significant differences were observed between the samples obtained from a different locality (Kusuura in Yatsushiro Sea) and at different dates, suggesting that the influence of diurnal sampling bias on plankton diversity, determined using the MPS-based survey, was not significant and acceptable.
26475647	We aimed to investigate the circadian rhythm on left ventricular (LV) function and infarct size, according to the onset of ST elevation myocardial infarction (STEMI), with echocardiography in patients with first STEMI successfully revascularised with primary percutaneous coronary intervention (PCI).We conducted a retrospective analysis of 252 STEMI patients. Patients were divided into the four, six-hour periods of the day. Conventional and tissue Doppler imaging (TDI) echocardiography were performed within 48hours after onset of chest pain. The average of peak systolic myocardial velocities (Sm) in each of the four myocardial segments and LV ejection fraction (LVEF) were calculated.	A negative linear correlation was shown between CK-MB levels and Sm (r= -0.209, p=0.001). There was an oscillation between time of day and average of Sm. The lowest Sm and largest infarct size were in the period of 06:00-noon compared with period of noon-18:00 and 18:00-midnight (p=0.029 and p=0.031, respectively). A secondary analysis showed that both LVEF and Sm were lower in the midnight-noon group compared with the noon-midnight group (44.9±7.3% versus 47.3±7.9%, p=0.018, and 7.6±1.4cm/s versus 8.2±1.6cm/s, p=0.003, respectively).	This study has shown that there was a circadian rhythm of infarct size and LV function evaluated by echocardiography according to time of STEMI onset. The largest infarct size and poor LV function occurred in the midnight-noon period, in particular in the 06:00-noon period.	
26475199	Arabidopsis thaliana has four NADP-dependent malic enzymes (NADP-ME 1-4) for reversible malate decarboxylation, with NADP-ME2 being the only cytosolic isoform ubiquitously expressed and responsible for most of the total activity. In this work, we further investigated its physiological function by characterizing Arabidopsis plants over-expressing NADP-ME2 constitutively. In comparison to wild type, these plants exhibited reduced rosette and root sizes, delayed flowering time and increased sensitivity to mannitol and polyethylene glycol. The increased NADP-ME2 activity led to a decreased expression of other ME and malate dehydrogenase isoforms and generated a redox imbalance with opposite characteristics depending on the time point of the day analyzed. The over-expressing plants also presented a higher content of C4 organic acids and sugars under normal growth conditions. However, the accumulation of these metabolites in the over-expressing plants was substantially less pronounced after osmotic stress exposure compared to wild type. Also, a lower level of several amino acids and osmoprotector compounds was observed in transgenic plants. Thus, the gain of NADP-ME2 expression has profound consequences in the modulation of primary metabolism in A. thaliana, which reflect the relevance of this enzyme and its substrates and products in plant homeostasis. 
26474965	Activation of numerous protective mechanisms during cold acclimation is important for the acquisition of freezing tolerance in perennial ryegrass (Lolium perenne L.). To elucidate the molecular mechanisms of cold acclimation in two genotypes ('Veyo' and 'Falster') of perennial ryegrass from distinct geographical origins, we performed transcriptome profiling during cold acclimation using RNA-Seq.We cold-acclimated plants from both genotypes in controlled conditions for a period of 17 days and isolated Total RNA at various time points for high throughput sequencing using Illumina technology. RNA-seq reads were aligned to genotype specific references to identify transcripts with significant changes in expression during cold acclimation.	The genes induced were involved in protective mechanisms such as cell response to abiotic stimulus, signal transduction, redox homeostasis, plasma membrane and cell wall modifications, and carbohydrate metabolism in both genotypes. 'Falster' genotype, adapted to cold climates, showed a stronger transcriptional differentiation during cold acclimation, and more differentially expressed transcripts related to stress, signal transduction, response to abiotic stimulus, and metabolic processes compared to 'Veyo'. 'Falster' genotype also showed an induction of more transcripts with sequence homology to fructosyltransferase genes (FTs) and a higher fold induction of fructan in response to low-temperature stress. The circadian rhythm network was perturbed in the 'Veyo' genotype adapted to warmer climates.	In this study, the differentially expressed genes during cold acclimation, potentially involved in numerous protective mechanisms, were identified in two genotypes of perennial ryegrass from distinct geographical origins. The observation that the circadian rhythm network was perturbed in 'Veyo' during cold acclimation may point to a low adaptability of 'Veyo' to low temperature stresses. This study also revealed the transcriptional mechanisms underlying carbon allocation towards fructan biosynthesis in perennial ryegrass.	
26474056	Human breast milk is an extremely dynamic fluid containing many biologically-active components which change throughout the feeding period and throughout the day. We designed a miRNA assay on minimized amounts of raw milk obtained from mothers of preterm infants. We investigated changes in miRNA expression within month 2 of lactation and then over the course of 24 hours.Analyses were performed on pooled breast milk, made by combining samples collected at different clock times from the same mother donor, along with time series collected over 24 hours from four unsynchronized mothers. Whole milk, lipids or skim milk fractions were processed and analyzed by qPCR. We measured hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-146-5p, and hsa-let-7a, d and g (all -5p). Stability of miRNA endogenous controls was evaluated using RefFinder, a web tool integrating geNorm, Normfinder, BestKeeper and the comparative ΔΔCt method.	MiR-21 and miR-16 were stably expressed in whole milk collected within month 2 of lactation from four mothers. Analysis of lipids and skim milk revealed that miR-146b and let-7d were better references in both fractions. Time series (5H-23H) allowed the identification of a set of three endogenous reference genes (hsa-let-7d, hsa-let-7g and miR-146b) to normalize raw quantification cycle (Cq) data. We identified a daily oscillation of miR-16-5p.	Our assay allows exploring miRNA levels of breast milk from mother with preterm baby collected in time series over 48-72 hours.	
26473939	Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. 
26473354	The molecular mechanisms underlying epileptogenesis have been widely investigated by differential gene expression approach, especially RT-qPCR methodology. However, controversial findings highlight the occurrence of unpredictable sources of variance in the experimental designs. Here, we investigated if diurnal rhythms of transcript's levels may impact on differential gene expression analysis in hippocampus of rats with experimental epilepsy. For this, we have selected six core clock genes (Per1, Per3, Bmal1, Clock, Cry1 and Cry2), whose rhythmic expression pattern in hippocampus had been previously reported. Initially, we identified Tubb2a/Rplp1 and Tubb2a/Ppia as suitable normalizers for circadian studies in hippocampus of rats maintained to 12:12 hour light:dark (LD) cycle. Next, we confirmed the temporal profiling of Per1, Per3, Bmal1, Cry1 and Cry2 mRNA levels in the hippocampus of naive rats by both Acrophase and CircWave statistical tests for circadian analysis. Finally, we showed that temporal differences of sampling can change experimental results for Per1, Per3, Bmal1, Cry1 and Cry2, but not for Clock, which was consistently decreased in rats with epilepsy in all comparison to the naive group. In conclusion, our study demonstrates it is mandatory to consider diurnal oscillations, in order to avoid erroneous conclusions in gene expression analysis in hippocampus of rats with epilepsy. Investigators, therefore, should be aware that genes with circadian expression could be out of phase in different animals of experimental and control groups. Moreover, our results indicate that a sub-expression of Clock may be involved in epileptogenicity, although the functional significance of this remains to be investigated. 
26472554	There are compelling reasons to study the role of steroids and sex differences in the circadian timing system. A solid history of research demonstrates the ubiquity of circadian changes that impact virtually all behavioral and biological responses. Furthermore, steroid hormones can modulate every attribute of circadian responses including the period, amplitude and phase. Finally, desynchronization of circadian rhythmicity, and either enhancing or damping amplitude of various circadian responses can produce different effects in the sexes. Studies of the neuroendocrine underpinnings of circadian timing systems and underlying sex differences have paralleled the overall development of the field as a whole. Early experimental studies established the ubiquity of circadian rhythms by cataloging daily and seasonal changes in whole organism responses. The next generation of experiments demonstrated that daily changes are not a result of environmental synchronizing cues, and are internally orchestrated, and that these differ in the sexes. This work was followed by the revelation of molecular circadian rhythms within individual cells. At present, there is a proliferation of work on the consequences of these daily oscillations in health and in disease, and awareness that these may differ in the sexes. In the present discourse we describe the paradigms used to examine circadian oscillation, to characterize how these internal timing signals are synchronized to local environmental conditions, and how hormones of gonadal and/or adrenal origin modulate circadian responses. Evidence pointing to endocrinologically and genetically mediated sex differences in circadian timing systems can be seen at many levels of the neuroendocrine and endocrine systems, from the cell, the gland and organ, and to whole animal behavior, including sleep/wake or rest/activity cycles, responses to external stimuli, and responses to drugs. We review evidence indicating that the analysis of the circadian timing system is amenable to experimental analysis at many levels of the neuraxis, and on several different time scales, rendering it especially useful for the exploration of mechanisms associated with sex differences. 
26471974	The mammalian clock system is composed of a master clock and peripheral clocks. At the molecular level, the rhythm-generating mechanism is controlled by a molecular clock composed of positive and negative feedback loops. However, the underlying mechanisms for molecular clock regulation that affect circadian clock function remain unclear. Here, we show that Egr1 (early growth response 1), an early growth response gene, is expressed in mouse liver in a circadian manner. Consistently, Egr1 is transactivated by the CLOCK/BMAL1 heterodimer through a conserved E-box response element. In hepatocytes, EGR1 regulates the transcription of several core clock genes, including Bmal1, Per1, Per2, Rev-erbα and Rev-erbβ, and the rhythm amplitude of their expression is dependent on EGR1's transcriptional function. Further mechanistic studies indicated that EGR1 binds to the proximal region of the Per1 promoter to activate its transcription directly. When the peripheral clock is altered by light or feeding behavior transposition in Egr1-deficient mice, the expression phase of hepatic clock genes shifts normally, but the amplitude is also altered. Our data reveal a critical role for EGR1 in the regulation of hepatic clock circuitry, which may contribute to the rhythm stability of peripheral clock oscillators. 
26471800	A more recent branch of research describes the importance of sleep problems in the development and treatment of mental disorders in children and adolescents, such as attention-deficit hyperactivity disorder (ADHD) and mood disorders (MD). Research about clock genes has continued since 2012 with a focus on metabolic processes within all parts of the mammalian body, but particularly within different cerebral regions. Research has focused on complex regulatory circuits involving clock genes themselves and their influence on circadian rhythms of diverse body functions. Current publications on basic research in human and animal models indicate directions for the treatment of mental disorders targeting circadian rhythms and mechanisms. The most significant lines of research are described in this paper.
26471034	A large body of research has been accumulated concerning the relationship between circadian preferences (chronotype) and certain personality traits and psychopathological symptoms. Given that chronotype is related to clinically relevant personality traits, risk factors as well as diurnal variations in behavioural performance, the reliable measurement of circadian preferences might become an important step in daily psychiatric practice. In the present study, we examined the psychometric properties of the Hungarian adaptation of the Morningness- Eveningness Questionnaire (MEQ-H).Based on the (online) questionnaire data of 840 healthy individuals, we examined the factor structure and the internal reliability of the questionnaire. The validity was assessed by different scales (sensory seeking, depressive symptoms and sleep complaints) that were previously shown to be associated with chronotype. Test-retest reliability was calculated from the data of 55 participants who completed the questionnaire twice (eight months apart).	We identified two strongly correlated but separate factors, that we called Morning freshness and Circadian rhythm. According to our results, the questionnaire is a reliable instrument in order to measure individual differences in these factors, however, to increase the reliability of the scale as well as in light of practical considerations, the use of a shortened 13-itemed version might be reasonable. The two factors of the MEQ-H showed the expected associations with the examined constructs, however, the independent predictors of Morning freshness were age, gender, depressive symptoms and sleep complaints (insomniac symptoms and morning misalignment), while the independent predictors of Circadian rhythm were age, gender, depressive symptoms, circadian misalignment and sensory seeking.	The MEQ-H fulfils the methodological requirements of reliability and validity testing, and proved to be an adequate instrument in order to measure circadian preferences: an important factor that could be included in experimental or clinical investigations.	
26470883	The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache. 
26470415	AIM. Study the effect of fluconazole antimycotic on temporal organization of biological properties of Candida albicans.Clinical isolates and a museum C. albicans strain were used. The study was carried out for 24 hours with a 4 hour interval, determining proliferative, adhesive, morphological, protease, catalase, phospholipase activity. The results of the study were treated statistically.	Maximal sensitivity to fluconazole was established for the museum C. albicans strain during the day, in clinical isolates--in the evening and at night. After the effect of 1/2 minimal inhibitory concentration (MIC) of the preparation, the rhythms of all the parameters changed in the museum culture from circadian to ultradian: The preparation reduced mesor and amplitude of the oscillation of proliferative and adhesive activity, but did not have an effect on chrono-infrastructure of morphogenesis and aggression enzymes. The temporal rows of biological activity of pathogenic C. albicans isolates after the incubation with fluconazole were characterized by synchronization of all the properties in a narrow temporal interval from 07:00 to 11:00 and from 16:00 to 23:00 hours.	The results obtained give evidence on the lability of adhesion factors and colonization and stability of virulence factors in the museum variant. A clear synchronization in time of all the pathogenicity factors of clinical isolates gives evidence on the economy of material and energy resources, opening a perspective of using the chronobiological approach in antibiotics therapy of candidoses.	
26470414	Study the effect of exometabolites of associative microbiota on circadian dynamics of functional parameters, that reflect pathogenic and persistence properties of fungi and bacteria.Clinical isolates of Candida albicans, isolated-from intestine of healthy individuals and patients with candidosis, as well as clinical isolates and museum ATCC strains Staphylococcus. aureus 25923, Escherichia coli 35218 and Pseudomonas aeruginosa 27853 were taken for study of proliferative, adhesive, catalase, protease, phospholipase, hemolytic, anti-lysozyme, biofilm-forming activity. The results were treated statistically.	C. albicans isolates, isolated from healthy individuals were revealed to be indifferent to the effect of bacterial metabolites. Chrono-infrastructure of biological properties of fungi altered under the effect of microbiota metabolites. Hospital isolates of S. aureus, E. coli and P. aeruginosa displayed a relative stability of physiological properties against the effect of bacterial-fungal metabolites as opposed to museum strains.	The alterations of chrono-infrastructure of biological rhythms of microorganisms by bacterial-fungal metabolites of associants reflect the intensity of the biological system, that is inevitable during the process of formation of inter-microbial interactions.	

26468624	Virtually all animals have endogenous clock mechanisms that "entrain" to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms "entrained" to the LD cycle can be overridden by entrainment to daily recurring threats. We show that unsignaled nocturnal footshock caused rats living in an "ethological" apparatus to switch their natural foraging behavior from the dark to the light phase and that this switch was maintained as a free-running circadian rhythm upon removal of light cues and footshocks. Furthermore, this fear-entrained circadian behavior was dependent on an intact amygdala and suprachiasmatic nucleus. Thus, time-specific fear can act as a non-photic entraining stimulus for the circadian system, and limbic centers encoding aversive information are likely part of the circadian oscillator network that temporally organizes behavior. 
26468131	Our understanding of the complex, transcriptional feedback loops in the circadian clock mechanism has depended upon quantitative, timeseries data from disparate sources. We measure clock gene RNA profiles in Arabidopsis thaliana seedlings, grown with or without exogenous sucrose, or in soil-grown plants and in wild-type and mutant backgrounds. The RNA profiles were strikingly robust across the experimental conditions, so current mathematical models are likely to be broadly applicable in leaf tissue. In addition to providing reference data, unexpected behaviours included co-expression of PRR9 and ELF4, and regulation of PRR5 by GI. Absolute RNA quantification revealed low levels of PRR9 transcripts (peak approx. 50 copies cell(-1)) compared with other clock genes, and threefold higher levels of LHY RNA (more than 1500 copies cell(-1)) than of its close relative CCA1. The data are disseminated from BioDare, an online repository for focused timeseries data, which is expected to benefit mechanistic modelling. One data subset successfully constrained clock gene expression in a complex model, using publicly available software on parallel computers, without expert tuning or programming. We outline the empirical and mathematical justification for data aggregation in understanding highly interconnected, dynamic networks such as the clock, and the observed design constraints on the resources required to make this approach widely accessible. 
26467605	Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1(nih)) and Sandhoff (Hexb knockout, Hexb(-/-)) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb(-/-) mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1(nih) mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level. 
26467286	In mammals, circadian rhythms in peripheral organs are impaired when animals are maintained in abnormal environmental light-dark cycles such as constant light (LL). This conclusion is based on averaged data from groups of experimental animals sacrificed at each time point. To investigate the effect of LL housing on the peripheral clocks of individual mice, an in vivo imaging system was used to observe the circadian bioluminescence rhythm in peripheral tissues of the liver, kidney, and submandibular salivary gland in PER2::LUCIFERASE knock-in mice. Using this technique, we demonstrated that the majority of individual peripheral tissues still had rhythmic oscillations of their circadian clocks in LL conditions. However, LL housing caused decreased amplitudes and a broad distribution of peak phases in PER2::LUCIFERASE oscillations irrespective of the state of the animals' behavioral rhythmicity. Because both scheduled feeding and scheduled exercise are effective recovery stimuli for circadian clock deficits, we examined whether scheduled feeding or scheduled exercise could reverse this impairment. The results showed that scheduled feeding or exercise could not restore the amplitude of peripheral clocks in LL. On the other hand, the LL-induced broad phase distribution was reversed, and peak phases were entrained to a specific time point by scheduled feeding but only slightly by scheduled exercise. The present results demonstrate that LL housing impairs peripheral circadian clock oscillations by altering both amplitude and phase in individual mice. The broad distribution of clock phases was clearly reversed by scheduled feeding, suggesting the importance of scheduled feeding as an entraining stimulus for impaired peripheral clocks.
26466871	Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist.Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2-31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4-39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26·4-100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]).	Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements.	Vanda Pharmaceuticals.	
