Origins of binary gene expression in post-transcriptional regulation by microRNAs.

MicroRNA-mediated regulation of gene expression is characterised by some distinctive features that set it apart from unregulated and transcription-factor-regulated gene expression. Recently, a mathematical model has been proposed to describe the dynamics of post-transcriptional regulation by microRNAs. The model explains the observations made in single-cell experiments quite well. In this paper, we introduce some additional features into the model and consider two specific cases. In the first case, a noncooperative positive feedback loop is included in the transcriptional regulation of the target gene expression. In the second case, a stochastic version of the original model is considered in which there are random transitions between the inactive and active expression states of the gene. In the first case we show that bistability is possible in a parameter regime, due to the presence of a nonlinear protein decay term in the gene expression dynamics. In the second case, we derive the conditions for obtaining stochastic binary gene expression. We find that this type of gene expression is more favourable in the case of regulation by microRNAs as compared to the case of unregulated gene expression. The theoretical predictions relating to binary gene expression are experimentally testable.

Emergent bistability: effects of additive and multiplicative noise.

Positive feedback and cooperativity in the regulation of gene expression are generally considered to be necessary for obtaining bistable expression states. Recently, a novel mechanism of bistability termed emergent bistability has been proposed which involves only positive feedback and no cooperativity in the regulation. An additional positive feedback loop is effectively generated due to the inhibition of cellular growth by the synthesized proteins. The mechanism, demonstrated for a synthetic circuit, may be prevalent in natural systems also as some recent experimental results appear to suggest. In this paper, we study the effects of additive and multiplicative noise on the dynamics governing emergent bistability. The calculational scheme employed is based on the Langevin and Fokker-Planck formalisms. The steady state probability distributions of protein levels and the mean first passage times are computed for different noise strengths and system parameters. In the region of bistability, the bimodal probability distribution is shown to be a linear combination of a lognormal and a Gaussian distribution. The variances of the individual distributions and the relative weights of the distributions are further calculated for varying noise strengths and system parameters. The experimental relevance of the model results is also pointed out.

A sequential scanning of the immune efficiency in astrocytoma (Grade I to Grade Iii), meningioma and secondary glioma patients with and without therapeutic scheduling.

PURPOSE: Glioma induces immune suppression. However, data revealing the immune status in glioma patients with sequential therapeutic interventions is missing. Thus, the study aims at evaluating the sequential immune status of glioma bearing patients (Astrocytoma Grade I to Grade III) receiving conventional therapeutic measures. The results were compared with the immune status of metastatic secondary glioma and meningioma patients where there is minimal immune suppression and the effect of therapeutic intervention on the above score. METHODS: Functional immune parameters of peripheral blood lymphocytes were assayed by CD2 receptors enumeration through E-rosetting and lymphocyte cytotoxicity assay and assessing the generation of reactive oxygen species by NBT assay of peripheral blood macrophages in patient groups bearing Astrocytoma (Grade I to Grade III), meningioma and secondary glioma. RESULTS: Patients bearing Astrocytoma (all 3 grades) showed maximum immune suppression as compared to the normal subjects, diseased meningioma controls, and secondary glioma. Therapeutic interventions viz. radiotherapy, surgery and radiotherapy after surgery and chemotherapy could not recover the suppressed activity of the CD2 bearing lymphocytes and that of peripheral blood macrophages. However, therapeutic scheduling could recover the functional activity of the CD8 bearing lymphocytes and the CD56 NK cells from that of tumor bearing patients. CONCLUSION: Astrocytoma and not meningioma is capable of causing immunesuppression. As the tumor progresses from Grade I to Grade III, a linear reduction in the functional efficacy of immunocytes is seen to occur. Radiotherapy, surgery, and chemotherapy also induces an inhibitory effect towards the host immune system. The inhibitory effect of tumor as well as of therapy were mainly directed towards the CD2 bearing lymphocyte population and the peripheral blood macrophage population.

Assembly of scaffold-mediated complexes containing Cdc42p, the exchange factor Cdc24p, and the effector Cla4p required for cell cycle-regulated phosphorylation of Cdc24p.

In budding yeast cells, the cytoskeletal polarization and depolarization events that shape the bud are triggered at specific times during the cell cycle by the cyclin-dependent kinase Cdc28p. Polarity establishment also requires the small GTPase Cdc42p and its exchange factor, Cdc24p, but the mechanism whereby Cdc28p induces Cdc42p-dependent polarization is unknown. Here we show that Cdc24p becomes phosphorylated in a cell cycle-dependent manner, triggered by Cdc28p. However, the role of Cdc28p is indirect, and the phosphorylation appears to be catalyzed by the p21-activated kinase family member Cla4p and also depends on Cdc42p and the scaffold protein Bem1p. Expression of GTP-Cdc42p, the product of Cdc24p-mediated GDP/GTP exchange, stimulated Cdc24p phosphorylation independent of cell cycle cues, raising the possibility that the phosphorylation is part of a feedback regulatory pathway. Bem1p binds directly to Cdc24p, to Cla4p, and to GTP-bound Cdc42p and can mediate complex formation between these proteins in vitro. We suggest that Bem1p acts to concentrate polarity establishment proteins at a discrete site, facilitating polarization and promoting Cdc24p phosphorylation at specific times during the cell cycle.