Collective Bioelectric Selection Under Crowding: a First-Passage Viability Model Connecting the VPP/SRP Regime to Epithelial Cell Extrusion

This deposit provides a reproducible computational framework that formalizes a bioelectric selection mechanism for crowding-induced epithelial extrusion, grounded in recent experimental work describing an ion-channel cascade linking crowding, depolarization, energy limitation, shrinkage, and extrusion. The model is formulated under the Variational Principle of Persistence (VPP) using a first-passage/viability perspective, with clearly defined state variables and experimentally motivated perturbation scenarios.

The repository includes mechanistic consistency checks aligned with established experimental perturbations (e.g., modulation of sodium entry, energy availability, and voltage-/volume-dependent channels), together with robustness analyses (parameter sweeps, scaling tests, bootstrapping, and systematic ablations) to assess stability of qualitative conclusions across plausible regimes. This release does not report new wet-lab experiments; its purpose is to provide a falsifiable, transparent modeling framework and a set of measurable experimental endpoints.

A central outcome is a testable prediction about coordination across spatial scales under reduced gap-junction coupling. The model predicts that decreasing gap-junctional coupling can substantially reduce the spatial coherence of the depolarization field (quantified via spatial autocorrelation and neighbor-coherence metrics) while leaving the global extrusion rate approximately unchanged under comparable conditions. This prediction motivates a quantitative dissociation between two coordination mechanisms that are often studied separately: (i) bioelectric spatial coherence shaping relative selection among crowded neighbors (expected to be gap junction–sensitive), and (ii) mechano-biochemical event spacing that limits clustered extrusions via ERK-mediated neighbor protection (frequently reported as gap junction–independent). Simultaneous measurement of both endpoints under controlled gap junction perturbation would provide a direct experimental test of this proposed dissociation.

Contents of the deposit typically include: (i) the main manuscript (preprint), (ii) supplementary information documenting robustness analyses and additional figures/tables, (iii) fully reproducible simulation code and configuration files, and (iv) an optional brief protocol outlining how to quantify the predicted spatial signatures using voltage imaging and gap-junction perturbations. All materials are intended to support reuse, reproduction, and independent evaluation.

**Update v2 (2026-01-26):** Added Supplementary Material 2 (Supplement2.pdf)

Supplement 2 presents detailed analyses of the Systemic Reduction Paradox (SRP) 
and attractor dynamics, including:

- SRP/PRS asymmetry analysis (risk asymmetry A(δ), SRP-index distribution)
- Attractor trajectory compression in (C_gap, Moran's I) phase space
- Baseline SRP verification (viability identity, organization increase)
- Information-theoretic operationalization of PRS via Shannon decomposition

All figures generated from Bundle 5 (BVP_SRPA_bundle__5_.zip, 10 paired seeds).
Statistical values verified against canonical computational outputs.