Transient hysteresis and inherent stochasticity in gene regulatory networks.

Cell fate determination, the process through which cells commit to differentiated states is commonly mediated by gene regulatory motifs with mutually exclusive expression states. The classical deterministic picture for cell fate determination includes bistability and hysteresis, which enables the persistence of the acquired cellular state after withdrawal of the stimulus, ensuring a robust cellular response. However, stochasticity inherent to gene expression dynamics is not compatible with hysteresis, since the stationary solution of the governing Chemical Master Equation does not depend on the initial conditions. We provide a quantitative description of a transient hysteresis phenomenon reconciling experimental evidence of hysteretic behaviour in gene regulatory networks with inherent stochasticity: under sufficiently slow dynamics hysteresis is transient. We quantify this with an estimate of the convergence rate to the equilibrium and introduce a natural landscape capturing system's evolution that, unlike traditional cell fate potential landscapes, is compatible with coexistence at the microscopic level.

Generic parameterization for a pharmacokinetic model to predict Cd concentrations in several tissues of different fish species.

In the present work, a set of generic parameters was proposed for a pharmacokinetic model, with the objective of predicting Cd concentration in the tissues of diverse fish species under different environmental conditions. Cd concentrations in a number of tissues of Oncorhynchus mykiss and Cyprinus carpio were estimated by a structurally identifiable multicompartmental model (unique solution). The 13 generic parameters of the model comprised exchange rates, tissue-blood partition coefficients, and weight-corrected elimination rate constants accounting for the routes of water respiration, excretion and egestion. On the other hand, absorption efficiencies from water and food were considered to be condition-specific and estimated for each experiment. These two parameters reflected the differences in fish exposure to diet (food type and metal concentration) or water (water chemistry and bioavailable metal concentration). A data set of 27 experiments of Cd bioaccumulation in fish tissues was compiled for model calibration. The selected dynamics on trout and carp were performed under very different experimental conditions, involving water and/or food exposure, different fish weights and exposure concentrations and the presence/absence of depuration periods. Model predicted, for most compartments and experiments, the tendency of Cd dynamics. However, accumulation in liver and kidney was underestimated in approximately a half of the experiments, due mainly to a rapid metallothionein (MT) sequestration phenomena and subsequent saturation on liver and kidney produced under high exposure concentrations. On the other hand, both generic and condition-specific parameter values were in accordance with the values reported in literature when available. Therefore, the results obtained in this work are an initial step indicating that a generic global input parameter set could be applied to physiology-based pharmacokinetic (PBPK) models for estimating Cd accumulation in fish in different types of scenarios.