26466325	To assess the short-term day-to-day reproducibility of 24-hour intraocular pressure (IOP) curves in various respects in untreated primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients.47 subjects with POAG and 34 subjects with OHT underwent IOP measurements every 2 hours in both eyes for consecutive 48 hours by a non-contact tonometer (NCT). IOP values at each time point were recorded. Mean IOP, peak IOP, time difference of peak IOP between two days and IOP fluctuation were also calculated. Intraclass correlation coefficients (ICCs) and Bland-Altman plots were used to evaluate reproducibility.	ICCs of the entire IOP values for a complete 24-hour curve were 0.577 and 0.561 in POAG and OHT patients, respectively. ICCs of IOP values at different time points ranged from 0.384 (10am) to 0.686 (4am) in POAG patients and from 0.347 (6am) to 0.760 (4am) in OHT patients. ICCs of mean IOP, peak IOP and IOP fluctuation were respectively 0.832, 0.704, 0.367 in POAG patients and 0.867, 0.816 0.633 in OHT patients. Only 37.23% and 35.29% of the peak IOP time points appeared within the time difference of 2 hours in POAG and OHT patients, respectively, while 53.19% and 48.53% appeared within 4 hours in POAG and OHT patients, respectively.	A 24-hour IOP curve in a single day is not highly reproducible in short-term and has limited use for evaluating individual IOP condition. Mean IOP and peak IOP for a 24-hour IOP curve are useful parameters in clinical follow-up, while IOP value at a certain time point, IOP fluctuation and peak IOP time point should be interpreted with caution.	
26466129	Circadian rhythms (CRs) persist in many physiological systems related to performance. The effects of circadian patterns on dynamic muscular power are minimal and conflicting. Furthermore, no study to date has investigated the effect of CR on bench press throws (BPTs) despite its popularity as a modality to increase muscular power. The purpose of this study was to examine the effects of circadian variations on muscular power output and hormonal changes in men. College aged men (n = 7, age: 23.6 ± 1.3 years, height: 179.9 ± 5.4 cm, and body mass: 81.5 ± 19.7 kg.) were recruited for this repeated measures study. Testing occurred at 4 different times of day (04:00, 10:00, 16:00, and 22:00 hours). Testosterone (T) and cortisol (C) hand dynamometer strength (GS), heart rate (HR), mental readiness (MR), BPT and squat jumps (SJs), power (P), and force (F) were measured at each time point. Statistical significance was set at (p ≤ 0.05). There were no significant differences in HR, MR, and GS among all time points. There were no decrements in P or F in BPT or SJ among any time point (p ≥ 0.05). Testosterone and C decreased significantly throughout the day (p ≤ 0.05). Although P and F output differed at various percentages of 1 repetition maximum, they were not affected by circadian pattern, such that muscular performance was not impaired at any time point. Practical implications of these data indicate that high force and power exercises using BPT or SJ may be performed any time of day without detrimental decreases in acute performance.
26465080	The neurohormone melatonin is secreted by the pineal gland and shows a circadian rhythm. It has been used in pathological conditions to evaluate its protective capacity against disease, often in connection to oxidative stress. The abundance of cases reported suggests that the mechanisms of action through which melatonin confers this protection may be linked to other molecular targets besides its G-protein-coupled receptors or its intrinsic scavenging capacity.In this review, 300 melatonin-induced protection cases are collated together with basic facts about melatonin. Some of the experimental results lead us to believe that, at high 'pharmacological' concentrations (500 µM and beyond), melatonin inhibits the 'newly' discovered target, quinone reductase 2 (QR2). It is possible that QR2 acts through its specific capacity to reduce orthoquinone to particularly unstable chemical species, which cycle spontaneously back to orthoquinone. This process generates high quantities of radical oxygen species, which are associated with many diseases states, such as inflammation. Therefore, inhibition of QR2 could explain some of the protective activities of melatonin.	The tools have been generated to further study this particular and singular mechanism of action of melatonin. The property of QR2 inhibition could unify the many aspects of melatonin action reported in the literature.	
26464996	Circadian timing systems, like most physiological processes, cannot escape the effects of aging. With age, humans experience decreased duration and quality of sleep. Aged mice exhibit decreased amplitude and increased fragmentation of the activity rhythm, and lengthened circadian free-running period in both light-dark (LD) and constant dark (DD) conditions. Several studies have shown that aging impacts neural activity rhythms in the central circadian clock in the suprachiasmatic nucleus (SCN). However, evidence for age-related disruption of circadian oscillations of clock genes in the SCN has been equivocal. We hypothesized that daily exposure to LD cycles masks the full impact of aging on molecular rhythms in the SCN. We performed ex vivo bioluminescent imaging of cultured SCN slices of young and aged PER2::luciferase knock-in (PER2::LUC) mice housed under LD or prolonged DD conditions. Under LD conditions, the amplitude of PER2::LUC rhythms differed only slightly between SCN explants from young and aged animals; under DD conditions, the PER2::LUC rhythms of aged animals showed markedly lower amplitudes and longer circadian periods than those of young animals. Recordings of PER2::LUC rhythms in individual SCN cells using an electron multiplying charge-coupled device camera revealed that aged SCN cells showed longer circadian periods and that the rhythms of individual cells rapidly became desynchronized. These data suggest that aging degrades the SCN circadian ensemble, but that recurrent LD cycles mask these effects. We propose that these changes reflect a decline in pacemaker robustness that could increase vulnerability to environmental challenges, and partly explain age-related sleep and circadian disturbances. 
26464315	The purpose of this review is to summarize the current knowledge from field studies on how many consecutive night shifts are required for adaptation of diurnal rhythms in cortisol, melatonin and heart rate variability (HRV) to night work.A systematic search of the databases PubMed and Web of Science resulted in 18 studies selected for review.	Cortisol was measured in five studies, melatonin in 11 studies and HRV in four studies. Diurnal rhythms were assessed by use of several different measures based on three to eight samples per day for cortisol and melatonin and 24-h recordings for HRV. Most of the studies in the review were small studies with less than 30 participants, and most studies evaluated diurnal rhythms after only two consecutive night shifts whereas only six studies used seven or more consecutive night shifts. The majority of studies found that adaptation to night work had not occurred after two consecutive night shifts, whereas a small number found evidence for full adaptation after seven consecutive night shifts based on diurnal rhythms in cortisol and melatonin.	There are methodological differences in the field studies analyzing diurnal rhythms and large diversity in the occupational fields studied. Nevertheless, we conclude that diurnal rhythms in cortisol, melatonin and HRV are not adapted to night work after 1-3 consecutive night shifts. Studies are needed to establish how many consecutive night shifts are needed for full adaptation of diurnal rhythms to night work.	
26464264	CK1 protein kinases form a family of serine/threonine kinases which are highly conserved through different species and ubiquitously expressed. CK1 family members can phosphorylate numerous substrates thereby regulating different biological processes including membrane trafficking, cell cycle regulation, circadian rhythm, apoptosis, and signal transduction. Deregulation of CK1 activity and/or expression contributes to the development of neurological diseases and cancer. Therefore, CK1 became an interesting target for drug development and it is relevant to further understand the mechanisms of its regulation. In the present study, Cyclin-dependent kinase 2/Cyclin E (CDK2/E) and Cyclin-dependent kinase 5/p35 (CDK5/p35) were identified as cellular kinases able to modulate CK1δ activity through site-specific phosphorylation of its C-terminal domain. Furthermore, pre-incubation of CK1δ with CDK2/E or CDK5/p35 reduces CK1δ activity in vitro, indicating a functional impact of the interaction between CK1δ and CDK/cyclin complexes. Interestingly, inhibition of Cyclin-dependent kinases by Dinaciclib increases CK1δ activity in pancreatic cancer cells. In summary, these results suggest that CK1δ activity can be modulated by the interplay between CK1δ and CDK2/E or CDK5/p35. These findings extend our knowledge about CK1δ regulation and may be of use for future development of CK1-related therapeutic strategies in the treatment of neurological diseases or cancer.
26463679	The problem of phase synchronization for a population of genetic oscillators (circadian clocks, synthetic oscillators, etc.) is considered in this paper, taking into account a cell division process and a common entrainment input in the population. The proposed analysis approach is based on the Phase Response Curve (PRC) model of an oscillator (the first order reduced model obtained for the linearized system and inputs with infinitesimal amplitude). The occurrence of cell division introduces state resetting in the model, placing it in the class of hybrid systems. It is shown that without common entraining input in all oscillators, the cell division acts as a disturbance causing phase drift, while the presence of entrainment guarantees boundedness of synchronization phase errors in the population. The performance of the obtained solutions is demonstrated via computer experiments for two different models of circadian/genetic oscillators (Neurospora׳s circadian oscillation model and the repressilator). 
26463420	The present study compared the effects of mandibular advancement therapy (MAD) with continuous positive airway pressure therapy (CPAP) on daytime cardiac autonomic modulation in a wide range of obstructive sleep apnea (OSA) patients under controlled conditions in a randomized, two-period crossover trial.Forty OSA patients underwent treatment with MAD and with CPAP for 12 weeks each. At baseline and after each treatment period, patients were assessed by polysomnography as well as by a daytime cardiac autonomic function test that measured heart rate variability (HRV), continuous blood pressure (BP), and baroreceptor sensitivity (BRS) under conditions of spontaneous breathing, with breathing at 6, 12, and 15/min.	Both CPAP and MAD therapy substantially eliminated apneas and hypopneas. CPAP had a greater effect. During daytime with all four conditions of controlled breathing, three-minute mean values of continuous diastolic BP were significantly reduced for both MAD and CPAP therapy. At the same time, selective increases due to therapy with MAD were found for HRV high frequency (HF) values. No changes were observed for BRS in either therapy mode.	These findings indicate that both MAD and CPAP result in similar beneficial changes in cardiac autonomic function during daytime, especially in blood pressure. CPAP is more effective than MAD in eliminating respiratory events.	
26462818	It remains unclear whether the abnormal circadian blood pressure (BP) rhythm in non-diabetic chronic kidney disease (CKD) is related to hypoalbuminemia. We evaluated relationships between circadian BP rhythm and serum albumin concentration (SAC) and also examined autonomic nervous activities. Non-diabetic CKD patients with proteinuria (n = 197; 105 men, 92 women; aged 47.0 ± 13.3 years; estimated glomerular filtration rate ≥30 ml/min) were divided into nephrotic syndrome (NS: n = 46, SAC ≤ 30 g/l), hypoalbuminemia (n = 65, 30 < SAC < 40 g/l) and normoalbuminemia (n = 86, SAC ≥ 40 g/l) groups. Non-proteinuria subjects (n = 97, urinary protein/creatinine ratio < 30 mg/g creatinine) were enrolled as the non-proteinuria group. Ambulatory 24 h BP monitoring was conducted in all subjects. Simultaneously, power spectral analysis of heart rate was performed to evaluate the sympathovagal balance. Waking BP was lower in the hypoalbuminemia and NS groups than the other groups. Sleeping/waking mean BP ratio was not different between non-proteinuria (0.87 ± 0.07) and normoalbuminemia (0.89 ± 0.08) groups, but increased significantly (p < 0.05) in the hypoalbuminemia (0.92 ± 0.08) and NS groups (0.96 ± 0.08). Significant reverse correlations were observed between SAC and sleeping/waking mean BP ratio (r = -0.274, p < 0.001) in all patients. Multivariate regression analysis identified SAC and sympathovagal balance as predictors of increased sleeping/waking BP ratios as the dependent variable. In non-diabetic CKD patients with proteinuria, disturbed circadian BP rhythms were related to SAC and 24 h sympathovagal imbalance. 
26462206	Stress biomarkers of the autonomic nervous system and hypothalamic-pituitary-adrenal axis (HPA-axis) can be measured via alpha-amylase (AA) and cortisol and cortisone in saliva. Objectives were to determine 1) the response patterns of cortisol, cortisone, and AA under both circadian conditions and the Trier Social Stress Test for Children (TSST-C), 2) which reactivity index is most suitable to differentiate internalizing or externalizing disorders from controls, and to explore 3) the interaction between AA and cortisol in the presence of internalizing or externalizing disorders.Saliva samples (n = 2893) from children with internalizing (n = 55) or externalizing disorders (n = 33) and healthy children (n = 81) were analyzed for cortisol, cortisone, and AA under circadian conditions and TSST-C.	Circadian rhythm of three biomarkers did not differ between diagnostic groups. Age and gender were significant predictors for cortisol and awakening time influenced all three biomarkers significantly. TSST-C responses appeared sequentially in the order of AA, cortisol, and cortisone. Trajectories of cortisol and cortisone responses, not in AA, were significantly lower in children with internalizing or externalizing disorders than in healthy children. Cortisol percentage increase appeared to be the most suitable reactivity index to detect the difference between the diagnostic groups. Internalizing disorders had a negative association between AA decrease and cortisol increase (β = -.199, p < .05, R(2) = .304). Externalizing disorders had a positive association between AA baseline and cortisol increase (β = .229, p < .05, R(2) = .304).	An altered HPA-axis response during stress might result from chronic allostatic load in internalizing disorders and underaroused stress response system in externalizing disorders.	
26461522	According to current recommendations, blood samples should be taken in the morning after 15 minutes' resting time. Some components exhibit diurnal variation and in response to pressures to expand opening hours and reduce waiting time, the aims of this study were to investigate the impact of resting time prior to blood sampling and diurnal variation on biochemical components, including albumin, thyrotropin (TSH), total calcium and sodium in plasma.All patients referred to an outpatient clinic for blood sampling were included in the period Nov 2011 until June 2014 (opening hours: 7am-3pm). Each patient's arrival time and time of blood sampling were registered. The impact of resting time and the time of day for all components was analysed using simple linear regression. The "maximum allowable bias" was used as quality indicator for the change in reference interval.	Significant diurnal variation was found for albumin (n = 15,544; p<2×10-16), TSH (n = 20,019; p<2×10-16), calcium (n = 13,588; p = 2.8×10-12) and sodium (n = 51,917; p<2×10-16). Further significant influence for resting time was found for albumin (p = 2.6×10-4), TSH (p = 0.004), calcium (p = 8.9×10-7) and sodium (p = 8.7×10-16). Only TSH and albumin were clinically significantly influenced by diurnal variation. Resting time had no clinically significant effect.	We found no need for resting 15 minutes prior to blood sampling. However, diurnal variation was found to have a significant and considerable impact on TSH and, to a minor degree, albumin. This has to be taken into account to ensure that reference intervals provided by the laboratory are valid on a 24-hour basis.	
26461299	The circadian clock generates rhythms with a periodicity of 24hours of various biochemical and physiological processes. Recent data suggest a mutual influence between the circadian clock and the cell cycle, and provide a functional connection between the circadian clock, cancer and ageing. In addition, the established link between the circadian clock and anti-oxidative defence suggests that elements of the redox homeostasis, including oxidized protein degradation pathways such as the proteasome, could be modulated by the circadian clock. Using HEK cells synchronized by a serum shock as an initial cellular model for studying the circadian influence on protein maintenance, we have shown that the level of carbonylated protein varies rhythmically following a 24hours period as well as the level of ROS. The proteasome also exhibits circadian rhythmicity in either its expression levels or activities. The rhythms match the circadian oscillations observed for protein oxidative damage. Moreover, adaptation to a Nrf2-dependent oxidative stress has been associated with an increase in the cellular capacity to degrade oxidized proteins that is attributable to an increased expression of the 20S proteasome and its activator Pa28αβ. Therefore, using our synchronized cellular models to investigate more precisely the modulation of proteasome function mediated by the circadian clock, we have shown that both Nrf2 and Pa28αβ exhibit a circadian expression. Interestingly, the circadian variation in ROS precedes the Nrf2 protein level and the transcript level of proteasome catalytic subunits and activators. If as we envisage, circadian rhythmicity is involved in damaged protein degradation, the age-associated alteration of the circadian system may therefore contribute to the accumulation of oxidized proteins and the decline of intracellular protein maintenance. Hence, strategies that could restore this vital function may be effective in slowing ageing and the onset of diseases for which a defect in the protein homeostasis has been proposed to play a key role. 
26460828	Several rodent species that are diurnal in the field become nocturnal in the lab. It has been suggested that the use of running-wheels in the lab might contribute to this timing switch. This proposition is based on studies that indicate feed-back of vigorous wheel-running on the period and phase of circadian clocks that time daily activity rhythms. Tuco-tucos (Ctenomys aff. knighti) are subterranean rodents that are diurnal in the field but are robustly nocturnal in laboratory, with or without access to running wheels. We assessed their energy metabolism by continuously and simultaneously monitoring rates of oxygen consumption, body temperature, general motor and wheel running activity for several days in the presence and absence of wheels. Surprisingly, some individuals spontaneously suppressed running-wheel activity and switched to diurnality in the respirometry chamber, whereas the remaining animals continued to be nocturnal even after wheel removal. This is the first report of timing switches that occur with spontaneous wheel-running suppression and which are not replicated by removal of the wheel. 
26460505	Childhood obesity is a growing health challenge. Recent studies show that children with late bedtime and late awakening are more obese independent of total sleep time. In adolescents and adults, a delayed sleep phase has been associated with higher caloric intake. Furthermore, an adult study showed a positive correlation between REM sleep and energy balance. This relationship has not been demonstrated in children. However, it may be important as a delayed sleep phase would increase the proportion of REM sleep.This study investigated the relationship between hunger score and sleep physiology in a paediatric population.	Thirty-six patients referred for a polysomnogram for suspected obstructive sleep apnoea were enrolled in the study. Sleep stages were recorded as part of the polysomnogram. Hunger scores were obtained using a visual analogue scale. Mean age was 9.6 ± 3.5 years.	Mean hunger scores were 2.07 ± 2.78. Hunger scores were positively correlated with percentage of total rapid eye movement (REM) sleep (r = 0.438, P < 0.01) and REM sleep duration in minutes (r = 0.471, P < 0.05). Percentage slow wave sleep (SWS) was negatively correlated with hunger score (r = -0.360, P < 0.05). There were no correlations between age, sex, body mass index percentiles, apnoea-hypopnoea index, total sleep time, sleep efficiency, sleep onset latency, stage 2 sleep duration and hunger scores.	These findings suggest that delayed bedtime, which increases the proportion of REM sleep and decreases the proportion of SWS, results in higher hunger levels in children.	
26459928	Three interconnected pathways to relapse have been identified as stressful life events, medication non-adherence and disruptions in social rhythms (daily activity and routine). The role of medication and stressful life events is generally better understood than the role of social rhythms. There is no previous review of interventions that target social rhythms.To identify the evidence for the effectiveness of interventions that target social rhythms for improving mood symptoms.	A quantitative systematic review was conducted. Results Seven studies were included in the review: four reporting interpersonal and social rhythm therapy (IPSRT) interventions and three sleep/light interventions.	The results suggest that IPSRT may have a potential benefit in improving mood symptoms and relapse, but it is not clear whether this is of greater benefit than an intensive supportive care intervention of similar duration. The sleep/light interventions demonstrated rapid mood improvements; however, it was not clear how long this improvement was sustained.	Attention to social rhythms and the implementation of interventions that target these could be useful for mental health nursing practice may provide people with BD a clinically effective adjunctive intervention to medication.	
