Neutral evolution of proteins: The superfunnel in sequence space and its relation to mutational robustness.

International audienceFollowing Kimura's neutral theory of molecular evolution [M. Kimura, The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983) (reprinted in 1986)], it has become common to assume that the vast majority of viable mutations of a gene confer little or no functional advantage. Yet, in silico models of protein evolution have shown that mutational robustness of sequences could be selected for, even in the context of neutral evolution. The evolution of a biological population can be seen as a diffusion on the network of viable sequences. This network is called a "neutral network." Depending on the mutation rate mu and the population size N, the biological population can evolve purely randomly (muN1). The stringency of the selection depends not only on the product muN but also on the exact topology of the neutral network, the special arrangement of which was named "superfunnel." Even though the relation between mutation rate, population size, and selection was thoroughly investigated, a study of the salient topological features of the superfunnel that could affect the strength of the selection was wanting. This question is addressed in this study. We use two different models of proteins: on lattice and off lattice. We compare neutral networks computed using these models to random networks. From this, we identify two important factors of the topology that determine the stringency of the selection for mutationally robust sequences. First, the presence of highly connected nodes ("hubs") in the network increases the selection for mutationally robust sequences. Second, the stringency of the selection increases when the correlation between a sequence's mutational robustness and its neighbors' increases. The latter finding relates a global characteristic of the neutral network to a local one, which is attainable through experiments or molecular modeling

Evaluation du projet Loisirs sans tabac du CIPRET-Vaud : Partie 1: Enquête auprès des centres socioculturels, avant déploiement du projet

La plupart des publications disponibles sur des interventions de prévention du tabagisme chez les jeunes concernent des interventions dans le cadre scolaire. Une revue systématique de la littérature sur les programmes de prévention dans les écoles, comprenant 49 cohortes préventives (N=142'447) a montré un effet préventif après plus d'un an de suivi, avec une réduction de l'initiation du tabagisme de 12% comparé aux groupes contrôles. Au Royaume-Uni, le National Institute for Heath and Care Excellence (NICE) recommande la mise en place d'interventions par le personnel dans les écoles, mais aussi par des professionnels externes formés pour travailler avec les enfants et les jeunes sur la problématique du tabac. Les interventions recommandées consistent non seulement à informer les jeunes sur les risques liés au tabagisme, mais aussi un travail avec les jeunes dans le but de les aider à développer leur capacité de décision, leur auto-estime et leur capacité à résister à la pression des médias, de leurs familles, de pairs et de l'industrie du tabac

Evaluation du projet Loisirs sans tabac du CIPRET-Vaud : Partie 2: Enquête auprès des centres socioculturels, après déploiement du projet

La présente évaluation vise à analyser si les activités prévues dans le cadre du projet ont effectivement été menées et si le projet a atteint ses objectifs. Elle explore également la place de la prévention du tabagisme dans les espaces de loisirs, la constitution d’un réseau de centres socioculturels, la position des centres socioculturels par rapport au tabac et l’appréciation globale du matériel mis à disposition. Le design évaluatif proposé combine un entretien avec la responsable du projet, une enquête en ligne auprès des professionnels de l’animation socioculturelle et des travailleurs sociaux de proximité (n= 21 ; taux de réponse : 24%) et une analyse des données de fréquentation du site Internet. L’évaluation a été réalisée entre le 1er octobre et le 12 décembre 2016. En prenant appui sur les besoins des centres socioculturels identifiés lors de la première phase évaluative, le CIPRET-Vaud a élaboré le site Internet http qui mutualise et valorise les informations et outils existants pour en faciliter l’accès et l’utilisation. Les centres socioculturels et les travailleurs sociaux de proximité ont été invités à une demi-journée de présentation à l'occasion de la journée mondiale sans tabac, le 31 mai 2016 ; une dizaine de personnes y ont effectivement participé. L'ensemble des centres socioculturels et des travailleurs sociaux de proximité a par ailleurs reçu en septembre 2016 un courrier accompagné d’un flyer de présentation du site Internet

TABAC-ALCOOL : Evaluation du projet du CIPRET Vaud "Aborder le tabagisme via d’autres problèmes de santé"

Dans le cadre du programme de prévention du tabagisme 2014-2017 cofinancé par le canton et le Fonds de prévention du tabagisme, le CIPRET-Vaud conduit un projet Aborder le tabagisme via d'autres problèmes de santé visant à apporter une prise en charge spécifique à des personnes fumeuses particulièrement vulnérables en raison d'autres problèmes de santé. Un sous-projet, Tabac-alcool, a été développé afin de favoriser la prise en charge du problème du tabagisme chez les personnes alcoolodépendantes traitées en milieu résidentiel. Deux groupes cibles sont visés, l'un direct, l'autre indirect. Le groupe cible direct est constitué des professionnels socioéducatifs des établissements résidentiels en traitement alcoologique. Le projet vise à les sensibiliser à la problématique, à les former et à les outiller pour offrir aux résidents de leurs centres une information de qualité sur la co-consommation de tabac et d'alcool, une aide spécifique et adaptée, et une orientation éventuelle vers des services spécialisés. Le groupe cible indirect est constitué des résidents de ces établissements. Les objectifs du projet Tabac-alcool tels que définis au démarrage du projet sont les suivants: Fin 2016, les professionnels de trois établissements résidentiels pour personnes alcoolo-dépendantes sont informés et sensibilisés aux liens existant entre la consommation d'alcool et de tabac et sont outillés pour aborder la question dans leur pratique. Fin 2016, les personnes dépendantes à la fois autabac et à l'alcool et traitées en résidentiel (trois établissements) sont informées et sensibilisées sur le lien existant entre le tabac et l'alcool. Parmi elles, les personnes intéressées ont accès à une aide à l'arrêt du tabagisme spécifique et adaptée à leur situation

Recognizing protein-protein interfaces with empirical potentials and reduced amino acid alphabets.

