Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusions Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic models with strong repressors

The hierarchy of KorB binding at its 12 binding sits on the broad-host-range plasmid RK2 and modulation of this binding by IncD1 protein

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Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases

Toll-like receptors (TLRs) are the best-studied family of pattern-recognition receptors (PRRs), whose task is to rapidly recognize evolutionarily conserved structures on the invading microorganisms. Through binding to these patterns, TLRs trigger a number of proinflammatory and anti-microbial responses, playing a key role in the first line of defence against the pathogens also promoting adaptive immunity responses. Growing amounts of data suggest that single nucleotide polymorphisms (SNPs) on the various human TLR proteins are associated with altered susceptibility to infection. This review summarizes the role of TLRs in innate immunity, their ligands and signalling and focuses on the TLR SNPs which have been linked to infectious disease susceptibility. © 2015 British Society for Immunology

Adaptation for protein synthesis efficiency in a naturally occurring self-regulating operon

The korAB operon in RK2 plasmids is a beautiful natural example of a negatively and cooperatively self-regulating operon. It has been particularly well characterized both experimentally and with mathematical models. We have carried out a detailed investigation of the role of the regulatory mechanism using a biologically grounded mechanistic multi-scale stochastic model that includes plasmid gene regulation and replication in the context of host growth and cell division. We use the model to compare four hypotheses for the action of the regulatory mechanism: increased robustness to extrinsic factors, decreased protein fluctuations, faster response-time of the operon and reduced host burden through improved efficiency of protein production. We find that the strongest impact of all elements of the regulatory architecture is on improving the efficiency of protein synthesis by reduction in the number of mRNA molecules needed to be produced, leading to a greater than ten-fold reduction in host energy required to express these plasmid proteins. A smaller but still significant role is seen for speeding response times, but this is not materially improved by the cooperativity. The self-regulating mechanisms have the least impact on protein fluctuations and robustness. While reduction of host burden is evident in a plasmid context, negative self-regulation is a widely seen motif for chromosomal genes. We propose that an important evolutionary driver for negatively self-regulated genes is to improve the efficiency of protein synthesis

Accidents vasculaires cérébraux ischémiques vertébro-basilaires (causes et pronostic)

Contexte : les études consacrées aux mécanismes et pronostic des accidents vasculaires cérébraux ischémiques (AVCI) vertébro-basilaires (VB) sont rares et présentent des limites liées au mode de recrutement des patients et au bilan étiologique réalisé. Méthodes : afin de mieux connaître la répartition des sous-groupes étiologiques et le pronostic des AVCIVB, nous avons réalisé une étude prospective sur 102 patients consécutifs ayant présenté un premier AICVB. Chaque patient a bénéficié d'un bilan étiologique détaillé incluant une exploration cardiaque et des troncs supra-aortiques par échodoppler et angiographie par résonance magnétique (ARM). Résultats : les causes identifiées étaient l'athérosclérose (24%), une maladie des petites artères (20%), une origine cardio-embolique (17%), une cause rare (4%) et l'étiologie était indéterminée dans 36% des cas. Après 15.1 mois de suivi, 10 évènements neuro-vasculaires (6 AVCI et 4 AIT) ont été observés. Le taux de récidive par sous-groupe était : athérosclérose : 16.7%, cardio-embolique : 20%, maladies des petites artères : 5% et origine indéterminée : 5.4%. L'athérosclérose est un sous-groupe étiologique à risque qui pourrait bénéficier de traitements spécifiques. Il semble donc nécessaire d'étudier le pronostic à moyen et long terme des sténoses et occlusions athéroscléreuses vertébro-basilaires, en particulier extracrâniennes qui reste encore mal connuPARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF