Cells live in contexts with limited resources, and evolution has selected mechanisms that allow them to accomplish the tasks essential for life by making optimal use of the resources. This idea spans from one extreme of complexity of the cellular world (bacteria) to another (cancer cells), and is, in essence, the basis of constraint-based modeling, possibly the most successful approach for unraveling cell energetics. More or less recent work aimed at correlating energetics with thermodynamic and regulatory properties has brought to light a number of facts that are not explained by current theories. To make progress and understand whether evolution has found optimal solutions requires us to dig deeper into the space of possible states of a cell's metabolic network, and into the nature of the constraints that define it. We shall see how important hints derived from thermodynamical and regulatory considerations lead to novel insights and (possibly) entirely new classes of…

Au sein de la grande diversité des modèles en Neurosciences Computationnelles, l’approche biophysique permet d’évaluer la manière dont les propriétés neuronales locales (excitabilité, transmission synaptique, règles de plasticité) participent à l’émergence de propriétés d’intérêt à l’échelle globale des réseaux de neurones (traitement de l’information, apprentissage, mémoire, organisation du comportement). Ces modèles reposent sur 1) un travail d’extraction des propriétés moléculaires et cellulaires pertinentes (bibliographie approfondie, collaboration avec les expérimentateurs), 2) la construction et la réduction de dimensionnalité – attentives – de modèles locaux réalistes résumant ces propriétés, 3) l’incorporation de celles–ci dans des modèles de réseaux de neurones, et l’étude de leur expression dans les propriétés émergentes observées. En filigrane, une notion récurrente dans cette approche matérialiste et déterministe est la dynamique des systèmes neuronaux étudiés, c’est à dire leur neurodynamique. Cette notion est importante car elle permet de prendre en compte l’interaction entre les informations externes et l’état interne de l’individu.…

Adaptation proceeds through the selection of mutations. The distribution of mutant fitness effect and the forces shaping this distribution are therefore keys to predict the evolutionary fate of organisms and their constituents such as enzymes. Here, by producing and sequencing a comprehensive collection of 10,000 mutants, we explore the mutational landscape of one enzyme involved in the spread of antibiotic resistance, the beta-lactamase TEM-1. We measured mutation impact on the enzyme activity through the estimation of amoxicillin Minimum Inhibitory Concentration (MIC) on a subset of 990 mutants carrying a unique missense mutation, representing 64% of possible amino acid changes in that protein reachable by point mutation. We established that mutation type, solvent accessibility of residues and the predicted effect of mutations on protein stability primarily determined alone or in combination changes in MIC of mutants. Moreover, we were able to capture the drastic modification of the mutational landscape induced by a single…

Dozens of genes are known to control the pathways of crossover formation between homologs during meiosis. In most species, crossovers interfere, a phenomenon first discovered in the Morgan lab nearly a century ago. Nevertheless the mechanisms producing crossover interference remain unknown. I will show how quantitative modeling has been used, what has been learned, and the road still ahead.

Microbes engage in a remarkable array of cooperative behaviors, secreting shared proteins that are essential for foraging, shelter, microbial warfare and virulence. These proteins are costly, rendering populations of cooperators vulnerable to exploitation by non-producing cheaters arising by gene loss or migration. In such conditions, how can cooperation persist? Our model predicts that more mobile loci generate higher relatedness, and therefore allow the maintenance of more cooperative traits via kin selection. By analyzing bacterial genomes we observe a massive amount of horizontal transfer and show that this is the predominant mechanism of innovation in bacterial genomes. Additionally, this shows that we are far from knowing the diversity of functions encoded in the species. We confirm that genes coding for secreted proteins - the secretome – are very frequently lost and gained and are associated with mobile elements, supporting our major prediction that gene mobility drives bacterial cooperation. We demonstrate that mobile elements…

To sample their environment and coordinate appropriate adaptation responses bacteria require a flurry of signal transduction systems. Among the most commonly utilized are the so-called two-component systems. These systems comprise (1) a sensor protein, the sensor histidine kinase which modulates an intrinsic autophosporylation activity in response to changing cellular and environmental clues and (2) a response regulator protein that interacts with DNA, RNA or protein targets to coordinate an appropriate response. This talk will discuss our recent findings studying selected systems in the Gram-positive model organism Bacillus subtilis by integrating information derived from a diverse set of experimental approaches such as genetics, enzymology and structural biology and in silico approaches such as Molecular Dynamics Simulations and Bioinformatic techniques. These studies identified some general rules by which these proteins coordinate a response on the molecular level, of relevance to all two-component systems and beyond. One system in particular, the YycFG system is conserved…

Aptamers are short oligonucleotides (< 100 bases) selected from large combinatorial pools of sequences (from 1012 to 1015) for their capacity to bind a target (amino acids, antibiotic, proteins…). Such ligands are isolated by a method of directed molecular evolution usually named SELEX (Systematic Evolution of Ligands by Exponential enrichment). Since 2005, our group and others have adapted the SELEX against whole living cells. Using this strategy, we selected several nuclease resistant 2'-Fluoro-pyrimidines (2'-F-Py) RNA aptamers against cell surface biomarkers that can represent surrogate markers of cancer cells (1-3). This technique, usually named cell-SELEX, allows the parallel selection of several aptamers against membrane proteins in a native conformation. However, although these aptamers are very important tools for in vitro experiments, their translation for in vivo uses is still difficult to predict. To solve this problem, we have developed fluorescence imaging techniques to investigate their biodistribution and tumour targeting capacities in small animal…