26459465	To maintain synchrony with the environment, circadian clocks use a wide range of cycling sensory cues that provide input to the clock (zeitgebers), including environmental temperature cycles (TCs). There is some knowledge about which clock neuronal groups are important for temperature synchronization, but we currently lack knowledge on the temperature receptors and their signaling pathways that feed temperature information to the (neuronal) clock. Since TRPA1 is a well-known thermosensor that functions in a range of temperature-related behaviors, and it is potentially expressed in clock neurons, we set out to test the putative role of TRPA1 in temperature synchronization of the circadian clock. We found that flies lacking TRPA1 are still able to synchronize their behavioral activity to TCs comparable to wild-type flies, both in 16°C : 25°C and 20°C : 29°C TCs. In addition, we found that flies lacking TRPA1 show higher activity levels during the middle of the warm phase of 20°C : 29°C TCs, and we show that this TRPA1-mediated repression of locomotor activity during the "siesta" is caused by a lack of sleep. Based on these data, we conclude that the TRPA1 channel is not required for temperature synchronization in this broad temperature range but instead is required to repress activity during the warm part of the day.
26458822	Quantitative models of gene regulatory activity have the potential to improve our mechanistic understanding of transcriptional regulation. However, the few models available today have been based on simplistic assumptions about the sequences being modeled or heuristic approximations of the underlying regulatory mechanisms. In this work, we have developed a thermodynamics-based model to predict gene expression driven by any DNA sequence. The proposed model relies on a continuous time, differential equation description of transcriptional dynamics. The sequence features of the promoter are exploited to derive the binding affinity which is derived based on statistical molecular thermodynamics. Experimental results show that the proposed model can effectively identify the activity levels of transcription factors and the regulatory parameters. Comparing with the previous models, the proposed model can reveal more biological sense. 
26458764	The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-β (TGF-β) expression. TGF-β mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-β signaling as a novel therapeutic target of cyclooxygenase inhibition. 
26457682	Light serves as the primary stimulus that synchronizes the circadian clock in the suprachiasmatic nucleus (SCN) to the external day/night cycle. Appropriately timed light exposure can reset the phase of the circadian clock. Some serotonergic drugs that bind to the serotonin 1A receptor can enhance phase shifts to light. The mechanism by which this potentiation occurs is not well understood. In this study, we examined where one of these drugs, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY7378), might be working in the hamster brain. Systemic (5 mg/kg), intra-dorsal raphe and intra-median raphe (both 15.6 nmol in 0.5 μL), but not intra-SCN (7.8 nmol or 15.6 nmol in 0.5 μL) injections of BMY7378 significantly potentiated phase shifts to light. Potentiation of photic shifts persisted when serotonergic innervation of the SCN was lesioned with infusions of the serotonin neurotoxin 5,7-dihydroxytryptamine into the SCN. Light-induced c-Fos expression in the rostral and caudal intergeniculate leaflet (IGL) was attenuated with systemic BMY7378, suggesting that the IGL may be involved in this response. Both complete IGL lesions and depletion of serotonergic innervation of the IGL prevented systemic BMY7378 from potentiating photic phase shifts. Together, these findings suggest that the mechanism by which BMY7378 enhances photic responses is by changing the activity of the raphe nuclei to influence how the IGL responds to light, which subsequently influences the SCN as one of its downstream targets. Identification of the network that underlies this potentiation could lead to the development of useful therapeutic interventions for treating sleep and circadian disorders.
26457327	The global burden of breast cancer in women is substantial and increasing. Efforts to address breast cancer have focused on primary prevention, reduction of modifiable risk factors, early detection, timely referral for appropriate treatment, and survivorship. Environmental and lifestyle factors that increase breast cancer risk include ionizing radiation, exogenous hormones, certain female reproductive factors, alcohol and other dietary factors, obesity, and physical inactivity. A variety of chemical exposures are purported to be associated with breast cancer.In this article, we summarize the influence of the natural, social, built, and policy environments on breast cancer incidence and cancer recurrence in women based upon bibliographic searches and relevant search terms.	Despite a lack of conclusive evidence from epidemiologic studies, exposures to chemicals with estrogenic or other properties relevant to sex steroid activity could influence breast cancer risk if the exposures occur at critical life stages or in combination with exposure to other similar chemicals. Results from several studies support an association between shift work and disruption of the circadian rhythm with breast cancer risk. The social environment likely influences breast cancer risk through several mechanisms including social norms pertaining to breast feeding, age at first live birth, parity, use of oral contraceptives and replacement estrogens, diet, and consumption of alcohol. Social norms also influence body weight, obesity, and physical activity, which have an effect on risk of breast cancer incidence and recurrence. Obesity, which is influenced by the social, built, and policy environments, is a risk factor for the development of postmenopausal breast cancer and certain other cancer types.	The natural, social, built, and policy environments affect breast cancer incidence and survival. Effective health care policies can encourage the provision of high-quality screening and treatment for breast cancer and public education about the value of proper diet, weight control, screening and treatment. Additional research and policy development is needed to determine the value of limiting exposures to potentially carcinogenic chemicals on breast cancer prevention.	
26456694	Fatigue is a major burden for breast cancer patients undergoing adjuvant therapy. Yet, its pathophysiology is still not well understood. Hypothesized mechanisms include dysregulations in the hypothalamic-pituitary-adrenal (HPA) axis, which may be reflected in alterations in the diurnal cortisol patterns. However, studies on the association between cortisol and fatigue during adjuvant cancer therapy are rare. We therefore assessed salivary cortisol at awakening, 0.5h post-awakening, noon, 5 pm and 10 pm/bedtime in 265 breast cancer patients undergoing adjuvant therapy at three timepoints. Cancer-related fatigue was assessed with the Fatigue Assessment Questionnaire (FAQ) covering the physical, affective, and cognitive fatigue dimensions. Multiple linear regression analyses were performed cross-sectionally at the three timepoints as well as longitudinally considering changes in cortisol and fatigue over time. The results showed that the physical dimension of cancer-related fatigue was significantly associated with increased evening cortisol levels and higher overall cortisol secretion. These associations were independent of depressive symptoms. Morning cortisol levels, the cortisol awakening response and the diurnal slope were not consistently associated with physical fatigue. Affective and cognitive fatigue showed no clear association with any of the cortisol parameters. In conclusion, the physical but not the affective or cognitive dimension of fatigue seems associated with cortisol dysregulations in breast cancer patients undergoing adjuvant therapy, characterized by an unaffected cortisol level in the morning but blunted decline to the evening level. Research focusing on disturbances of the cortisol rhythm and HPA dysregulations during and after cancer treatment may open new strategies to reduce cancer-related fatigue.
26456390	Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.
26456331	Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age. 

26454468	Although salt intake derived from data on urinary sodium excretion in free-living populations has been used in public policy, a population study on urinary sodium excretion has not been done in Canada. We assessed dietary sodium and potassium intake using a 24-hour urine collection in a large survey of urban and rural communities from 4 Canadian cities and determined the association of these electrolytes with blood pressure (BP).One thousand seven hundred consecutive individuals, aged 37-72 years, attending their annual follow-up visits of the ongoing Prospective and Urban Rural Epidemiology (PURE) study in Vancouver, Hamilton, Ottawa, and Quebec City, Canada, collected a 24-hour urine sample using standardized procedures.	Mean sodium excretion was 3325 mg/d and mean potassium excretion was 2935 mg/d. Sodium excretion ranged from 3093 mg/d in Vancouver to 3642 mg/d in Quebec City, after adjusting for covariates. Potassium excretion ranged from 2844 mg/d in Ottawa to 3082 mg/d in Quebec City. Both electrolytes were higher in men than in women and in rural populations than in urban settings (P < 0.001 for all). Sodium excretion was between 3000 and 6000 mg/d in 48.3% of the participants, < 3000 mg/d in 46.7%, and > 6000 mg/d in only 5%. No significant association between sodium or potassium excretion and BP was found.	Sodium consumption in these Canadians is within a range comparable to other Western countries, and intake in most individuals is < 6000 mg/d, with only 5% at higher levels. Within this range, sodium or potassium levels were not associated with BP.	
26453313	The aim of this study was to investigate the effect of an Olympic-Weightlifting-session followed by 48-h recovery period on the oxidative and antioxidant parameters' diurnal variation. Nine weightlifters (21 ± 0.5 years) performed, in randomized order, three Olympic-Weightlifting-sessions at 08 h:00, 14 h:00 and 18 h:00. Blood samples were collected: at rest and 3 min and 48 h after each session. C-reactive protein (CRP), rate of lipid peroxidation and antioxidant activities were assessed. At rest, analysis of variance showed a significant time of day (TOD) effect (p < 0.05) for uric acid, catalase and glutathione peroxidase with higher values at 14 h:00 and 18 h:00 compared with 08 h:00. However, no significant TOD effect for malondialdehyde, total bilirubin and CRP was observed. Given the profound changes (p < 0.001) in the post-training session values, these diurnal variations have been altered immediately and even 48 h after the training sessions. Despite the significant decreases in the post-training values after the 48-h recovery period (p < 0.05), levels of lipid peroxidation and enzymatic defense remained elevated (p < 0.05) 48 h after the morning training session. However, after the afternoon and evening sessions, the same period was sufficient to return values to the baseline levels. In conclusion, the morning session seems to generate the most important acute and delayed lipid peroxidation responses. Therefore, weightlifting coaches should avoid scheduling their training sessions in the morning-hours. 
26453284	The menstrual cycle is an example of a human infradian rhythm, but an altered sleep-wake cycle or a disrupted circadian rhythm can change the regularity of the menstrual cycle. In this study, we investigated whether an irregular menstrual cycle is associated with polymorphisms in the CLOCK (3111T > C) and/or PER3 (variable number tandem repeat, VNTR) genes, which are known to have an impact on the circadian rhythm. One hundred ninety-seven postmenarchal, adolescent girls from two girls' high schools in Seoul, Korea, were studied. All participants were requested to complete the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) to assess the emotional distress that might cause menstrual irregularity. Every participant donated a blood sample from which DNA was extracted and genotyped for the CLOCK 3111T > C and PER3 VNTR polymorphisms. A significant association was found between the CLOCK 3111T > C genotype and irregular menstrual cycles. Subjects with the 3111T > C genotype had a high risk of an irregular menstrual cycle compared with 3111T/T homozygous subjects (odds ratio [OR] = 2.88; 95% confidence interval [CI]: 1.26-6.55). When multivariate logistic regression analysis was performed to adjust for age, PSS, STAI, BDI and BMI, subjects with the 3111T > C polymorphism showed a significantly increased OR for irregular menstrual cycles (OR = 3.09; 95% CI: 1.32-7.21). There was no significant association between the PER3 VNTR polymorphism and the irregularity of the menstrual cycle (p > 0.05). The results of this study suggest that the CLOCK 3111T > C polymorphism could be an independent risk factor for irregular menstrual cycles, irrespective of psychological distress and endocrine or metabolic conditions, and could be used as a molecular marker for gynecological studies on this aspect.
26453069	Historically, the sympathetic nervous system (SNS) has been mostly associated with the 'fight or flight' response and the regulation of cardiovascular function. However, evidence over the past 30 years suggests that SNS may also influence the function of immune cells. In this review we describe the basic research being done in the area of SNS regulation of immune function. Further, we show that the SNS-immune interplay during circadian rhythm may modulate the robustness of the inflammatory response, critical for survival during periods of increased activity. Finally, new concepts of a close relationship between these systems in the pathogenesis of hypertension are discussed.
26451842	In rodents, fibroblast growth factor 21 (FGF21) has emerged as a key metabolic regulator produced by liver. To gather preliminary data on the potential importance of FGF1, co-regulated genes, and upstream metabolic genes, we examined the hepatic mRNA expression in response to nutrition and inflammation in dairy cows. In experiment 1, induction of ketosis through feed restriction on d 5 postpartum upregulated FGF21, its co-receptor KLB, and PPARA but only elicited a numerical increase in serum FGF21 concentration. In experiment 2, cows in control (CON) or receiving 50 g/d of L-carnitine (C50) from -14 through 21 d had increased FGF21, PPARA, and NFIL3 on d 10 compared with d 2 postpartum. In contrast, compared with CON and C50, 100 g/d L-carnitine (C100) resulted in lower FGF21, KLB, ANGPTL4, and ARNTL expression on d 10. In experiment 3, cows were fed during the dry period either a higher-energy (OVE; 1.62 Mcal/kg DM) or lower-energy (CON; 1.34 Mcal/kg DM) diet and received 0 (OVE:N, CON:N) or 200 μg of LPS (OVE:Y, CON:Y) into the mammary gland at d 7 postpartum. For FGF21 mRNA expression in CON, the LPS challenge (CON:Y) prevented a decrease in expression between d 7 and 14 postpartum such that cows in CON:N had a 4-fold lower expression on d 14 compared with d 7. The inflammatory stimulus induced by LPS in CON:Y resulted in upregulation of PPARA on d 14 to a similar level as cows in OVE:N. In OVE:Y, expression of PPARA was lower than CON:N on d 7 and remained unchanged on d 14. On d 7, LPS led to a 4-fold greater serum FGF21 only in OVE but not in CON cows. In fact, OVE:Y reached the same serum FGF21 concentration as CON:N, suggesting a carryover effect of dietary energy level on signaling mechanisms within liver. Overall, results indicate that nutrition, ketosis, and inflammation during the peripartal period can alter hepatic FGF21, co-regulated genes, and upstream metabolic genes to various extents. The functional outcome of these changes merits further study, and in particular the mechanisms regulating transcription in response to changes in energy balance and feed intake. 
26451290	Maintaining natural feeding rhythms with time-restricted feeding (TRF), without altering nutritional intake, prevents and reverses diet-induced obesity (DIO) and its associated metabolic disorders in mice. TRF has a direct effect on animal adiposity, causes an alteration of adipokine signaling, and diminishes white adipose tissue inflammation. Many genes involved in lipid metabolism are normally circadian, but their expression is perturbed with DIO; TRF restores their cyclical expression. One mechanism through which TRF could affect host metabolism is by altering the gut microbiome. Changes in the gut microbiome are coupled with an altered stool bile acid profile. Hence, TRF could affect lipid metabolism by altering bile acid signaling. TRF introduces many new possibilities in treating obesity and its associated metabolic disorders. However, further studies are needed to show whether these physiological findings in mice translate to humans. 
26450680	Nocturnal eating have recently increased. Serum phosphorus levels and regulators of phosphorus have circadian variations, so it is suggested that the timing of eating may be important in controlling serum phosphorus levels. However, there have been no reports on the effects of nocturnal eating on phosphorus metabolism. The objective was to evaluate the effects of nocturnal eating on phosphorus metabolism.Fourteen healthy men participated in two experimental protocols with differing dinner times. The design of this study was a crossover study. The subjects were served test meals three times (breakfast; 07:30 h, lunch; 12:30 h, dinner; 17:30 or 22:30 h) a day. Blood and urine samples were collected to assess diurnal variation until the following morning.	The following morning, fasting serum phosphorus levels in the late dinner group were markedly higher than those in the early dinner group (p < 0.001), although serum calcium levels were maintained at approximately constant levels throughout the day in both groups. Fluctuations in urinary calcium excretion were synchronized with the timing of dinner eating, however, fluctuations in urinary phosphorus excretion were not synchronized. Urinary phosphorus excretions at night were inhibited in the late dinner group. In the late dinner group, intact parathyroid hormone levels didn't decrease, and they were significantly higher in this group compared with the early dinner group at 20:00 h (p = 0.004). The following morning, fasting serum fibroblast growth factor 23 levels in the late dinner group had not changed, but those in the early dinner group were significantly increased (p = 0.003). Serum free fatty acid levels before dinner were significantly higher in the late dinner group compared with the early dinner group.	Our results indicate that nocturnal eating inhibits phosphorus excretion. It is suggested that nocturnal eating should be abstained from to manage serum phosphorus levels to within an adequate range.	
26450456	We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open-label, two-period, crossover trial. After individual titration and a steady-state period, patients performed 30 min of moderate-intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter-regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) -0.15, 0.42; p = 0.34], as was mean BG (ETD -0.16 mmol/l; 95% CI -0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post-exercise mean BG, counter-regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal-bolus regimen, the risk of hypoglycaemia induced by moderate-intensity exercise was low with IDeg and similar to that with IGlar. 
26450397	Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies. 
26448877	Reduced immune functioning may have a negative impact on sleep and health, and vice versa. A survey among Dutch young adults (18-35 years old) was administered to collect information on perception of reduced immunity and its relationship to sleep disorders, sleep duration, and quality. Sleep disorders were assessed with the SLEEP-50 questionnaire subscales of sleep apnea, insomnia, circadian rhythm disorder, and daily functioning. Dutch young adults (N = 574) completed the survey. Among them, subjects (N = 209; 36.4%) reported perceived reduced immunity. Relative to those with a normal immune status, subjects reporting reduced immunity had significantly higher scores (p = 0.0001) on sleep apnea (2.6 versus 3.6), insomnia (5.1 versus 6.8), and circadian rhythm disorder (2.1 versus 2.7). Subjects reporting reduced immunity also had significantly poorer daily functioning scores (5.4 versus 7.6, p = 0.0001). No differences were observed in total sleep time, but those reporting reduced immunity had significantly poorer ratings of sleep quality (6.8 versus 7.2, p = 0.0001). Our findings suggest that perceived reduced immunity is associated with sleep disturbances, impaired daily functioning, and a poorer sleep quality. Experimental studies including the assessment of immune biomarkers and objective measures of sleep (polysomnography) should confirm the current observations. 
26448833	The previous investigations in diurnal variation of endurance sports performance did not reach a consensus and have been limited. This study would be a valuable resource for endurance sports trainers and event managers to plan their training and competition in a specific time of day.The aim of this study is to find out the diurnal variation in cardiovascular endurance performance in the young athletes.	Thirty five athlete students (15.17 ± 1.62 years) participated in this study. Maximal oxygen uptake (VO2max), post-exercise percentage of maximal heart rate (MHR% post-ex), post-exercise body temperature (BTemppost-ex), and post exercise blood lactic acid level (LApost-ex) were measured in this study. Three non-consecutive testings: A) Morning (09:00-10:00; AM), B) Noon (12:00-13:00; NN) and C) Afternoon (16:00-17:00; PM) were conducted. Participants were required to follow the meal plan and resting schedule for all testing days.	VO2max was significantly higher at NN (F2. 68 = 3.29, P < 0.05, η2 = 0.088) in comparison with PM. The MHR%post-ex, BTemppost-ex, LApost-ex was not significantly different among three times of day.	Diurnal effect on endurance performance was found and the highest exercise VO2max was identified at noon. Secondary school students or young athletes are recommended to have sports training related to VO2max at noon for the purpose of maximizing training effectiveness.	

26446874	Circadian clocks drive daily oscillations in a variety of biological processes through the coordinate orchestration of precise gene expression programs. Global expression profiling experiments have suggested that a significant fraction of the transcriptome and proteome is under circadian control, and such output rhythms have historically been assumed to rely on the rhythmic transcription of these genes. Recent genome-wide studies, however, have challenged this long-held view and pointed to a major contribution of posttranscriptional regulation in driving oscillations at the messenger RNA (mRNA) level, while others have highlighted extensive clock translational regulation, regardless of mRNA rhythms. There are various examples of genes that are uniformly transcribed throughout the day but that exhibit rhythmic mRNA levels, and of flat mRNAs, with oscillating protein levels, and such observations have largely been considered to result from independent regulation at each step. These studies have thereby obviated any connections, or coupling, that might exist between the different steps of gene expression and the impact that any of them could have on subsequent ones. Here, we argue that due to both biological and technical reasons, the jury is still out on the determination of the relative contributions of each of the different stages of gene expression in regulating output molecular rhythms. In addition, we propose that through a variety of coupling mechanisms, gene transcription (even when apparently arrhythmic) might play a much relevant role in determining oscillations in gene expression than currently estimated, regulating rhythms at downstream steps. Furthermore, we posit that eukaryotic genomes regulate daily RNA polymerase II (RNAPII) recruitment and histone modifications genome-wide, setting the stage for global nascent transcription, but that tissue-specific mechanisms locally specify the different processes under clock control. 
26446873	The chicken pineal gland synthesizes and releases melatonin rhythmically in light/dark (LD) cycles, with high melatonin levels during the dark phase, and in constant darkness (DD) for several cycles before it gradually damps to arrhythmicity in DD. Daily administration of norepinephrine (NE) in vivo and in vitro prevents the damping and restores the melatonin rhythm. To investigate the role of the circadian clock on melatonin rhythm damping and of its restoration by NE, the effects of NE administration at different phases of the melatonin cycle revealed a robust rhythm in NE sensitivity in which NE efficacy in increasing melatonin amplitude peaked in late subjective night and early subjective day, suggesting a clock underlying NE sensitivity. However, NE itself had no effect on circadian phase or period of the melatonin rhythms. Transcriptional analyses indicated that even though the rhythm of melatonin output damped to arrhythmicity, messenger RNA (mRNA) encoding clock genes gper2, gper3, gBmal1, gclock, gcry1, and gcry2; enzymes associated with melatonin biosynthesis; and enzymes involved in cyclic nucleotide signaling remained robustly rhythmic. Of these, only gADCY1 (adenylate cyclase 1) and gPDE4D (cAMP-specific 3',5'-cyclic phosphodiesterase 4D) were affected by NE administration at the mRNA levels, and only ADCY1 was affected at the protein level. The data strongly suggest that damping of the melatonin rhythm in the chick pineal gland occurs at the posttranscriptional level and that a major role of the clock is to regulate pinealocytes' sensitivity to neuronal input from the brain.
26446872	In this commentary (which is by no means a review of chronotyping), I try to clarify the distinction between 2 different ways of assessing chronotype by questionnaires. The morningness/eveningness questionnaire (MEQ) determines daily preferences producing a score, and the Munich ChronoType Questionnaire aims to determine phase of entrainment producing a time. An understanding of the MEQ requires knowledge of its history. Although both have their respective validity, they mean very different things and should be used appropriately in studies with different aims and questions. Although they show correlations in population comparisons, they should not be amalgamated when reviewing the literature.
26446213	Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3a(m-/p+) mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3a(m-/p+) mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus--the site of the mammalian circadian clock--indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3a(m-/p+) mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3a(m+/p+)) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3a(m-/p+) mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.	
26446116	Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome.We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr (m+/p-) heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects.	By studying the mouse mutant line PWScr(m+/p-), we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScr(m+/p-) mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients.	Our study indicates that paternally expressed Snord116 is involved in the 24-h regulation of sleep physiological measures, suggesting that it is a candidate gene for the sleep disturbances that most individuals with PWS experience.	
26446021	Alcoholism has an estimated heritability of between 40 and 60% and it is thought that several genes of small effect may contribute to the risk of developing this disorder. Studies of the genetics of alcohol use disorder (AUD) may, however, be confounded by issues of comorbidity. The aim of this investigation was to assess associations between variants in a range of candidate genes and AUD in a unique sample of adolescents without comorbidity. Our cohort consisted of 80 adolescents with an AUD diagnosis and 80 matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 SNPs in 378 candidate genes. Association analysis, gene-based analysis and polygenic scoring were performed. There was no statistical association between any of the investigated SNPs and AUD after correction for multiple testing. However, from the gene-based analysis it was found that the circadian rhythm genes NR1D1 and BHLHE41 are associated with AUD. While preliminary, these data provide some evidence that the circadian pathway may be relevant to the pathophysiology of AUD. Study of early onset non-comorbid populations with AUD may be useful in identifying target genes for study in larger more representative samples.
26445645	Each year Muslims fast from dawn to sunset for 1 month (Ramadan). In Saudi Arabia, the sleep-wake cycle during Ramadan is severely disturbed and is associated with abolition of the circadian cortisol rhythm, exposing Saudis to continuously increased cortisol levels, which may influence the immune response. In addition to cortisol, sleep and fasting affect the secretion of parathyroid hormone (PTH) and hence bone metabolism.Our objective was to investigate the effect of Ramadan type fasting on secretory patterns of PTH, markers of bone metabolism, and serum immunoglobulins. Blood samples from healthy young volunteers were collected at 9 a.m. and 9 p.m. (± 1 hour) before (Shaban) and 2 weeks into Ramadan. Calcium, phosphorus, magnesium, albumin, alkaline phosphatase, 25-OH vitamin D, intact PTH (iPTH), and immunoglobulin (Ig) A, M and G were measured.	During Ramadan, evening-adjusted calcium was higher (p = 0.036) and phosphate lower (p < 0.001) than the corresponding morning value. Moreover, the Ramadan mean morning phosphate was higher and the evening level lower was than Shabaan values (p = 0.010 and p <0.001, respectively), while mean iPTH level was decreased compared with the morning value (p = 0.001), and the evening mean during Shabaan (p = 0.029). Mean IgG concentration was significantly lower during Ramadan (p = 0.003 and p = 0.021 for morning and evening, respectively).	Changes in dietary practices during Ramadan modulated PTH secretion to a pattern which might be beneficial to bone health. Combined effects of fasting and disturbed sleep led to a noted decrease in IgG level. Therefore, a possible beneficial effect of fasting on bone turnover is combined with decreased immune response.	
26445644	The objective of this study was to profile over a 24 h period the prolactin responses of exercise-trained men on a day involving rest with no exercise in comparison to a day involving exercise training sessions.This is a quasi-experimental design study using repeated measures determination of 24 h prolactin responses in exercise-trained men (n = 16; age = 27.3± 3.3 years (mean ± standard deviation)). Blood samples were taken hourly over a 24 h period on a day involving two intensive exercise training sessions (ED), and on a separate control day (CD) with no exercise activity. The order of the ED and CD was randomized. Physical activity and diet were controlled and replicated for the ED and CD. Blood specimens were handled, prepared and analyzed utilizing appropriate standard clinical practices. The data were analyzed with the Friedman analysis of variance and Nemenyi post hoc statistical procedure for repeated measures.	On the CD, prolactin displayed a typical circadian rhythm with daytime values of the hormone being less than the nocturnal rise once sleep had begun (p < 0.05; 16:00-20:00 h > all other times). On the ED, prolactin responses were noticeably different from those of the CD. The morning and afternoon exercise sessions included significant increases in prolactin immediately at the end of the exercise sessions, being greater than corresponding CD time points (p < 0.01; 01:00 h and 10:00 h); also for the second hour (2 h) following the morning exercise session. On the ED there was a displayed circadian nocturnal response in the hormone with 16:00-24:00 h being elevated above the all nonexercise effected values for that specific day (p < 0.01). Finally, the ED nocturnal elevation for prolactin for 16:00-24:00 h was significantly greater than the same respective hours on the CD (p < 0.05).	Findings clearly demonstrated that nocturnal prolactin responses are augmented in exercise-trained men on days when they perform exercise. The mechanisms inducing this adaptive response are unclear but warrant further investigation.	
26444903	Rhythmic arylalkylamine N-acetyltransferase (AANAT) synthesis is a prominent circadian-controlled response that occurs in most mammals. AANAT is the core enzyme in melatonin production; because melatonin participates in many physiological processes, the regulation of AANAT is an important research topic. In this study, we focused on the role of heterogeneous ribonucleoprotein R (hnRNP R) in the translation of AANAT. A novel RNA-binding protein hnRNP R widely interacted with the 5' untranslated region (UTR) of AANAT mRNA and contributed to translation through an internal ribosomal entry site (IRES). Fine-tuning of AANAT protein synthesis occurred in response to knockdown and overexpression of hnRNP R. Nocturnal elevation of AANAT protein was dependent on the rhythmic changes of hnRNP R, whose levels are elevated in the pineal gland during nighttime. Increases in hnRNP R additionally improved AANAT production in rat pinealocytes under norepinephrine (NE) treatment. These results suggest that cap-independent translation of AANAT mRNA plays a role in the rhythmic synthesis of melatonin through the recruitment of translational machinery to hnRNP R-bound AANAT mRNA.
26442846	Early research on the cyanobacterial clock focused on characterizing the genes needed to keep, entrain, and convey time within the cell. As the scope of assays used in molecular genetics has expanded to capture systems-level properties (e.g., RNA-seq, ChIP-seq, metabolomics, high-throughput screening of genetic variants), so has our understanding of how the clock fits within and influences a broader cellular context. Here we review the work that has established a global perspective of the clock, with a focus on (a) an emerging network-centric view of clock architecture, (b) mechanistic insights into how temporal and environmental cues are transmitted and integrated within this network, 
26441524	The retina and the first optic neuropil (lamina) of Drosophila show circadian rhythms in various processes. To learn about the regulation of circadian rhythms in the retina and lamina and in two cell types, glial and the lamina L2 interneurons, we examined expression of the following clock genes; per, tim, clk, and cry and clock-controlled genes (ccgs); Atpα, nrv2, brp, Pdfr. We found that the expression of gene studied is specific for the retina and lamina. The rhythms of per and tim expression in the retina and glial cells are similar to that observed in the whole head and in clock neurons, while they differ in the lamina and L2 cells. In both the retina and lamina, CRY seems to be a repressor of clk expression. In L2 interneurons per expression is not cyclic indicating the other function of PER in those cells than in the circadian molecular clock. In contrast to per and tim, the pattern of clk and cry expression is similar in both the retina and lamina. The retina holds the autonomous oscillators but the expression of cry and ccgs, Atpα and nrv2, is also regulated by inputs from the pacemaker transmitted by PDF and ITP neuropeptides. 
26441501	Methamphetamine (MA) consumption causes disruption of many biological rhythms including the sleep-wake cycle. This circadian effect is seen shortly following MA exposure and later in life following developmental MA exposure. MA phase shifts, entrains the circadian clock and can also alter the entraining effect of light by currently unknown mechanisms. We analyzed and compared immunoreactivity of the immediate early gene c-Fos, a marker of neuronal activity, to assess neuronal activation 2 h following MA exposure in the light and dark phases. We used network analyses of correlation patterns derived from global brain immunoreactivity patterns of c-Fos, to infer functional connectivity between brain regions. There were five distinct patterns of neuronal activation. In several brain areas, neuronal activation following exposure to MA was stronger in the light than the dark phase, highlighting the importance of considering circadian periods of increased effects of MA in defining experimental conditions and understanding the mechanisms underlying detrimental effects of MA exposure to brain function. Functional connectivity between the ventromedial hypothalamus (VMH) and other brain areas, including the paraventricular nucleus of the hypothalamus and basolateral and medial amygdala, was enhanced following MA exposure, suggesting a role for the VMH in the effects of MA on the brain. 
26441231	The cortisol awakening response (CAR) is a phenomenon describing the sharp increase in basal cortisol levels shortly after waking from sleep. While extensively studied, little is known about the role of sleep architecture contributing to CAR. Furthermore, the potential for CAR after a shorter bout of sleep--a nap--has not been directly investigated. The current studies thus aimed at assessed sleep duration, time of day, and sleep architecture as potential determinants of the cortisol awakening response. Saliva samples were collected during the first hour (0, 30, 45, 60 min) following several EEG-monitored laboratory sleep conditions. Those included afternoon naps wherein 17 participants (4 men; ages 18-26) napped for 50 min and 24 participants (11 men; ages 18-24) napped for 90 min. Furthermore, 20 participants (10 men; ages 18-35) visited the lab twice and in addition to staying overnight, napped 90 min in the morning either under placebo conditions or pharmacologically-manipulated sleep conditions (5mg Zolpidem). Cortisol increases were observed in response to each sleep condition except to 50-min afternoon naps. Furthermore, CARs were predicted by Stage 2 sleep when following nighttime sleep (r=.46, p=.04) and by Stage 1 sleep when following placebo morning naps (r=.54, p=.01). The current study established cortisol awakening responses to naps and implicates sleep duration and architecture in the generation of CAR to both napping and nighttime sleep. Assessing CAR in conjunction with the specific type of sleep may thus contribute to our understanding of mechanisms underlying positive and negative health effects of napping.
26440425	Mild traumatic brain injury (mTBI) causes transient sleep disorders and circadian dysrhythmia. One of the clock genes, PERIOD3 (PER3), regulates the circadian rhythm and contains a genetic polymorphism, namely a variable-number tandem repeat in the coding area with either four or five repeats. PER3(5) carriers are inclined to have a morning preference and associated with higher risk of bipolar disorder and diabetes. This study investigated the effects of PER3 polymorphism on sleep quality changes after mTBI.From May 2012 to May 2014, a total of 96 mTBI patients completed the baseline (1 week after mTBI) and follow-up (6 weeks after mTBI) assessments, including the Pittsburgh Sleep Quality Index (PSQI) and anxiety and depression questionnaires. Statistics were analyzed using the Mann-Whitney U test, Wilcox signed-rank test or chi-squared test.	Among the 96 patients, 24 were heterozygous PER3(5) carriers (PER3(4/5)), and the rest of 72 were PER3(5) noncarriers (PER3(4/4)). The subscale of PSQI questionnaire results indicated that the PER3(5) allele was associated with significant sleep duration shortening, but improvement in overall sleep quality. Furthermore, analyzing patients with sleep disturbance at the baseline (PSQI >5) revealed that only the PER3(5) noncarriers exhibited a significant improvement in overall PSQI scores.	PER3(5) carriers exhibited sleep duration shortening and improved daytime function 6 weeks after mTBI compared with the baseline values. On the other hand, among poor sleepers, PER3(5) carriers did not embrace a significant improvement of overall PSQI scores as noncarriers. The underlying mechanisms and clinical significances must be investigated further.	
26440419	Numerous clinical investigations have revealed the circadian rhythm changes in the perception of chronic pain, and most clinical chronic pain types peak in the night. However, it is still undiscovered whether circadian rhythm of pain exists in rodents and the specific mechanism that may underlie it. Our study was conducted to investigate the rhythmic changes of hyperalgesia behavior in a chronic constrictive injury (CCI) model of rodents and to explore the role of the N-methyl-d-aspartate receptor 2B (NR2B)-cAMP response element binding protein (CREB)-CREB-regulated transcription coactivator 1 (CRTC1) signaling pathway in this pain rhythm.A CCI operation was performed to mimic clinical chronic pain. Paw mechanical withdrawal threshold and paw withdrawal thermal latency were used to test pain behavior in rats; a von Frey cilia test was used to test mechanical hyperalgesia in mice at Zeitgeber time (ZT) 4, ZT10, ZT16, and ZT22 for 14 contiguous days. The relative mRNA and protein expression of NR2B, CREB and CRTC1 in the suprachiasmatic nuclei and the dorsal horn were measured by real-time polymerase chain reaction and Western blot. CRTC1 and CREB interference adenovirus vectors were injected intrathecally at 2 time points, respectively (ZT12 and ZT0), to further explore the proper time point for pain treatment.	During the period of chronic pain state, the pain behavior of CCI rodents showed a circadian rhythm with the peak at ZT4 or ZT10 daily. The pain thresholds were significantly different between the activity period and the rest period. The expressions of NR2B, CRTC1, and CREB at the spinal level were consistent with the pain rhythm. The intrathecal treatment with CRTC1 or CREB interference adenovirus from day 7 to day 9 after CCI surgery markedly improved pain behaviors. Nevertheless, when given at ZT0, they were both more effective at relieving peak pain than drugs given at ZT12.	Pain behavior in the chronic pain of CCI displayed circadian rhythm and was associated with circadian secretion of pain-related receptors. The NR2B-CREB-CRTC1 signaling pathway may play a crucial role in this rhythm. Moreover, our results suggest that measures to relieve pain should be taken before pain reaches its peak.	
26440142	The sequence as well as the distribution pattern of SIFamide in the brain of different insects is highly conserved. As a general rule, at least four prominent SIFamide-immunoreactive somata occur in the pars intercerebralis. They arborize throughout the brain and the ventral nerve cord. Whereas SIFamide is implicated in mating and sleep regulation in Drosophila, other functions of this peptide remain largely unknown. To determine whether SIFamide plays a role in the circadian system of cockroaches, we studied SIFamide in Rhyparobia (= Leucophaea) maderae (Blaberidae), Periplaneta americana (Blattidae), and Therea petiveriana (Polyphagidae). Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry revealed identical SIFamide sequences (TYRKPPFNGSIFamide) in the three species. In addition to four large immunoreactive cells in the pars intercerebralis (group 1), smaller SIFamide-immunoreactive somata were detected in the pars intercerebralis (group 2), in the superior median protocerebrum (group 3), and in the lateral protocerebrum (group 4). Additional cells in the optic lobe (group 5) and posterior protocerebrum (group 6) were stained only in P. americana. Almost the entire protocerebrum was filled with a beaded network of SIFamide-immunoreactive processes that especially strongly invaded the upper unit of the central body. Double-label experiments did not confirm colocalizations with γ-aminobutyric acid (GABA) or the circadian coupling peptide pigment-dispersing factor (PDF). In contrast to locusts, colocalization of SIFamide and histamine immunoreactivity occurred not in group 1, but in group 4 cells. Because the accessory medulla displayed SIFamide immunoreactivity and injections of SIFamide delayed locomotor activity rhythms circadian time-dependently, SIFamide plays a role in the circadian system of cockroaches. J. Comp. Neurol. 524:1337-1360, 2016. © 2015 Wiley Periodicals, Inc. 
