Integrating time-resolved nrf2 gene-expression data into a full GUTS model as a proxy for toxicodynamic damage in zebrafish embryo

Florian Schunck, Bernhard Kodritsch, Wibke Busch, Martin Krauss, Andreas Focks

correctmedium confidence

Category: Not specified
Journal tier: Specialist/Solid
Processed: Sep 28, 2025, 12:56 AM
arXiv Links: Abstract ↗PDF ↗

Audit review

The paper defines the GUTS-RNA-pulse ODEs, with an activation bounded between 0 and 1 and a threshold hazard h(t) = kk·max(0, R − z) + hb with S(t) = exp(−∫ h), and argues that modeling reversible damage allows describing constant survival at continuous exposure. The candidate solution rigorously derives the uniform bound R(t) ≤ R0 + rrt/krd (krd > 0), the background-hazard-only regime if z is above this bound, and global well-posedness/positivity. These formal results are consistent with (and strengthen) the paper’s qualitative claims, though the candidate’s “constant-survival” phrasing is better interpreted as “constant hazard = hb.”

Referee report (LaTeX)

\textbf{Recommendation:} minor revisions

\textbf{Journal Tier:} specialist/solid

\textbf{Justification:}

The manuscript delivers a biologically anchored TKTD model that incorporates nrf2 dynamics and convincingly reproduces survival patterns under continuous exposure. While the modeling framework is solid and the empirical fits persuasive, the paper would benefit from a short mathematical appendix (or remarks) establishing boundedness of R, a sufficient condition for background-only hazard, and a brief note on existence/uniqueness and positivity. The candidate’s solution provides these elements succinctly. Small clarifications around terminology (e.g., constant survival vs. constant hazard) will avoid misinterpretation.