In budding yeast, overcoming of a critical size to enter S phase and the mitosis/mating switch—two central cell fate events—take place in the G1 phase of the cell cycle. Here we present a mathematical model of the basic molecular mechanism controlling the G1/S transition, whose major regulatory feature is multisite phosphorylation of nuclear Whi5. Cln3–Cdk1, whose nuclear amount is proportional to cell size, and then Cln1,2–Cdk1, randomly phosphorylate both decoy and functional Whi5 sites. Full phosphorylation of functional sites releases Whi5 inhibitory activity, activating G1/S transcription. Simulation analysis shows that this mechanism ensures coherent release of Whi5 inhibitory action and accounts for many experimentally observed properties of mitotically growing or conjugating G1 cells. Cell cycle progression and transcriptional analyses of a Whi5 phosphomimetic mutant verify the model prediction that coherent transcription of the G1/S regulon and ensuing G1/S transition requires full phosphorylation of Whi5 functional sites.

The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli.

An optimal control algorithm is proposed for impulsive differential systems, i.e. systems evolving according to ordinary differential equations between any two control actions, occurring impulsively at discrete time instants. Measurements are as well acquired at discrete time instants. The model-based control law is conceived for medical and health-care frameworks and, indeed, is applied to synthesize a feedback antiangiogenic tumor therapy. To cope with unavailable or temporally sparse measurements, the control law benefits of a state observer properly designed for continuous-discrete systems by suitably exploiting recent results on observers for time-delay systems. The closed-loop algorithm is validated by building up an exhaustive simulation campaign on a population of virtual subjects, each sampled from a multivariate Gaussian distribution whose mean and covariance matrix are identified from experimental data taken from the literature. In silico results are encouraging and pave the way to further clinical verifications.