26440008	Cortisol in dairy cows is released in an episodic manner underlying a circadian rhythm. The involvement of cortisol in numerous adaptive processes to cope with adverse conditions such as pain and inflammation is well characterized. Recent studies described contradictory effects of nutrition and metabolism on the secretory pattern of cortisol. However, up to now, the direct effects of single metabolites during various metabolic conditions without the profound endocrine changes around parturition on the glucocorticoid secretion in dairy cows have not been described. The objective of this study was to investigate the effects of long-term (56-h) manipulated metabolic states, that is, manipulated plasma concentrations of glucose and β-hydroxybutyrate (BHBA), on the release of cortisol in midlactation dairy cows. Besides the concentration of cortisol at defined time points, its pulsatile secretory pattern was studied in combination with an acute immune challenge through an intramammary lipopolysaccharide (LPS) challenge. Twenty-five midlactation dairy cows were randomly assigned to 1 of 4 treatments (hyperinsulinemic hypoglycemic clamp [HypoG], hyperinsulinemic–euglycemic clamp [EuG], continuous infusion of BHBA [HyperB], or infusion of saline solution for the control group [Control). Different metabolic states induced by infusion treatments affected the characteristics of cortisol secretion (elevation of baseline [the HypoG and HyperB treatments] and decreased peak length [the HypoG treatment]; P < 0.05), whereas amplitude, peak interval, height, peak area, area under the curve (AUC) above the baseline cortisol concentration (AUCb), and the total AUC (AUCt) were not different between infusion treatments. The induced inflammatory response due to the intramammary LPS challenge at simultaneously maintained infusion treatments diminished the pulsatile nature of cortisol release, whereas AUCb (and AUCt, respectively) was lowest for the HypoG treatment compared with the HyperB and Control treatments (P < 0.05). This study indicates that single metabolites (glucose and BHBA) and their availability or turnover (in case of glucose) have a different impact on the regulation of cortisol secretion resulting in changes of its pulsatile release. Furthermore, cortisol release during intramammary inflammation was found to be greater in the HyperB, EuG, and Control treatments compared with the HypoG treatment (P < 0.05). This finding emphasizes the regulatory role of the current metabolic status on the cortisol release during inflammation.
26439850	Extremely low-frequency electromagnetic fields (ELF-EMFs) can affect male reproductive function, but the underlying mechanism of this effect remains unknown. miRNA-mediated regulation has been implicated as an important epigenetic mechanism for regulatory pathways. Herein, we profiled miRNA expression in response to ELF-EMFs in vitro. Mouse spermatocyte-derived GC-2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. Cell viability was assessed using the CCK-8 assay. Apoptosis and the cell cycle were analyzed with flow cytometry. miRNA expression was profiled using Affymetrix Mouse Genechip miRNA 3.0 arrays. Our data showed that the growth, apoptosis or cell cycle arrest of GC-2 cells exposed to the 50 Hz ELF-EMF did not significantly change. However, we identified a total of 55 miRNAs whose expression significantly changed compared with the sham group, including 19 differentially expressed miRNAs (7 miRNAs were upregulated, and 12 were downregulated) in the 1 mT exposure group and 36 (9 miRNAs were upregulated, and 27 were downregulated) in the 3 mT exposure group. The changes in the expression of 15 selected miRNAs measured by real-time PCR were consistent with the microarray results. A network analysis was used to predict core miRNAs and target genes, including miR-30e-5p, miR-210-5p, miR-196b-5p, miR-504-3p, miR-669c-5p and miR-455-3p. We found that these miRNAs were differentially expressed in response to different magnetic field intensities of ELF-EMFs. GO term and KEGG pathway annotation based on the miRNA expression profiling results showed that miRNAs may regulate circadian rhythms, cytokine-cytokine receptor interactions and the p53 signaling pathway. These results suggested that miRNAs could serve as potential biomarkers, and the miRNA-mediated regulation of signaling pathways might play significant roles in the biological effects of ELF-EMFs. 
26439540	The rhythmic opening/closing and volatile emissions of flowers are known to attract pollinators at specific times. That these rhythms are maintained under constant light or dark conditions suggests a circadian clock involvement. Although a forward and reverse genetic approach has led to the identification of core circadian clock components in Arabidopsis thaliana, the involvement of these clock components in floral rhythms has remained untested, probably because of the weak diurnal rhythms in A. thaliana flowers. Here, we addressed the role of these core clock components in the flowers of the wild tobacco Nicotiana attenuata, whose flowers open at night, emit benzyl acetone (BA) scents and move vertically through a 140° arc. We first measured N. attenuata floral rhythms under constant light conditions. The results suggest that the circadian clock controls flower opening, BA emission and pedicel movement, but not flower closing. We generated transgenic N. attenuata lines silenced in the homologous genes of Arabidopsis LATE ELONGATED HYPOCOTYL (LHY) and ZEITLUPE (ZTL), which are known to be core clock components. Silencing NaLHY and NaZTL strongly altered floral rhythms in different ways, indicating that conserved clock components in N. attenuata coordinate these floral rhythms. 
26439342	A circadian oscillation can be reconstituted in vitro from three proteins that cycles with a period of ∼ 24 h. Two recent studies provide surprising biochemical answers to why this remarkable oscillator has such a long time constant and how it can switch effortlessly between alternating enzymatic modes.
26439128	Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during differentiation, but they generated normal percentages of neuronal cells. Neuronal fate commitment therefore appears to be controlled through a non-clock function of BMAL1. This study provides insight into how cell autonomous circadian clocks and clock genes regulate adult neural stem cells with implications for treating neurodegenerative disorders and impaired brain functions by manipulating neurogenesis. 
26439079	The purpose of this report is to provide evidence of an association between within-person variability in diurnal testosterone over 1 year, lifetime exposure to violence, and the manifestation of antisocial behavior in 135 pubertal-aged adolescents across 1 year. Adolescents' sex and lifetime history of violence exposure moderated the association between within-person variability in diurnal testosterone and antisocial behavior. Furthermore, sex-stratified analyses revealed that lifetime history of exposure to violence moderated the association between within-person variability in diurnal testosterone and antisocial behavior in females only. This report is unique in that it illuminates sex differences in within-person associations among exposure to violence, individual variability in diurnal testosterone, and antisocial behavior. 
26438221	Behavior rhythms of insect vectors directly interfere with the dynamics of pathogen transmission to humans. The sand fly Lutzomyia longipalpis is the main vector of visceral leishmaniasis in America and concentrates its activity around dusk. Despite the accumulation of behavioral data, very little is known about the molecular bases of the clock mechanism in this species. This study aims to characterize, within an evolutionary perspective, two important circadian clock genes, Clock and vrille.We have cloned and isolated the coding sequence of L. longipalpis' genes Clock and vrille. The former is structured in eight exons and encodes a protein of 696 amino acids, and the latter comprises three exons and translates to a protein of 469 amino acids. When compared to other insects' orthologues, L. longipalpis CLOCK shows a high degree of conservation in the functional domains bHLH and PAS, but a much shorter glutamine-rich (poly-Q) C-terminal region. As for L. longipalpis VRILLE, a high degree of conservation was found in the bZIP domain. To support these observations and provide an elegant view of the evolution of both genes in insects, phylogenetic analyses based on maximum-likelihood and Bayesian inferences were performed, corroborating the previously known insect systematics.	The isolation and phylogenetic analyses of Clock and vrille orthologues in L. longipalpis bring novel and important data to characterize this species' circadian clock. Interestingly, the poly-Q shortening observed in CLOCK suggests that its transcription activity might be impaired and we speculate if this effect could be compensated by other clock factors such as CYCLE.	
26438218	In grapevines, the increased expression of VvFT , genes involved in the photoperiodic control of seasonal growth ( VvAP1, VvAIL2 ) and cell cycle genes ( VvCDKA, VvCDKB2, VvCYCA1, VvCYCB, VvCYCD3.2 ) in the shoot apex relative to the latent bud, suggests a high mitotic activity of the apex which could prevent them to enter into endodormancy. Additionally, the up-regulation of these genes by the dormancy-breaking compound hydrogen cyanamide (H 2 CN 2 ) strongly suggests that VvFT plays a key role in regulating transcriptionally cell cycle genes. At the end of the growing season, short-day (SD) photoperiod induces the transition of latent grapevine buds (Vitis vinifera L) from paradormancy (PD) to endodormancy (ED), which allows them to survive the cold temperatures of winter. Meanwhile, the shoot apex gradually decreases its growth without entering into ED, and as a result of the fall of temperatures at the beginning of autumn, dies. To understand developmental differences and contrasting responses to environmental cues between both organs, the expression of cell cycle genes, and of genes involved in photoperiodic control of seasonal growth in trees, such as FLOWERING LOCUS T (FT), APETALA1 (AP1) and AINTEGUMENTA-like (AIL) was analyzed at the shoot apex and latent buds of vines during the transition from PD to ED. After shift to SD photoperiod, increased expression of cell cycle genes in the shoot apex suggests a high mitotic activity in this organ which could prevent them from entering into ED. Additionally, the increased expression of VvFT, VvAP1and VvAIL2 in the shoot apex, and the up-regulation of VvFT, VvAP1and cell cycle genes VvCDKA, VvCDKB2, VvCYCA.1, by the dormancy-breaking compound hydrogen cyanamide (H2CN2), strongly suggests that VvFT plays a key role in regulating transcriptionally cell cycle genes, giving thus, more support to the model for photoperiodic control of seasonal growth in trees. Furthermore, downregulation of VvFT by the SD photoperiod detected in leaves and buds of grapevines highlights the importance of VvFT in the induction of growth cessation and in ED development, probably by regulating the expression of cell cycle genes.
26438100	The morning hours are associated with increased cardiovascular (CV) risk, and vascular endothelial function (VEF) is a strong predictor of CV disease. A diurnal rhythm in VEF has been established but the morning variation in VEF is not well-documented. Thus, we tested if VEF is impaired across the vulnerable morning period.After overnight fasts, eight healthy men (age 26.3 ± 3 yr) underwent assessments of VEF under standardized testing conditions every 2 h from 0700 to 1300 h on two separate days. VEF was estimated following 5 min brachial artery occlusions by hyperemic flow-mediated dilation (FMD).	There was no significant change in FMD or hyperemic shear stimulus across the 6 h vulnerable period on either day, despite changes in physical activity and meals across these periods.	In this healthy group of young men, VEF is stable across the vulnerable morning period when typical behaviors occurred (breakfast and physical activity). Future research should focus on the roles of sleep, physical inactivity during sleep and endogenous circadian rhythm in VEF.	
26434674	According to classification manuals for sleep disorders, nine disorders are directly related to biological clock timing misalignments. Of all, delayed sleep phase disorder (DSPD) is the most commonly diagnosed, predominantly affecting adolescents, young adults, and insomnia patients. It is a persistent inability to fall asleep at earlier, more desirable and socially conventional times, coupled with extreme difficulty awakening in the morning. Considerable evidence shows a delay in the circadian clock to be associated with DSPD. Therefore, treatments have mainly focused on advancing the biological clock and sleep timing through pharmacotherapy, phototherapy and behavioral therapies. The clinical evidence indicates that these treatments are efficacious, at least in the short term. However, follow up studies show frequent patient relapse, leading researchers to speculate that alternative etiologies may be contributing to sleep and circadian clock delays in DSPD. The aim of the present paper is to review and collate current literature related to DSPD etiology in order to outline gaps in current knowledge and suggest future research. 
26434551	The circadian rhythm, as part of a broad time structure (chronome) of lipid peroxides and antioxidant defense mechanisms may relate to prevention, efficacy and management of preventive and curative chronotherapy.Fifty newly diagnosed patients with peptic ulcers, 30-45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for one week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was served around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical systems were not taken. Blood samples were collected at 6-hour intervals for 24h under standardized, presumably 24-hour synchronized conditions. Plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT) activities, and serum total protein, albumin, ascorbic acid, total serum cholesterol, and HDL-cholesterol concentrations were determined.	By population-mean cosinor analysis, a marked circadian variation was demonstrated for all variables in healthy subjects and in ulcer patients (p<0.001). As compared to controls, patients had a lower MESOR of MDA, SOD, GPx, GR, ascorbic acid, and HDL-C. They also had smaller circadian amplitude of SOD, CAT, GPx, GR, ascorbic acid, T-C, and HDL-C, but larger circadian amplitude of MDA and albumin. As compared to healthy subjects, the circadian acrophase of ulcer patients occurred later for MDA and GR and earlier for GPx.	Mapping circadian rhythms, important chronome components that include trends with age and extra-circadian components characterizing antioxidants and pro-oxidants, is needed for exploring their putative role as markers in the treatment and management of peptic ulcers.	
26431774	The goal of this study was to examine how heroin self-administration, abstinence, and extinction/reinstatement affect circadian sleep-wake cycles and the associated sleep architecture. We used electroencephalography (EEG) and electromyography (EMG) to measure sleep patterns in male Sprague-Dawley rats over 16 trials of heroin self-administration (acquisition), 14 days of abstinence, and a single day of extinction and drug-induced reinstatement. Rats self-administering heroin showed evidence of reversed (diurnal) patterns of wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep throughout acquisition. During abstinence, their wake and NREM sleep patterns were immediately restored to the normal nocturnal distribution. REM patterns remained inverted for the first 3-6 days of abstinence in heroin self-administering rats. The single extinction/reinstatement test was without effect. These data suggest that heroin may have the ability to affect circadian distribution of sleep and wakefulness, either indirectly, where animals shift their sleep-wake cycle to allow for drug taking, or directly, through wake-promoting actions or actions at circadian oscillators in the brain. 
26431771	Gene expression levels exhibit stochastic variations among genetically identical organisms under the same environmental conditions (called gene expression "noise" or phenotype "fluctuation"). In yeast and Escherichia coli, positive correlations have been found between such gene expression noise and "plasticity" with environmental variations. To determine the universality of such correlations in both unicellular and multicellular organisms, we focused on the relationships between gene expression "noise" and "plasticity" in Arabidopsis thaliana, a multicellular model organism. In recent studies on yeast and E. coli, only some gene groups with specific properties of promoter architecture, average expression levels, and functions exhibited strong noise-plasticity correlations. However, we found strong noise-plasticity correlations for most gene groups in Arabidopsis; additionally, promoter architecture, functional essentiality of genes, and circadian rhythm appeared to have only a weak influence on the correlation strength. The differences in the characteristics of noise-plasticity correlations may result from three-dimensional chromosomal structures and/or circadian rhythm. 
26431700	Pollen is an important cause of allergic respiratory ailments in the Mexico City Metropolitan Area (MCMA). However, very little is known if ambient air temperature correlates with the early blooming of plants observed in other urban areas around the world. A research study was conducted during the dry season of 2012-2013 at three representative sites of the MCMA with different urban characteristics with the aim to understand the relationships between the profusion and diversity of pollen against temperature and other meteorological variables and degree of urbanization. Pollen samples were collected using a Hirst-type trap sampler in the sites: Merced (highly urbanized), Iztapalapa (medium-high urbanized) and Coyoacan (moderately urbanized). Urbanization levels were determined using a composite index based on population density, proportion of surface covered by construction and asphalt, and urban heat island intensity. A set of representative pollen sampling tapes were assayed under a light microscope at magnification of ×1,000 and converted to grains per cubic meter. The most representative pollen types found in the three sites were, regardless of urbanization levels were: Fraxinus, Cupressaceae/Taxodiaceae, Casuarina, Alnus, Myrtaceae, and Pinus. Total pollen concentration was greatest in the moderately urbanized area, although earlier blooming took place at the highly urbanized zone. Total pollen concentration in the medium-high urbanized site has the lowest because the green areas in this zone of MCMA are few. In a diurnal basis, the most abundant pollen types peaked near midday or in the afternoon evening at the three sites. A Spearman test showed a positive correlation among bihourly pollen concentrations, temperature and relative humidity in all sites, but wind speed just correlated in Iztapalapa and Coyoacan. The results obtained suggest that Urban Heat Island Intensity can disturb flowering periods and pollen concentrations, largely in the highly urbanized areas. A principal components analysis established that the concentrations of each pollen type differed across the urbanization gradients. Additionally, it was found that a large number of allergenic pollens are produced by ornamental trees, some only recently introduced by urban planners. 
26431025	Period (PER) protein phosphorylation is a critical regulator of circadian period, yet an integrated understanding of the role and interaction between phosphorylation sites that can both increase and decrease PER2 stability remains elusive. Here, we propose a phosphoswitch model, where two competing phosphorylation sites determine whether PER2 has a fast or slow degradation rate. This mathematical model accurately reproduces the three-stage degradation kinetics of endogenous PER2. We predict and demonstrate that the phosphoswitch is intrinsically temperature sensitive, slowing down PER2 degradation as a result of faster reactions at higher temperatures. The phosphoswitch provides a biochemical mechanism for circadian temperature compensation of circadian period. This phosphoswitch additionally explains the phenotype of Familial Advanced Sleep Phase (FASP) and CK1ε(tau) genetic circadian rhythm disorders, metabolic control of PER2 stability, and how drugs that inhibit CK1 alter period. The phosphoswitch provides a general mechanism to integrate diverse stimuli to regulate circadian period. 
26429755	The current study aimed to determine the differences between sleep-wake habits and circadian preference in Mexican adolescents attending classes at a morning shift or an afternoon shift.The sample consisted of 568 students of a secondary school in Reynosa, northeastern Mexico, of whom 280 were boys and 288 were girls (mean age 14.08 ± 0.72 years, age range 13-16 years). In the morning shift, 287 students attend classes on a schedule from 7:30 to 13:00 and the afternoon shift, 281 students, on a schedule from 13:20 to 19:00. Students completed a general information questionnaire, the Sleep Timing Questionnaire and the Spanish version of the Morningness-Eveningness Questionnaire.	The adolescents who attended the morning shift had earlier bedtime and waking time, but shorter sleep duration than those who attended the afternoon shift. Those oriented to eveningness had later bedtime, waking time, and a shorter sleep duration than those oriented to morningness. Two interactions were found between school shift and chronotype. First, with regard to waking time during weekdays, students who attended the afternoon shift and were oriented to eveningness woke up later than those who attended the morning shift and were oriented to eveningness; during weekdays, there were no differences between the waking time of morning-type and evening-type students who attended the morning shift. Second, with regard to sleep duration on weekdays, students who attended the morning shift and were oriented to eveningness had the shortest sleep duration. Furthermore, there were no differences between sleep duration on weekdays in evening-type and morning-type students of the afternoon shift.	Adolescents who attend classes in the morning shift and are oriented to eveningness are the most sleep deprived. Those who attend the afternoon shift will have optimal sleep duration, regardless of their circadian preference.	
26428686	Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. 
