Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF.
Vaccines exert strong selective pressures on pathogens, favouring the spread of antigenic variants. We propose a simple mathematical model to investigate the dynamics of a novel pathogenic strain that emerges in a population where a previous strain is maintained at low endemic level by a vaccine. We compare three methods to assess the ability of the novel strain to invade and persist: algebraic rate of invasion; deterministic dynamics; and stochastic dynamics. These three techniques provide complementary predictions on the fate of the system. In particular, we emphasize the importance of stochastic simulations, which account for the possibility of extinctions of either strain. More specifically, our model suggests that the probability of persistence of an invasive strain (i) can be minimized for intermediate levels of vaccine cross-protection (i.e. immune protection against the novel strain) and (ii) is lower if cross-immunity acts through a reduced infectious period rather than through reduced susceptibility. This version of the model can be used for both the stochastic and the deterministic simulations described in the article. For deterministic interpretations with infinite population sizes, set the population size N = 1. The model does reproduces the deterministic time course. The initial values are set to the steady state values for a latent infection with strain 1 with an invading infection of strain 2 (I2=1e-06), 100 percent vaccination with a susceptibility reduction τ=0.7 at birth (p=1), and all other parameters as in figure 3 of the publication.
This is a model of one presynaptic and one postsynaptic cell, as described in the article: Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. Wang XJ, Buzsáki G. J Neurosci. 1996 Oct 15;16(20):6402-13. PMID: 8815919 ;
Fast neuronal oscillations (gamma, 20-80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for the population synchronization, on properties of single cells and the circuit, were identified. These include the following: (1) that the amplitude of spike afterhyperpolarization be above the GABAA synaptic reversal potential; (2) that the ratio between the synaptic decay time constant and the oscillation period be sufficiently large; (3) that the effects of heterogeneities be modest because of a steep frequency-current relationship of fast-spiking neurons.