International audienceBACKGROUND: In structural genomics, an important goal is the detection and classification of protein-protein interactions, given the structures of the interacting partners. We have developed empirical energy functions to identify native structures of protein-protein complexes among sets of decoy structures. To understand the role of amino acid diversity, we parameterized a series of functions, using a hierarchy of amino acid alphabets of increasing complexity, with 2, 3, 4, 6, and 20 amino acid groups. Compared to previous work, we used the simplest possible functional form, with residue-residue interactions and a stepwise distance-dependence. We used increased computational resources, however, constructing 290,000 decoys for 219 protein-protein complexes, with a realistic docking protocol where the protein partners are flexible and interact through a molecular mechanics energy function. The energy parameters were optimized to correctly assign as many native complexes as possible. To resolve the multiple minimum problem in parameter space, over 64000 starting parameter guesses were tried for each energy function. The optimized functions were tested by cross validation on subsets of our native and decoy structures, by blind tests on series of native and decoy structures available on the Web, and on models for 13 complexes submitted to the CAPRI structure prediction experiment. RESULTS: Performance is similar to several other statistical potentials of the same complexity. For example, the CAPRI target structure is correctly ranked ahead of 90% of its decoys in 6 cases out of 13. The hierarchy of amino acid alphabets leads to a coherent hierarchy of energy functions, with qualitatively similar parameters for similar amino acid types at all levels. Most remarkably, the performance with six amino acid classes is equivalent to that of the most detailed, 20-class energy function. CONCLUSION: This suggests that six carefully chosen amino acid classes are sufficient to encode specificity in protein-protein interactions, and provide a starting point to develop more complicated energy functions

Neutral evolution of Protein-protein interactions: a computational study using simple models

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions are central to cellular organization, and must have appeared at an early stage of evolution. To understand better their role, we consider a simple model of protein evolution and determine the effect of an explicit selection for Protein-protein interactions.</p> <p>Results</p> <p>In the model, viable sequences all have the same fitness, following the neutral evolution theory. A very simple, two-dimensional lattice representation of the protein structures is used, and the model only considers two kinds of amino acids: hydrophobic and polar. With these approximations, exact calculations are performed. The results do not depend too strongly on these assumptions, since a model using a 3D, off-lattice representation of the proteins gives results in qualitative agreement with the 2D one. With both models, the evolutionary dynamics lead to a steady state population that is enriched in sequences that dimerize with a high affinity, well beyond the minimal level needed to survive. Correspondingly, sequences close to the viability threshold are less abundant in the steady state, being subject to a larger proportion of lethal mutations. The set of viable sequences has a "funnel" shape, consistent with earlier studies: sequences that are highly populated in the steady state are "close" to each other (with proximity being measured by the number of amino acids that differ).</p> <p>Conclusion</p> <p>This bias in the the steady state sequences should lead to an increased resistance of the population to environmental change and an increased ability to evolve.</p

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Computational Protein Design: Validation and Possible Relevance as a Tool for Homology Searching and Fold Recognition

International audienceBACKGROUND: Protein fold recognition usually relies on a statistical model of each fold; each model is constructed from an ensemble of natural sequences belonging to that fold. A complementary strategy may be to employ sequence ensembles produced by computational protein design. Designed sequences can be more diverse than natural sequences, possibly avoiding some limitations of experimental databases. METHODOLOGY/PRINCIPAL FINDINGS: WE EXPLORE THIS STRATEGY FOR FOUR SCOP FAMILIES: Small Kunitz-type inhibitors (SKIs), Interleukin-8 chemokines, PDZ domains, and large Caspase catalytic subunits, represented by 43 structures. An automated procedure is used to redesign the 43 proteins. We use the experimental backbones as fixed templates in the folded state and a molecular mechanics model to compute the interaction energies between sidechain and backbone groups. Calculations are done with the Proteins@Home volunteer computing platform. A heuristic algorithm is used to scan the sequence and conformational space, yielding 200,000-300,000 sequences per backbone template. The results confirm and generalize our earlier study of SH2 and SH3 domains. The designed sequences ressemble moderately-distant, natural homologues of the initial templates; e.g., the SUPERFAMILY, profile Hidden-Markov Model library recognizes 85% of the low-energy sequences as native-like. Conversely, Position Specific Scoring Matrices derived from the sequences can be used to detect natural homologues within the SwissProt database: 60% of known PDZ domains are detected and around 90% of known SKIs and chemokines. Energy components and inter-residue correlations are analyzed and ways to improve the method are discussed. CONCLUSIONS/SIGNIFICANCE: For some families, designed sequences can be a useful complement to experimental ones for homologue searching. However, improved tools are needed to extract more information from the designed profiles before the method can be of general use