26427480	Renewal of rod photoreceptor outer segments in the mammalian eye involves synchronized diurnal shedding after light onset of spent distal outer segment fragments (POS) linked to swift clearance of shed POS from the subretinal space by the adjacent retinal pigment epithelium (RPE). Engulfed POS phagosomes in RPE cells mature to acidified phagolysosomes, which accomplish enzymatic degradation of POS macromolecules. Here, we used an acidophilic fluorophore LysoTracker to label acidic organelles in freshly dissected, live rat RPE tissue flat mounts. We observed that all RPE cells imaged contained numerous acidified POS phagolysosomes whose abundance per cell was dramatically increased 2 h after light onset as compared to either 1 h before or 4 h after light onset. Lack of organelles of similar diameter (of 1-2 μm) in phagocytosis-defective mutant RCS rat RPE confirmed that LysoTracker live imaging detected POS phagolysosomes. Lack of increase in lysosomal membrane protein LAMP-1 in RPE/choroid during the diurnal phagocytic burst suggests that formation of POS phagolysosomes in RPE in situ may not involve extra lysosome membrane biogenesis. Taken together, we report a new imaging approach that directly detects POS phagosome acidification and allows rapid tracking and quantification of POS phagocytosis by live RPE -tissue ex situ.
26426769	To characterize cyclic day-night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures.Epileptiform events as defined by the physician (also termed more generally as "epileptiform activity" or EA) were recorded in 65 patients with partial onset (also referred to as "focal onset") seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed.	There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets.	This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patient's unique circadian pattern of EA.	
26425836	The prognostic significance of abnormal circadian blood pressure (BP) patterns is well established. Research to date has focused on both nocturnal dipping and absolute night-time BP levels; however, which of these variables should be the primary target for therapy remains unclear. The aim of this study is to determine whether dipping status or absolute night-time BP levels have a stronger association with subclinical target organ damage (TOD).The Mitchelstown Cohort was established to examine cardiovascular health in an adult population sample recruited from primary care. Night-time BP was categorized by dipping status. Subclinical TOD was defined as Cornell Product left ventricular hypertrophy (LVH) voltage criteria on ECG and urine albumin : creatinine ratio (ACR) at least 1.1 mg/mmol. Multivariable logistic regression analysis was used to assess the association between night-time BP and TOD.	Of 2047 participants, 1207 (response rate 59%), underwent 24-h ambulatory BP monitoring. We excluded 161 studies due to incomplete data. Of 1046 participants, 178 (17%) had evidence of TOD. Each 10-mmHg rise in night-time SBP increased the odds of TOD. Odds ratio (OR) ACR at least 1.1 mg/mmol 1.5 [95% confidence interval (95% CI) 1.2-1.8] and OR LVH 1.4 (95% CI 1.1-1.8).	Absolute BP level rather than dipping status may be a superior early marker of risk associated with night-time BP. Interventional studies are required to determine whether there is a benefit in specifically targeting absolute night-time BP levels to prevent clinically important outcomes.	
26424417	Childhood maltreatment increases risk for mood, anxiety, substance use and personality disorders and is associated with alterations in structure, function and connectivity of brain regions involved in emotional regulation. We sought to assess whether maltreatment was specifically associated with disturbances in positive or negative mood regulation. Ecological momentary ratings were collected with a wristwatch-like device with joy-stick (Seiko ecolog) approximately six times per day over a week in 60 unmedicated participants (22 control, 38 maltreated, 18-25 years old). Forty-five percent of maltreated subjects had a history of major depression but all were currently euthymic. Principal component analysis with varimax rotation was used to provide orthogonal measures of positive and negative valence, which were analyzed for indices of variability, circadian rhythmicity and persistence, using linear and non-linear hierarchical modeling and Hurst analysis. Groups did not differ in mean levels of positive or negative affect. Maltreated subjects had increased variability and circadian and hemicircadian abnormalities in ratings of positive but not negative affect. Conversely, they had higher estimated Hurst exponents for negative but not positive affect ratings indicating a greater degree of persistence. Abnormalities in variability, rhythmicity and persistence were present in both maltreated subjects with and without histories of major depression. These findings suggest that both positive and negative valence systems may be dysregulated in individuals with childhood maltreatment. However the nature of the dysregulation appears to differ fundamentally in these domains, as positive mood ratings were more variable and negative ratings more persistent. 
26422661	Maternal negative affect in the early environment is believed to sensitize long-term coping capacities in children. Yet, little work has identified physiological systems associated with coping responses, which may serve as mechanisms for links between early maternal negativity and child outcomes. Using a longitudinal twin sample (N=89), we found that high levels of maternal negative affect during infancy were associated with dysregulation of diurnal cortisol and electroencephalograph (EEG) asymmetry, two physiological systems that may support active approach-oriented coping when children are 7years old. Flattened slopes of diurnal cortisol were also associated with greater numbers of concurrent overanxious behaviors in children. A mediation analysis supported the role of dysregulated diurnal cortisol as a mediator of the link between maternal negative affect in the early environment and childhood risk for anxiety problems. 
26422423	Kisspeptin is an essential gatekeeper of reproductive function. During pregnancy high circulating levels of kisspeptin have been described, however the clear role of this neuropeptide in pregnancy remains unknown. We tested the existence of rhythmic kisspeptin expression in human full-term placenta from healthy pregnant women at six different time points during the day. The data obtained by Western blotting were fitted to a mathematical model (Fourier series), demonstrating, for the first time, the existence of a circadian rhythm in placental kisspeptin expression. 
26422411	We utilized an NMR-based metabolomic approach to profile the metabolites in Drosophila melanogaster that cycle with a daily rhythm. 1H 1D and 2D NMR experiments were performed on whole-body extracts sampled from flies that experienced strong time cues in the form of both light and temperature cycles. Multivariate and univariate statistical analysis was used to identify those metabolites whose concentrations oscillate diurnally. We compared metabolite levels at two time points twelve hours apart, one close to the end of the day and the other close to the end of the night, and identified metabolites that differed significantly in their relative concentrations. We were able to identify 14 such metabolites whose concentrations differed significantly between the two time points. The concentrations of metabolites such as sterols, fatty acids, amino acids such as leucine, valine, isoleucine, alanine and lysine as well as other metabolites such as creatine, glucose, AMP and NAD were higher close to the end of the night, whereas the levels of lactic acid, and a few amino acids such as histidine and tryptophan were higher close to the end of the day. We compared signal intensities across 12 equally spaced time points for these 14 metabolites, in order to profile the changes in their levels across the day, since the NMR metabolite peak intensity is directly proportional to its molar concentration. Through this report we establish NMR-based metabolomics combined with multivariate statistical analysis as a useful method for future studies on the interactions between circadian clocks and metabolic processes.
26420792	We investigated the interspecific variability in nocturnal whole-plant stomatal conductance under well-watered and drought conditions in seedlings of four species of Populus from habitats characterized by abundant water supply (mesic and riparian) or from drier upland sites. The study was carried out to determine whether (i) nocturnal conductance varies across different species of Populus according to their natural habitat, (ii) nocturnal conductance is affected by water stress similarly to daytime conductance based on species habitat and (iii) differences in conductance among species could be explained partly by differences in stomatal traits. We measured whole-plant transpiration and conductance (G) of greenhouse-grown seedlings using an automated high-resolution gravimetric technique. No relationship was found between habitat preference and daytime G (GD), but night-time G (GN) was on average 1.5 times higher in riparian and mesic species (P. deltoides Bartr. ex Marsh. and P. trichocarpa Torr. & Gray) than in those from drier environments (P. tremuloides Michx. and P. × petrowskyana Schr.). GN was not significantly reduced under drought in riparian species. Upland species restricted GN significantly in response to drought, but it was still at least one order of magnitude greater that the cuticular conductance until leaf death was imminent. Under both well-watered and drought conditions, GN declined with increasing vapour pressure deficit (D). Also, a small increase in GN towards the end of the night period was observed in P. deltoides and P. × petrowskyana, suggesting the involvement of endogenous regulation. The anatomical analyses indicated a positive correlation between G and variable stomatal pore index among species and revealed that stomata are not likely to be leaky but instead seem capable of complete occlusion, which raises the question of the possible physiological role of the significant GN observed under drought. Further comparisons among closely related species that occupy ecologically diverse habitats may provide a better understanding of the genetic versus environmental regulations of nocturnal water loss. 
26420755	Two experiments were conducted to clarify the effect of water-soluble carbohydrate (WSC) content in orchardgrass pasture on the diurnal distribution of grazing time. Six ruminally cannulated, non-lactating dairy cows were grazed on either of two pastures with different orchardgrass cultivars containing low WSC (LWSC; cultivar: 'Hokkai 28') or high WSC (HWSC; cultivar: 'Harunemidori'). The cows were grazed in morning and evening sessions in experiment 1, whereas the cows were grazed throughout the day in experiment 2. In experiment 1, grazing time of the cows on HWSC was longer than that of the cows on LWSC (P < 0.01). This difference was larger in the morning session than in the evening session (pasture × grazing session: P < 0.05). Effects on herbage intake were similar to those on grazing time. In experiment 2, daily total grazing time was longer for the cows on HWSC than for those on LWSC (P < 0.05). The cows on HWSC spent a longer time grazing than those on LWSC in the morning between 03.00 and 09.00 hours (P < 0.01). The results indicated that prolonged grazing time in the period between dawn and early morning could increase daily herbage intake in cows grazed on pastures of orchardgrass cultivars with high-WSC content. 
26420687	Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it.
26420542	Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night.

26419529	Sleep disorders are common in stroke patients. Sleep-disordered breathing (SDB), which is present in up to 72% of stroke patients, is the most frequent cause of excessive daytime sleepiness (EDS) in common population. The aim of this study was to assess the frequency of EDS in stroke patients and to analyze the impact of SDB, stroke severity, and location of stroke on EDS in the acute phase of stroke.We enrolled 102 patients with the clinical diagnosis of acute stroke. Baseline clinical characteristics were recorded on admission. An Epworth sleepiness scale score higher than 9 was considered as EDS. To detect SDB, we performed standard overnight polysomnography within 4 ± 2 days after the stroke onset.	EDS was present in 21 patients (20.6%). In a population with EDS, we found a significantly higher number of obstructive apneic pauses, central apneic pauses, as well as significantly higher values of respiratory disturbance index (RDI), RDI during nonrapid eye movement sleep, desaturation index, and significant decrease of REM sleep duration. RDI (odds ratio [OR], 1.031; 95% confidence interval [CI], 1.007-1.056; P = .01) and duration of REM sleep (OR, .922; 95% CI, .853-.997; P = .042) were the only independent variables significantly associated with EDS in a binary multivariate regression model.	SDB is a common, significant, and treatable cause of EDS in acute stroke patients. We suppose that examination in sleep laboratories is reasonable in all stroke patients with EDS, although the impact of SDB therapy on EDS and overall outcome in acute stroke remains unknown.	
26419240	For an organism to be successful in an evolutionary sense, it and its offspring must survive. Such survival depends on satisfying a number of needs that are driven by motivated behaviors, such as eating, sleeping, and mating. An individual can usually only pursue one motivated behavior at a time. The circadian system provides temporal structure to the organism's 24 hour day, partitioning specific behaviors to particular times of the day. The circadian system also allows anticipation of opportunities to engage in motivated behaviors that occur at predictable times of the day. Such anticipation enhances fitness by ensuring that the organism is physiologically ready to make use of a time-limited resource as soon as it becomes available. This could include activation of the sympathetic nervous system to transition from sleep to wake, or to engage in mating, or to activate of the parasympathetic nervous system to facilitate transitions to sleep, or to prepare the body to digest a meal. In addition to enabling temporal partitioning of motivated behaviors, the circadian system may also regulate the amplitude of the drive state motivating the behavior. For example, the circadian clock modulates not only when it is time to eat, but also how hungry we are. In this chapter we explore the physiology of our circadian clock and its involvement in a number of motivated behaviors such as sleeping, eating, exercise, sexual behavior, and maternal behavior. We also examine ways in which dysfunction of circadian timing can contribute to disease states, particularly in psychiatric conditions that include adherent motivational states. 
26417842	Atmospheric vapour pressure deficit (VPD) is the driving force for plant transpiration. Plants have different strategies to respond to this 'atmospheric drought'. Deposited aerosols on leaf surfaces can interact with plant water relations and may influence VPD response. We studied transpiration and water use efficiency of pine, beech and sunflower by measuring sap flow, gas exchange and carbon isotopes, thereby addressing different time scales of plant/atmosphere interaction. Plants were grown (i) outdoors under rainfall exclusion (OD) and in ventilated greenhouses with (ii) ambient air (AA) or (iii) filtered air (FA), the latter containing <1% ambient aerosol concentrations. In addition, some AA plants were sprayed once with 25 mM salt solution of (NH4 )2 SO4 or NaNO3 . Carbon isotope values (δ(13) C) became more negative in the presence of more particles; more negative for AA compared to FA sunflower and more negative for OD Scots pine compared to other growth environments. FA beech had less negative δ(13) C than AA, OD and NaNO3 -treated beech. Anisohydric beech showed linearly increasing sap flow with increasing VPD. The slopes doubled for (NH4 )2 SO4 - and tripled for NaNO3 -sprayed beech compared to control seedlings, indicating decreased ability to resist atmospheric demand. In contrast, isohydric pine showed constant transpiration rates with increasing VPD, independent of growth environment and spray, likely caused by decreasing gs with increasing VPD. Generally, NaNO3 spray had stronger effects on water relations than (NH4 )2 SO4 spray. The results strongly support the role of leaf surface particles as an environmental factor affecting plant water use. Hygroscopic and chaotropic properties of leaf surface particles determine their ability to form wicks across stomata. Such wicks enhance unproductive water loss of anisohydric plant species and decrease CO2 uptake of isohydric plants. They become more relevant with increasing number of fine particles and increasing VPD and are thus related to air pollution and climate change. Wicks cause a deviation from the analogy between CO2 and water pathways through stomata, bringing some principal assumptions of gas exchange theory into question.
26417679	The suprachiasmatic nucleus (SCN) in mammals is the master clock which regulates circadian rhythms. Neural activity of SCN neurons is synchronized to external light through the retinohypothalamic tract (RHT). The paraventricular thalamic nucleus (PVT) is a neural structure that receives synaptic inputs from, and projects back to, the SCN. Lesioning the anterior PVT (aPVT) modifies the behavioral phase response curve induced by short pulses of bright light. In order to study the influence of the aPVT on SCN neural activity, we addressed whether the stimulation of the aPVT can modulate the electrical response of the SCN to either retinal or RHT stimulation. Using in vitro and in vivo recordings, we found a large population of SCN neurons responsive to the stimulation of either aPVT or RHT pathways. Furthermore, we found that simultaneous stimulation of the aPVT and the RHT increased neuronal responsiveness and spontaneous firing rate (SFR) in neurons with a low basal SFR (which also have more negative membrane potentials), such as quiescent and arrhythmic neurons, but no change was observed in neurons with rhythmic firing patterns and more depolarized membrane potentials. These results suggest that inputs from the aPVT could shift the membrane potential of an SCN neuron to values closer to its firing threshold and thus contribute to integration of the response of the circadian clock to light.
26417012	Rapid evolutionary change in seasonal timing can facilitate ecological speciation and resilience to climate warming. However, the molecular mechanisms behind shifts in animal seasonality are still unclear. Evolved differences in seasonality occur in the European corn borer moth (Ostrinia nubilalis), in which early summer emergence in E-strain adults and later summer emergence in Z-strain adults is explained by a shift in the length of the termination phase of larval diapause. Here, we sample from the developmental time course of diapause in both strains and use transcriptome sequencing to profile regulatory and amino acid changes associated with timing divergence. Within a previously defined quantitative trait locus (QTL), we nominate 48 candidate genes, including several in the insulin signaling and circadian rhythm pathways. Genome-wide transcriptional activity is negligible during the extended Z-strain termination, whereas shorter E-strain termination is characterized by a rapid burst of regulatory changes involved in resumption of the cell cycle, hormone production and stress response. Although gene expression during diapause termination in Ostrinia is similar to that found previously in flies, nominated genes for shifts in timing are species specific. Hence, across distant relatives the evolution of insect seasonality appears to involve unique genetic switches that direct organisms into distinct phases of the diapause pathway through wholesale restructuring of conserved gene regulatory networks. 
26415770	The hypocretin/orexin system regulates, among other things, sleep and energy homeostasis. The system is likely regulated by both homeostatic and circadian mechanisms. Little is known about local differences in the regulation of hypocretin activity. The aim of this study was to establish an optimized peptide quantification method for hypocretin-1 extracted from different mouse brain areas and use this method for investigating circadian fluctuations of hypocretin-1 levels in these areas. The results show that hypocretin-1 peptide can be extracted from small pieces of intact tissue, with sufficient yield for measurements in a standard radioimmunoassay. Utilizing the optimized method, it was found that prepro-hypocretin mRNA and peptide show circadian fluctuations in the mouse brain. This study further demonstrates that the hypocretin-1 peptide level in the frontal brain peaks during dark as does prepro-hypocretin mRNA in the hypothalamus. However, in midbrain and brainstem tissue caudal to the hypothalamus, there was less circadian fluctuation and a tendency for higher levels during the light phase. These data suggest that regulation of the hypocretin system differs between brain areas. 
26415624	The aim of this study was to evaluate the mediating effects of nocturnal blood pressure (BP) and morning surge on the contribution of arterial stiffness and sodium intake to morning BP in a middle-aged general population.The study included 124 subjects aged 30-59 years, from rural Yeoju County, Gyeonggi Province, South Korea. Ambulatory BP monitoring, 24 h urinary sodium excretion (24 h UNa) and brachial-ankle pulse wave velocity (baPWV) measurements were performed in all subjects.	The mean ± SD age was 48.1 ± 8.2 years and the proportion of male subjects was 41.1%. After adjusting for covariates, morning systolic blood pressure (SBP) was significantly correlated with morning surge [coefficient = 0.761, 95% confidence interval (CI) 0.651-0.872, p < 0.001], nocturnal SBP (coefficient = 0.576, 95% CI 0.454-0.698, p < 0.001) and baPWV (coefficient = 3.550, 95% CI 1.447-5.653, p = 0.001). Path analysis modeling revealed that baPWV had significant direct (0.035, p = 0.013) and indirect effects (0.042, p = 0.012) on morning SBP. The indirect effect mediated by nocturnal SBP was statistically significant (0.054, p = 0.005), but the indirect effect mediated by the morning surge was not significant. The 24 h UNa had no significant direct or indirect effects on morning SBP.	baPWV had significant direct and indirect effects on morning SBP. The indirect effect was mediated by nocturnal SBP, but not by morning surge. The 24 h UNa had neither significant direct nor indirect effects on morning SBP.	
