The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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From Krebs to clinic: glutamine metabolism to cancer therapy.

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Fear of crime : interpreting victimization risk

There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.

Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases

Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19.

The metabolome, the collection of small-molecule chemical entities involved in metabolism, has traditionally been studied with the aim of identifying biomarkers in the diagnosis and prediction of disease. However, the value of metabolome analysis (metabolomics) has been redefined from a simple biomarker identification tool to a technology for the discovery of active drivers of biological processes. It is now clear that the metabolome affects cellular physiology through modulation of other 'omics' levels, including the genome, epigenome, transcriptome and proteome. In this Review, we focus on recent progress in using metabolomics to understand how the metabolome influences other omics and, by extension, to reveal the active role of metabolites in physiology and disease. This concept of utilizing metabolomics to perform activity screens to identify biologically active metabolites - which we term activity metabolomics - is already having a broad impact on biology.

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Identification of bioactive metabolites using activity metabolomics

In vivo imaging of cytotoxic T lymphocyte (CTL) killing activity revealed that infected cells have a higher observed probability of dying after multiple contacts with CTLs, suggesting memory effect in CTLs or infected cells. We developed a three-dimensional agent-based model of CTL killing activity to discriminate different hypotheses about how infected cells get killed based on quantitative 2-photon in vivo observations. We compared a constant CTL killing probability with mechanisms of signal integration in CTL or infected cells. The most likely scenario implied increased susceptibility of infected cells with increasing number of CTL contacts where the total number of contacts was a critical factor as opposed to signal integration over many contacts. However, when allowing in silico T cells to interact with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with the experimental datasets. We showed that contacts that take place between CTLs and dying infected cells impact the observed killing dynamics because even in absence of modulation of cell properties, we saw an increase of the observed probability of killing infected cells with more interactions. The duration taken by an infected cell to die and the per capita killing rate (PCKR) of CTLs, parameters hard to measure directly, were determined from the model and turned out predictive to distinguish the different CTL killing models in future experiments. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided prediction for additional measurements to distinguish CTL killing models. HighlightsO_LIKilling of infected cells by cytotoxic T cells typically involves more than a single contact. C_LIO_LICytotoxic T cells or infected cells integrate signals from multiple interactions. C_LIO_LIT cell contacts with dying infected cells have a major impact on in vivo data interpretation. C_LI Significance StatementDespite having a clear understanding of cytotoxic T lymphocyte (CTL) mediated cytotoxicity mechanisms, the quantitative dynamics remain unexplored at a cellular level. We developed an agent-based model to compare different hypotheses for mechanisms of CTL mediated cytotoxicity that could lead to an increase in observed probability of killing infected cells at higher interactions with CTLs as seen in vivo. We showed that this behaviour can be explained by modulation of properties by infected cells or CTLs with increasing number of contacts. For the modulation, we compared two modes of signal integration and showed that time is not a relevant parameter in signal integration. We also studied the impact of contacts between CTLs and apoptotic infected cells on observed killing properties.

https://www.biorxiv.org/content/biorxiv/early/2019/11/04/830505.full.pdf

Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments

S’attachant a l’un des themes favoris du professeur Landreville, la peine, l’auteur montre l’interet de le mettre en perspective dans le long terme historique. Il commence par expliquer comment l’emergence decisive de la penalite est liee a celle de l’etatisation de nos societes. Puis il etudie la liaison entre differentes formes d’Etat et differents regimes de penalites. Enfin, il s’attache, a partir de donnees provenant d’un pays de l’Europe occidentale, la France, a scruter les recompositions actuelles de la penalite, dans un Etat devenu moins social et plus liberal.

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Les transformations de la pénalité

Deep neural-network-based language models (LMs) are increasingly applied to large-scale protein sequence data to predict protein function. However, being largely black-box models and thus challenging to interpret, current protein LM approaches do not contribute to a fundamental understanding of sequence-function mappings, hindering rule-based biotherapeutic drug development. We argue that guidance drawn from linguistics, a field specialized in analytical rule extraction from natural language data, can aid with building more interpretable protein LMs that are more likely to learn relevant domain-specific rules. Differences between protein sequence data and linguistic sequence data require the integration of more domain-specific knowledge in protein LMs compared to natural language LMs. Here, we provide a linguistics-based roadmap for protein LM pipeline choices with regard to training data, tokenization, token embedding, sequence embedding, and model interpretation. Incorporating linguistic ideas into protein LMs enables the development of next-generation interpretable machine-learning models with the potential of uncovering the biological mechanisms underlying sequence-function relationships. 

/pdf/linguistically-inspired-roadmap-for-building-biologically-1yap3lf8.pdf

Linguistically inspired roadmap for building biologically reliable protein language models

Tous les deux ans depuis 2001, l'Institut d'amenagement et d'urbanisme de la region Ile-de-France (IAU-IdF) mene une enquete sur la victimation et l'insecurite des Franciliens. Qu'est-ce qu'une enquete de victimation ? C'est un sondage aupres d'un echantillon representatif de la population. On interroge les membres de l'echantillon sur les atteintes incriminables qu'ils declarent avoir subi au cours d'une periode delimitee. Il existe des enquetes de victimation internationales, nationales et locales. Leurs apports a la connaissance sociologique du crime sont nombreux. Et d'abord ces enquetes procurent une information sur des faits ignores des services de police pour n'avoir pas donne lieu a un enregistrement. Par suite, elles mesurent la propension des personnes a alerter les autorites apres avoir subi une atteinte. Ce n'est pas le seul avantage des enquetes. Les statistiques de police ne comptent que des faits et des suspects. Les enquetes de victimation, en plus de denombrer des atteintes, decrivent leurs circonstances, le profil des victimes, ainsi que les liens entre l'experience de victimation et le sentiment d'insecurite. Ces apports ont assure le succes des enquetes de victimation. Ils ont fait d'elles un instrument de pilotage et d'evaluation des politiques publiques de securite, notamment aux niveaux regional et local ou de telles politiques sont habituellement mises en œuvre.

https://hal.archives-ouvertes.fr/hal-00742291/document

Victimations et insécurité en Île-de-France 2006-2007-2008 : analyse de la 5e enquête (2009) de l'Institut d'Aménagement et d'Urbanisme d'Île-de-France (IAU-IdF)

89 * Centre de recherches sociologiques sur le droit et les institutions pénales (CESDIP) [Université de Versailles Saint Quentin (UVSQ), Centre national de la recherche scientifique (CNRS), ministère de la Justice]. Cet article tire principalement son origine d’une synthèse opérée sous la direction de Renée Zauberman (2008 a, b) dans le cadre d’une action de coordination (CRIMPREV) du 6o Programme Cadre de Recherche et Développement Technologique (PCRDT), et d’une enquête ultérieure réalisée par Van Dijk et al. (2010), pour le compte d’Eurostat, dans les 28 pays-membres de l’Union européenne. CONDITIONS DE VIE ET SOCIÉTÉ

Philippe Robert

Papers

Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments

Les transformations de la pénalité

Linguistically inspired roadmap for building biologically reliable protein language models

Victimations et insécurité en Île-de-France 2006-2007-2008 : analyse de la 5e enquête (2009) de l'Institut d'Aménagement et d'Urbanisme d'Île-de-France (IAU-IdF)

Les enquêtes de victimation en Europe