26415550	The study explored the relationship between time- and frequency-domain indices of cardiac autonomic control and 24 h blood pressure variability (BPV) in a sample of healthy men and women. Vagally mediated cardiac control was inversely related to 24 h BPV, and measures of cardiac autonomic control were better predictors of systolic BPV in men and better predictors of diastolic BPV in women. These findings may help researchers to understand the disparity in cardiovascular disease morbidity and mortality between men and women. 
26414996	Sleep is affected by the circadian cycle and its features. Amplitude and stability of circadian rhythm are important parameters of the circadian cycle. This study aims to examine the relationship between amplitude and stability of circadian rhythm with sleep quality and sleepiness.In this cross-sectional research, 315 shift nurses and health care workers from educational hospitals of Kerman University of Medical Sciences (KUMS), Iran, were selected using a random sampling method. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Circadian Type Inventory (CTI) were used to collect the required data.	In this study, 83.2% suffered from poor sleep and one-half had moderate and excessive sleepiness. The results showed that flexibility in circadian rhythm stability, job stress and sleepiness are among the factors affecting quality sleep in shift workers.	Those whose circadian rhythm amplitude was languid suffered more from sleepiness and those whose circadian stability was flexible had a better sleep. Variables including circadian rhythm stability (flexible/rigid) and amplitude (languid/vigorous) can act as predictive indices in order to employ people in a shift work system so that sleepiness and a drop in quality of sleep are prevented.	

26414986	A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.

26414948	Eukaryotic protein kinases represent one of the largest gene families involved in diverse regulatory functions. WNK (With No Lysine) kinases are members of ser/thr protein kinase family, which lack conserved catalytic lysine (K) residue at protein kinase subdomain II and is replaced by either asparagine, serine or glycine residues. They are involved in regulation of flowering time, circadian rhythms and abiotic stresses in Arabidopsis thaliana. In the present study, we have identified 9 members of WNK in rice, showed resemblance to Arabidopsis and human WNK and clustered into five main clades phylogenetically. The predicted genes structure, bonafide conserved signature motif and domains strongly support their identity, as members of WNK kinase family. We have analyzed their chromosomal distribution, physio-chemical properties, subcellular localizations and cis-elements in the promoter regions in silico. Further, transcript analysis of OsWNK by qRT-PCR revealed their differential regulation in tissue specific and abiotic stresses libraries. In conclusion, the identification of nine OsWNK and transcript level expression pattern under abiotic stress using qRT-PCR in rice will significantly contribute towards the understanding of WNK genes in monocots and thus provide a set up for functional genomics studies of WNK protein kinases. 
26414405	An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined. 
26414329	We have developed and implemented a noninvasive, objective neurofunctional assessment for evaluating the sustained effects of traumatic brain injury (TBI) in piglets with both diffuse and focal injury types. Derived from commercial actigraphy methods in humans, this assessment continuously monitors the day/night activity of piglets using close-fitting jackets equipped with tri-axial accelerometers to monitor movements of the thorax. Acceleration metrics were correlated (N = 7 naïve piglets) with video images to define values associated with a range of activities, from recumbancy (rest) to running. Both focal (N = 8) and diffuse brain injury (N = 9) produced alterations in activity that were significant 4 days post-TBI. Compared to shams (N = 6) who acclimated to the animal facility 4 days after an anesthesia experience by blurring the distinction between day and night activity, post-TBI time-matched animals had larger fractions of inactive periods during the daytime than nighttime, and larger fractions of active time in the night were spent in high activity (e.g., constant walking, intermittent running) than during the day. These persistent disturbances in rest and activity are similar to those observed in human adults and children post-TBI, establishing actigraphy as a translational metric, used in both humans and large animals, for assessment of injury severity, progressions, and intervention. 
26413281	Both albuminuria and kidney dysfunction may affect circadian blood pressure (BP) rhythm, while exacerbating each other's effects. We investigated associations and interactions of these two risk factors with circadian BP rhythm variation and non-dipper pattern progression in community-dwelling older men.This was a cross-sectional and longitudinal analyses in the third and fourth cycles of the Uppsala Longitudinal Study of Adult Men, including 1051 men (age 71 years) with assessments on urinary albumin excretion rate (UAER), 24-h ambulatory BP monitoring (ABPM) and cystatin-C-estimated glomerular filtration rate (eGFR). Of these, 574 men attended re-examination after 6 years. Study outcomes were ABMP changes and non-dipping BP pattern (prevalence and progression).	UAER associated with circadian BP rhythm both cross-sectionally and longitudinally. Longitudinally, significant interactions were observed between UAER and kidney dysfunction (eGFR < 60 mL/min/1.73 m(2)) in its association with the changes of both night-time systolic BP (SBP) and night-day SBP ratio. After stratification, UAER strongly predicted night-day SBP ratio change only in those with concurrent kidney dysfunction. At re-examination, 221 new cases of non-dipper were identified. In multivariable logistic models, high UAER associated with increased likelihood of non-dipper progression, but more strongly so among individuals with concurrent kidney dysfunction. These associations were evident also in the subpopulation of non-diabetics and in participants with normal range UAER.	UAER associates with circadian BP rhythm variation and non-dipper progression in elderly men. Concurrent renal dysfunction modifies and exacerbates these associations.	
26412130	Persistent free-running circannual (approximately year-long) rhythms have evolved in animals to regulate hormone cycles, drive metabolic rhythms (including hibernation), and time annual reproduction. Recent studies have defined the photoperiodic input to this rhythm, wherein melatonin acts on thyrotroph cells of the pituitary pars tuberalis (PT), leading to seasonal changes in the control of thyroid hormone metabolism in the hypothalamus. However, seasonal rhythms persist in constant conditions in many species in the absence of a changing photoperiod signal, leading to the generation of circannual cycles. It is not known which cells, tissues, and pathways generate these remarkable long-term rhythmic processes. We show that individual PT thyrotrophs can be in one of two binary states reflecting either a long (EYA3(+)) or short (CHGA(+)) photoperiod, with the relative proportion in each state defining the phase of the circannual cycle. We also show that a morphogenic cycle driven by the PT leads to extensive re-modeling of the PT and hypothalamus over the circannual cycle. We propose that the PT may employ a recapitulated developmental pathway to drive changes in morphology of tissues and cells. Our data are consistent with the hypothesis that the circannual timer may reside within the PT thyrotroph and is encoded by a binary switch timing mechanism, which may regulate the generation of circannual neuroendocrine rhythms, leading to dynamic re-modeling of the hypothalamic interface. In summary, the PT-ventral hypothalamus now appears to be a prime structure involved in long-term rhythm generation. 
26411460	To evaluate the effect of preservative-free (PF) tafluprost on diurnal variation of intraocular pressure (IOP) and ocular perfusion pressure (OPP), measured by use of home IOP and blood-pressure (BP) monitoring devices, for primary open angle glaucoma (POAG) patients.Twenty-two eyes from 22 patients with POAG were studied. Initially, IOP was measured at the hospital by Goldmann applanation tonometry (GAT) and Icare-ONE rebound tonometry. Each patient was then instructed how to use the Icare-ONE and BP home monitoring devices. IOP and BP were measured at home by the patients, every 4 h, before and 2 weeks after once daily treatment with PF tafluprost (0.0015%) ophthalmic solution.	Intraclass correlations between different IOP measurements were greater than 0.8. PF tafluprost reduced mean diurnal IOP significantly for patients with POAG, from 15.7 ± 1.2 mmHg at baseline to 12.5 ± 0.6 mmHg 2 weeks after treatment (p < 0.001). It increased mean diurnal OPP from 48.5 ± 7.3 mmHg at baseline to 51.3 ± 7.0 mmHg post-treatment (p < 0.017).	Icare-ONE enables glaucoma patients to measure their own diurnal IOP fluctuations. Patient-measured Icare-ONE IOP readings showed that PF tafluprost effectively reduced diurnal IOP in eyes with POAG.	
26410959	The aim of the work was to study dynamics of daily arterial pressure profile during combined antihypertensive therapy starting from calcium and angiotensin II antagonists (amlodipine-valsartan) in Far North employees suffering arterial hypertension engaged on different working schedules. A total of 137 patients with grade I-III AH were divided into 2 groups. Those in group 1 worked day shifts (n=70) and the remaining ones worked night shifts (group 2). 129 patients completed the course of therapy. The final mean daily doses of amlodipine-valsartan were 8.2 ± 1.1/144.8 1.8 and 9.4 ± 1.6/197.8 ± 3.5 mg in groups I and 2 respectively. AP monitoring was performed before, 4 weeks and 6 months after therapy. Six months after the onset of amlodipine-valsartan therapy 97.2 and 97.6% of the patients in groups 1 and 2 respectively showed the target AP level and normalization of daily AP profile. Daily variability of AP in group 2 (excepting night-time variability) was also normal. Morning AP dynamics markedly improved in both groups. Most patients demonstrated excellent compliance with therapy due to its high efficacy and good tolerability.
26410671	Chronic subjective dizziness (CSD) is a form of chronic dizziness. Many patients report fewer symptoms when they get up with an aggravation over of the day. Therefore, the change in the severity of the symptoms during daytime was evaluated and compared with other chronic vestibular diseases: bilateral vestibulopathy (BVP) and downbeat nystagmus (DBN).In a prospective study 131 patients with CSD, 108 patients with BVP, and 38 patients with DBN filled out a questionnaire asking about the symptom intensity (0 = no symptoms, 1 = light, 2 = moderate, 3 = strong) at 6 time-points. The influences of duration of the disease and physical activity on the change of symptoms were also investigated.	The symptom intensity score in CSD was lower after getting up in comparison to later time points. In BVP a strong sensation of dizziness after getting up with worsening in the evening was observed. In DBN symptoms significantly improved during daytime. In BVP, the symptom intensity scores were significantly higher in patients with symptoms more than six month as less than six month. In the other groups, no association between duration of illness and intensity of perceived dizziness could be seen.	There are considerable differences in the change in symptoms between the three diseases. Taking the patient history simply asking how the symptoms are when the patient gets up in the morning and how they change during daytime can be helpful in the differential diagnosis. Having less or no symptoms after getting up may be a diagnostic criterion for CSD.	
26408964	Ketogenic diet (KD) is used for weight loss or to treat epilepsy. KD leads to liver AMP-activated protein kinase (AMPK) activation, which would be expected to inhibit gluconeogenesis. However, KD leads to increased hepatic glucose output. As AMPK and its active phosphorylated form (pAMPK) show circadian oscillation, this discrepancy could stem from wrong-time-of-day sampling. The effect of KD was tested on mouse clock gene expression, AMPK, mTOR, SIRT1 and locomotor activity for 2 months and compared to low-fat diet (LFD). KD led to 1.5-fold increased levels of blood glucose and insulin. Brain pAMPK/AMPK ratio was 40% higher under KD, whereas that in liver was not affected. KD led to 40% and 20% down-regulation of the ratio of pP70S6K/P70S6K, the downstream target of mTOR, in the brain and liver, respectively. SIRT1 levels were 40% higher in the brain, but 40% lower in the liver of KD-fed mice. Clock genes showed delayed rhythms under KD. In the brain of KD-fed mice, amplitudes of clock genes were down-regulated, whereas 6-fold up-regulation was found in the liver. The metabolic state under KD indicates reduced satiety in the brain and reduced anabolism alongside increased gluconeogenesis in the liver. 
26407844	Disruption of circadian rhythm is a major cause of breast cancer in humans. Cryptochrome (CRY), a circadian transcription factor, is a risk factor for initiation of breast cancer, and it is differentially expressed between normal and breast cancer tissues. Here, we evaluated the anti-proliferative and pro-apoptotic activity of KS15, a recently discovered small-molecule inhibitor of CRY, in human breast cancer cells. First, we investigated whether KS15 treatment could promote E-box-mediated transcription by inhibiting the activity of CRY in MCF-7 human breast cancer cells. Protein and mRNA levels of regulators of cell cycle and apoptosis, as well as core clock genes, were differentially modulated in response to KS15. Next, we investigated whether KS15 could inhibit proliferation and increase sensitivity to anti-tumor drugs in MCF-7 cells. We found that KS15 decreased the speed of cell growth and increased the chemosensitivity of MCF-7 cells to doxorubicin and tamoxifen, but had no effect on MCF-10A cells. These findings suggested that pharmacological inhibition of CRY by KS15 exerts an anti-proliferative effect and increases sensitivity to anti-tumor drugs in a specific type of breast cancer. 
26406960	Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. Presently, one of the most important clinical predictors of survival in DLBCL patients is the International Prognostic Index (IPI). Circadian rhythms are the approximate 24 hour biological rhythms with more than 10 genes making up the molecular clock.Determine if functional single nucleotide polymorphism in circadian genes may contribute to survival status in patients diagnosed with diffuse large B-cell lymphoma.	Sixteen high-risk non-synonymous polymorphisms in circadian genes (CLOCK, CRY2, CSNK1E, CSNK2A1, NPAS2, PER1, PER2, PER3, PPP2CA, and TIM) were genotyped by screening PCR. Results were visualized by agarose gel electrophoresis and confirmed by two-direction sequencing. Clinical variables were compared between mutated and non-mutated groups. LogRank survival analysis and Kaplan-Meier method were used to calculate the overall survival.	PER3 rs10462020 variant showed significant difference in overall survival between patients containing mutated genotypes and those with non-mutated genotypes (p = 0.047). LDH levels (p = 0.021) and IPI score (p < 0.001) also showed differences in overall survival. No clinical differences were observed in mutated vs. non-mutated patients.	This work suggests a role of PER3 rs10462020 in predicting a prognosis in DLBCL overall survival of patients.	
26406375	Short- and long-distance circadian communication is essential for integration of temporal information. However, a major challenge in plant biology is to decipher how individual clocks are interconnected to sustain rhythms in the whole plant. Here we show that the shoot apex is composed of an ensemble of coupled clocks that influence rhythms in roots. Live-imaging of single cells, desynchronization of dispersed protoplasts, and mathematical analysis using barycentric coordinates for high-dimensional space show a gradation in the strength of circadian communication in different tissues, with shoot apex clocks displaying the highest coupling. The increased synchrony confers robustness of morning and evening oscillations and particular capabilities for phase readjustments. Rhythms in roots are altered by shoot apex ablation and micrografting, suggesting that signals from the shoot apex are able to synchronize distal organs. Similarly to the mammalian suprachiasmatic nucleus, shoot apexes play a dominant role within the plant hierarchical circadian structure. 
26405844	The knowledge of circadian variation of microparticles (MPs) in stable coronary artery disease (SCAD) is limited. The aim of this study was to evaluate the daily variation of platelet-, endothelial- and monocyte-derived MPs in whole blood and their tissue factor expression (TF) in SCAD and whether these MPs were related to other endothelial and coagulation markers.Serial blood samples from patients with SCAD were collected during one day. Flow cytometry was used to evaluate the amount of large MPs 0.5-1.0 μm, positive for annexin, and their expression of CD41, CD62P, CD144, CD14 and TF. The lag time and endogenous thrombin potential (ETP) was calculated by Calibrated Automated Thrombogram and soluble (s)P-selectin, sTF and vWF by ELISA.	The majority of MPs in whole blood consisted of CD41 + MPs with no significant daily variation. In contrast, the concentration of CD62P + MPs described a daily variation with the lowest concentrations found in the evening (p = 0.031). CD62P + and CD144 + MPs had the highest expression of TF, 52.6% and 42.9%, respectively, and correlated to the endothelial activity evaluated by vWF. There was a circadian rhythm of lag time (p < 0.001) and ETP (p = 0.001). The CD62P+, CD14 + and CD144 + MPs correlated to the lag time.	The different subsets of platelet-, endothelial- and monocyte-derived MPs do not present the same circadian variation and they differ in TF expression in SCAD. The MPs from activated platelets, endothelial cells and monocytes exist in low concentrations in whole blood but are related to the endothelial and coagulation activity found in SCAD.	
26404624	The diagnosis of hypertension and the clinical decisions regarding its treatment are usually based on daytime clinic blood pressure (BP) measurements. However, the correlation between BP levels and target organ damage, cardiovascular (CV) risk, and long-term prognosis, is higher for ambulatory (ABPM) than clinic measurements, both in the general population as well as in patients with diabetes. Moreover, there is consistent evidence in numerous studies that the asleep BP better predicts CV events than either the awake or 24h means. The prevalence of abnormal BP pattern and sleep-time hypertension is extensive in diabetes, often leading to inaccurate diagnoses of hypertension and its therapeutic control in the absence of complete and careful assessment of the entire 24h, i.e., daytime and night-time, BP pattern. Accordingly, ABPM should be the preferred method to comprehensively assess and decide the optimal clinical management of patients with diabetes directed to properly reduce elevated sleep-time BP, which might also lead to a significant reduction of CV events. 
26403971	Clock gene regulates the circadian rhythm of various physiological functions. The expression of clock gene has been shown to be attenuated by certain drugs, resulting in a rhythm disorder. Mitomycin C (MMC) is often used in combination with ophthalmic surgery, especially in trabeculectomy, a glaucoma surgical procedure. The purpose of this study was to investigate the influence of MMC on clock gene expression in fibroblasts, the target cells of MMC. Following MMC treatment, Bmal1 mRNA levels was significantly decreased, whereas Dbp, Per1, and Rev-erbα mRNA levels were significantly increased in the mouse fibroblast cell line NIH3T3 cells. Microarray analysis was performed to explore of the gene(s) responsible for MMC-induced alteration of clock gene expression, and identified Nr3c1 gene encoding glucocorticoid receptor (GR) as a candidate. MMC suppressed the induction of Per1 mRNA by dexamethasone (DEX), ligand of GR, in NIH3T3 cells. MMC also modulated the DEX-driven circadian oscillations of Per2::Luciferase bioluminescence in mouse-derived ocular fibroblasts. Our results demonstrate a previously unknown effect of MMC in GR signaling and the circadian clock system. The present findings suggest that MMC combined with trabeculectomy could increase the risk for a local circadian rhythm-disorder at the ocular surface. 
26403397	This study aimed to determine the seasonality of reproduction throughout the year in Japanese wood mice (Apodemus speciosus). The effect of seasonal changes on testicular morphology and the periodic expression of circadian clock genes in the hypothalamus and testes of male individuals was evaluated. We also examined the morphology of the testes and caudae epididymides of male mice. In addition, RT-PCR analysis was carried out with mRNA extracted from the hypothalamus and testes to evaluate the expression of the circadian clock genes Clock, Bmal1, Per1, and Cry1. The complete induction of testicular activity was detected from February to April and from August to October, with testes weight increasing with the completion of spermatogenesis (reproductive season). From May to early June and from November to early January, testicular weight declined, the seminiferous tubules reduced in size, spermatogenesis was arrested, and sperm were not produced (non-reproductive season). From mid- June to July and mid-January, the re-induction of testicular activity for spermatogenesis was observed in the seminiferous tubules (transitional season). Out of the four examined genes, Cry1 had the highest expression level in both the hypothalamus and testes throughout the year, followed by Bmal1, Per1, and Clock. The expression of Bmal1 was significantly lower in the hypothalamus and testes during the transitional season compared to the reproductive and non-reproductive seasons. Cry1 transcript levels were also significantly lower in the hypothalamus and testes during the transitional season compared to the reproductive season. In conclusion, the results indicating changes in testicular morphology revealed annual reproductive, non-reproductive, and transmission periods in Japanese wood mice. When an increase in testicular activity was observed indicating the onset of the reproductive season, the mean day length was approximately 11–13 h. The expression of the circadian clock genes Bmal1 and Cry1 in the hypothalamus and testes during the reproductive season was significantly higher than that of the same genes during the transitional season. Consequently, completion of spermatogenesis occurred in the seminiferous tubules of Japanese wood mice testes during the reproductive period. 
26403254	In patients with rheumatoid arthritis (RA), morning stiffness is linked more to functional disability and pain than disease activity, as assessed by joint counts and markers of inflammation. As part of the Asia Pacific Morning Stiffness in Rheumatoid Arthritis Expert Panel, a group of eight rheumatologists met to formulate consensus points and develop recommendations for the assessment and management of morning stiffness in RA.On the basis of a systematic literature review and expert opinion, a panel of Asian rheumatologists formulated recommendations for the assessment and medical treatment of RA.	The panel agreed upon 10 consensus statements on morning stiffness, its assessment and treatment. Specifically, the panel recommended that morning stiffness, pain and impaired morning function should be routinely assessed in clinical practice. Although there are currently no validated tools for these parameters, they should be assessed as part of the patients' reported outcomes in RA. The panel also agreed on the benefits of low-dose glucocorticoids in RA, particularly for the improvement of morning stiffness.	These recommendations serve to guide rheumatologists and other stakeholders on the assessment and management of morning stiffness, and help implement the treat-to-target principle in the management of RA.	
26402759	Melatonin is a multifunctional molecule and plays a crucial role in the regulation of circadian rhythms. The role of melatonin in the protection of the central nervous system is well documented. Therefore, melatonin was proposed as a possible therapeutic agent for reducing the severity of Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by cognitive decline and memory dysfunction. Recently, we showed beneficial neuroprotective effects of prophylactic supplementation with melatonin in a suitable model of sporadic AD: OXYS rats, which exhibit disturbances in melatonin secretion. In the present study, we demonstrated that melatonin administration, when started at the age of active progression of AD-like pathology, decreased the amyloid-β1 - 42 and amyloid-β1 - 40 levels in the hippocampus and amyloid-β1 - 42 levels in the frontal cortex of OXYS rats. Furthermore, oral administration of melatonin slowed down degenerative alterations in hippocampal neurons of OXYS rats. The most noticeable improvement was observed in the CA1 region of the hippocampus. Melatonin administration prevented the decrease in the mitochondria-occupied portion of the neuronal volume and improved the ultrastructure of mitochondria in the neurons of the CA1 region. Additionally, melatonin treatment of OXYS rats slowed down an increase in anxiety and deterioration of reference memory. Thus, melatonin administration could alleviate the burden of AD and may be considered a promising pharmaceutical treatment of the disease.
26402449	Biological rhythmicity has been extensively studied in animals for many decades. Although temporal patterns of physical activity have been identified in humans, no large-scale, multi-national study has been published, and no comparison has been attempted of the ubiquity of activity rhythms at different time scales (such as daily, weekly, monthly, and annual).Using individually worn actigraphy devices, physical activity of 2,328 individuals from five different countries (adults of African descent from Ghana, South Africa, Jamaica, Seychelles, and the United States) was measured for seven consecutive days at different times of the year.	Analysis for rhythmic patterns identified daily rhythmicity of physical activity in all five of the represented nationalities. Weekly rhythmicity was found in some, but not all, of the nationalities. No significant evidence of lunar rhythmicity or seasonal rhythmicity was found in any of the groups.	These findings extend previous small-scale observations of daily rhythmicity to a large cohort of individuals from around the world. The findings also confirm the existence of modest weekly rhythmicity but not lunar or seasonal rhythmicity in human activity. These differences in rhythm strength have implications for the management of health hazards of rhythm misalignment.	
26399403	We investigated the prognostic value of clinic and ambulatory BP (ABP) to predict new-onset diabetes and whether risk reduction is related to the progressive decrease of clinic BP or awake or asleep ABP.We prospectively evaluated 2,656 individuals without diabetes, 1,292 men and 1,364 women, 50.6 ± 14.3 years of age, with baseline BP ranging from normotension to hypertension according to ABP criteria. At baseline and annually (more frequently if hypertension treatment was adjusted based on ABP) thereafter, ABP and physical activity (wrist actigraphy) were simultaneously monitored for 48 h to accurately derive the awake and asleep BP means.	During a 5.9-year median follow-up, 190 participants developed type 2 diabetes. The asleep systolic ABP mean was the most significant predictor of new-onset diabetes in a Cox proportional-hazard model adjusted for age, waist circumference, glucose, chronic kidney disease (CKD) and hypertension treatment. Daytime clinic BP and awake or 48 h ABP mean had no predictive value when corrected by the asleep ABP mean. Analyses of BP changes during follow-up revealed a 30% reduction in the risk of new-onset diabetes per 1-SD decrease in asleep systolic ABP mean, independent of changes in clinic BP or awake or 48 h ABP means.	Sleep-time BP is a highly significant independent prognostic marker for new-onset diabetes. Alteration in sleep-time BP regulation seems to precede, rather than follow, the development of new-onset diabetes. Most important, lowering asleep BP, a novel therapeutic target requiring ABP evaluation, could be a significant method for reducing new-onset diabetes risk.	
26398936	The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface receptor for the transforming growth factor-β (TGF-β) family of proteins. Hypertension is related to TGF-β1, because increased TGF-β1 expression is correlated with an elevation in arterial pressure (AP) and TGF-β expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1(+/-)). We observed that systolic and diastolic AP were significantly higher in Alk1(+/-) than in Alk1(+/+) mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography) were similar in both groups. Alk1(+/-) mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1(+/+) mice during most of the light period. Higher AP in Alk1(+/-) mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1(+/-) and not in Alk1(+/+) mice. Alk1(+/-) mice showed a greater hypotensive response to the β-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1(+/+) mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1(+/-) mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1(+/-) mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons. 
26398799	Control of the fine structure of transitory starch synthesized during the day in leaves is required for its normal degradation during the subsequent night. In this study, the molecular structure of transitory starch from Sorghum leaves over the diurnal cycle was characterized using size-exclusion chromatography. This is the first study of diurnal changes in the chain-length distribution (CLD) of amylopectin and amylose over the entire range of chain lengths, and in the size distribution of whole starch molecules. It was found that the outer layers of leaf starch granules, which were synthesized during the daytime and degraded during the night, contained more large molecules, including amylopectin with more short chains and more branching, than those in the inner layers. The outer layers also had lower amylose content. Starch molecular sizes in leaves are much smaller than in grain starch. The starch structures observed are likely to give optimal energy control during plant growth. Lack of this control may contribute to poor plant growth. 
26395952	Information regarding salt intake in pregnant women in Japan is limited. An electronic system for the assessment of salt intake using a 24-h dietary recall method has been developed in Japan. The objectives of the present study were to investigate salt intake in pregnant women and to compare the salt intake estimated by the electronic salt intake assessment system with that measured by 24-h urinary salt excretion (24-hUNaCl).Data were collected on 24-hUNaCl and salt intake estimated by the salt intake assessment system for 35 pregnant Japanese women at approximately 20 weeks of gestation. The adjusted 24-hUNaCl (24-hUNaCl/[the number of urinations during the examination day--the number of missing urine collections] × the number of urinations during the examination day, g/day) was used as a standard.	The mean adjusted 24-hUNaCl was 7.7 ± 2.5 g/day, and mean systolic/diastolic blood pressure values were 106.1 ± 8.6/62.8 ± 6.5 mmHg. The adjusted 24-hUNaCl was significantly correlated with the salt intake estimated by the salt intake assessment system (r = 0.47, p = 0.004). Bland-Altman analysis showed no significant mean difference (adjusted 24-hUNaCl--salt intake estimated by the assessment system = -0.36 g/day, p = 0.4) and no significant proportional bias (p = 0.1).	These results suggest that pregnant women in Japan restrict their salt intake, at least when they are being examined for salt intake. They also suggest that repeated use of the described system may be useful in estimating salt intake in pregnant women.	
26395949	Among the several methods used to assess salt intake, estimating 24 h urinary salt excretion by spot urine seems appropriate for clinical practice. In this study, we investigated variability in urinary salt excretion using spot urine in hypertensive outpatients. Participants included 200 hypertensive patients who underwent spot urinary salt excretion at least three times during the observation period. Mean urinary salt excretion and the coefficient of the variation were 8.62 ± 1.96 g/day and 19.0 ± 10.2%, respectively. In the analysis of participants who underwent assessment of urinary salt excretion at least eight times (n = 54), a significant reduction in mean urinary salt excretion was found at the 5th measurement. On the contrary, the coefficient of the variation of urinary salt excretion continued to increase until the 5th measurement, and became stable thereafter. Mean urinary salt excretion was positively correlated with mean clinic diastolic blood pressure (r = 0.27, p < 0.05). Clinic diastolic blood pressure in the high urinary salt excretion group (≥ 10 g/day) was significantly higher than that of the low group (76.2 ± 7.5 vs 73.4 ± 8.3 mmHg, p < 0.05). Mean urinary salt excretion in summer was significantly lower than that of the other seasons (7.75 ± 1.94 vs 9.09 ± 2.68 (spring), 8.72 ± 2.12 (autumn), 8.92 ± 2.17 (winter) g/day, p < 0.01). In conclusion, repeated measurements of urinary salt excretion using spot urine are required to assess daily salt intake of hypertensive patients.

26395455	The night eating syndrome (NES) has been included into the Diagnostic and Statistical Manual of Mental Disorders 5 as an example of an 'other-specified feeding or eating disorder'. The prevalence of NES has found to be higher in obese populations than in the general population and seems to rise with increasing body mass index. Recent studies suggest a prevalence of 2%-20% in bariatric surgery samples. Given that the core feature of this eating disorder may involve a shift in the circadian pattern of eating that disrupts sleep, and not the ingestion of objectively large amounts of food, it is a pattern that can continue after bariatric surgery. Nonetheless, symptoms of NES appear to decrease after weight loss surgery, and there is no evidence that pre-surgery NES negatively impacts weight loss following surgery. Prospective and longitudinal studies of the course of night eating symptoms are warranted using clear criteria and standardized assessment instruments.
26395309	The circadian clock system in peripheral tissues can endogenously oscillate and is entrained by the light-dark and fasting-feeding cycles in mammals. Although the system's range of entrainment to light-dark cycles with a non-24 h (<24 h) interval has been studied, the range of entrainment to fasting-feeding cycles with shorter periods (<24 h) has not been investigated in peripheral molecular clocks. In the present study, we measured this range by monitoring the mouse peripheral PER2::LUCIFERASE rhythm in vivo at different periods under each feeding cycle (Tau (T) = 15-24 h) under normal light-dark conditions. Peripheral clocks could be entrained to the feeding cycle with T = 22-24 h, but not to that with T = 15-21 h. Under the feeding cycle with T = 15-18 h, the peripheral clocks oscillated at near the 24-h period, suggesting that they were entrained to the light-dark cycle. Thus, for the first time, we demonstrated the range of entrainment to the non-24 h feeding cycle, and that the circadian range (T = 22-24 h) of feeding stimulus is necessary for peripheral molecular clock entrainment under light-dark cycles. 
26394143	The mammalian circadian clock is an endogenous biological timer comprised of transcriptional/translational feedback loops of clock genes. Bmal1 encodes an indispensable transcription factor for the generation of circadian rhythms. Here, we report a new circadian mutant mouse from gene-trapped embryonic stem cells harboring a C-terminus truncated Bmal1 (Bmal1GTΔC) allele. The homozygous mutant (Bmal1GTΔC/GTΔC) mice immediately lost circadian behavioral rhythms under constant darkness. The heterozygous (Bmal1+/GTΔC) mice displayed a gradual loss of rhythms, in contrast to Bmal1+/- mice where rhythms were sustained. Bmal1GTΔC/GTΔC mice also showed arrhythmic mRNA and protein expression in the SCN and liver. Lack of circadian reporter oscillation was also observed in cultured fibroblast cells, indicating that the arrhythmicity of Bmal1GTΔC/GTΔC mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in Bmal1+/GTΔC and Bmal1GTΔC/GTΔC mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1GTΔC was unable to activate transcription of Per1 promoter and BMAL1-dependent CLOCK degradation. These results indicate that the C-terminal region of Bmal1 has pivotal roles in the regulation of circadian rhythms and the Bmal1GTΔC mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1. 
26393668	The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors.This was done by gene profiling using quantitative polymerase chain reaction in mice deficient in MT1 or D4 receptors.	The data obtained determined Pgc-1α and Nr4a1 as transcriptional targets of circadian melatonin and dopamine signaling, respectively.	The results suggest that Pgc-1α and Nr4a1 represent candidate genes for linking circadian neurohormone release with functional adaptation and healthiness of retina and photoreceptor cells.	
26393492	Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT1 and MT2) receptor agonist with 2 - 4 times greater affinity for the MT2 receptor.Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function.	A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 - 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments.	Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.	
26392558	Regulated degradation of proteins by the proteasome is often critical to their function in dynamic cellular pathways. The molecular clock underlying mammalian circadian rhythms relies on the rhythmic expression and degradation of its core components. However, because the tools available for identifying the mechanisms underlying the degradation of a specific protein are limited, the mechanisms regulating clock protein degradation are only beginning to be elucidated. Here we describe a cell-based functional screening approach designed to quickly identify the ubiquitin E3 ligases that induce the degradation of potentially any protein of interest. We screened the nuclear hormone receptor RevErbα (Nr1d1), a key constituent of the mammalian circadian clock, for E3 ligases that regulate its stability and found Seven in absentia2 (Siah2) to be a key regulator of RevErbα stability. Previously implicated in hypoxia signaling, Siah2 overexpression destabilizes RevErbα/β, and siRNA depletion of Siah2 stabilizes endogenous RevErbα. Moreover, Siah2 depletion delays circadian degradation of RevErbα and lengthens period length. These results demonstrate the utility of functional screening approaches for identifying regulators of protein stability and reveal Siah2 as a previously unidentified circadian clockwork regulator that mediates circadian RevErbα turnover. 
26392540	The molecular circadian clocks in the mammalian retina are locally synchronized by environmental light cycles independent of the suprachiasmatic nuclei (SCN) in the brain. Unexpectedly, this entrainment does not require rods, cones, or melanopsin (OPN4), possibly suggesting the involvement of another retinal photopigment. Here, we show that the ex vivo mouse retinal rhythm is most sensitive to short-wavelength light but that this photoentrainment requires neither the short-wavelength-sensitive cone pigment [S-pigment or cone opsin (OPN1SW)] nor encephalopsin (OPN3). However, retinas lacking neuropsin (OPN5) fail to photoentrain, even though other visual functions appear largely normal. Initial evidence suggests that OPN5 is expressed in select retinal ganglion cells. Remarkably, the mouse corneal circadian rhythm is also photoentrainable ex vivo, and this photoentrainment likewise requires OPN5. Our findings reveal a light-sensing function for mammalian OPN5, until now an orphan opsin. 
26392078	Circadian control of gene expression is well characterized at the transcriptional level, but little is known about diel or circadian control of translation. Genome-wide translation state profiling of mRNAs in Arabidopsis thaliana seedlings grown in long day was performed to estimate ribosome loading per mRNA. The experiments revealed extensive translational regulation of key biological processes. Notably, translation of mRNAs for ribosomal proteins and mitochondrial respiration peaked at night. Central clock mRNAs are among those subject to fluctuations in ribosome loading. There was no consistent phase relationship between peak translation states and peak transcript levels. The overlay of distinct transcriptional and translational cycles can be expected to alter the waveform of the protein synthesis rate. Plants that constitutively overexpress the clock gene CCA1 showed phase shifts in peak translation, with a 6-h delay from midnight to dawn or from noon to evening being particularly common. Moreover, cycles of ribosome loading that were detected under continuous light in the wild type collapsed in the CCA1 overexpressor. Finally, at the transcript level, the CCA1-ox strain adopted a global pattern of transcript abundance that was broadly correlated with the light-dark environment. Altogether, these data demonstrate that gene-specific diel cycles of ribosome loading are controlled in part by the circadian clock. 
26391351	This integrative single-case study investigated the 12 h-to-12 h cause-effect relations between 55 kD soluble tumor necrosis factor receptor type 1 (sTNF-R55) and specific and unspecific symptoms in a 52-year-old Caucasian woman with mild systemic lupus erythematosus (SLE) disease activity.The patient collected her entire urine for 56 days in 12 h-intervals to determine sTNF-R55/creatinine and protein/creatinine levels (ELISA, HPLC). Additionally, twice a day, she took notes on oral ulceration and facial rash; answered questionnaires (VAS) on fatigue, weakness, and joint pain; and measured body temperature orally. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (significance level = p < 0.05).	Time series analysis revealed both a circadian and a circasemiseptan rhythm in the urinary sTNF-R55 data. Moreover, several significant lagged correlations between urinary sTNF-R55 concentrations and SLE symptoms in both directions of effect were identified. Specifically, increased urinary sTNF-R55 concentrations preceded decreased urinary protein levels by 36-48 h (r = -0.213) and, in the opposite direction of effect, increased protein levels preceded increased sTNF-R55 concentrations by 24-36 h (r = +0.202). In addition, increased urinary sTNF-R55 levels preceded increased oral ulcers by 36-48 h (r = +0.277) and, conversely, increased oral ulceration preceded decreased sTNF-R55 levels by 36-48 h (r = -0.313). Moreover, increased urinary sTNF-R55 levels preceded decreased facial rash by 36-48 h (r = -0.223) and followed increased body temperature after 36-48 h (r = +0.209). Weakness, fatigue and joint pain were not significantly correlated with urinary sTNF-R55 levels.	This study gathered first evidence of real-life, long-term feedback loops between cytokines and SLE symptoms in mild SLE disease activity. Such insights into the potential role of sTNF-R55 in SLE would not have been possible had we applied a pre-post design group study. These findings require replication before firm conclusions can be drawn.