Régulation et implication physiologique de la voie ecto-F1-ATPase/P2Y13 dans le transport retour du cholestérol

Le rôle athéroprotecteur des lipoprotéines de haute densité (HDL) est principalement attribué à leur participation essentielle à la voie de transport retour du cholestérol (RCT) dans laquelle les HDL transportent le cholestérol des tissus périphériques au foie, où il sera éliminé via les voies biliaires. Notre équipe a décrit à la surface d'hépatocytes humains une nouvelle voie de captation des holoparticules HDL (protéines + lipides) stimulée par l'activation du récepteur P2Y13 par l'ADP produit suite à la liaison de l'apoA-1 (protéine majoritaire des HDL) sur une ecto-F1-ATPase de surface. Ces travaux mettent en évidence à la surface des hépatocytes humains une activité adénylate kinase qi régule cette voie d'endocytose des HDL. De plus, ces travaux démontrent l'implication physiologique de cette voie ecto-F1-ATPase/P2Y13 dans le RCT in vivo chez la souris. La voie ecto-F1-ATPase/P2Y13 pourrait donc constituer une nouvelle cible thérapeutique pour le traitement de l'athérosclérose.The protective effect of HDL (High Density Lipoprotein) against atherosclerosis is mainly attributed to its role in Reverse Cholesterol Transport (RCT) by removing cholesterol from peripheral tissues and by delivering cholesterol to the liver for metabolism and bile excretion. In our research team, a new pathway for holo-HDL particle uptake (protein + lipid) has been recently identified in human hepatocytes. This pathway strictly depends on extracellular ADP level and involves different cell surface partners: ADP generated by the cell surface ecto-F1-ATPase (which activity is stimulated by apoA-I, the main HDL apolipoprotein) activates the P2Y13 ADP-receptor and subsequent holo-HDL endocytosis. In this work, we have shown the presence of an adenylate kinase activity (AK : 2ADP-->ATP+AMP) at the cell surface of human hepatocytes that appeared to naturally downregulate the ecto-F1-ATPase/P2Y13 mediated HDL endocytosis pathway by consuming the ADP generated by the ecto-F1-ATPase. Furthermore, we have demonstrated the physiological implication of P2Y13 in reverse cholesterol transport in vivo. Preliminaries results suggest a protective role of P2Y13 in atherosclerosis development. Thus, ecto-F1-ATPase/P2Y13 pathway could be an attractive therapeutic target to fight against the development of atherosclerosis

Good Contexts for Translators-A First Account of the Cristal Project

International audienceThis paper questions the notion of good contexts for translators and describes an experiment which tests the usefulness of two specific kinds of contexts in a translation task, namely (1) contexts that provide conceptual information about a term, and (2) contexts that provide linguistic information about the collocational profile of this term. In the experiment, trainee translators are asked to use several types of resources, including a set of pre-annotated contexts of various types, and to identify the contexts that they consider to be the most relevant for their task. We present the first results of this experiment, which confirm our general assumption about the usefulness of such rich contexts and indicate some differences regarding the use of contexts in the source and target language. This study takes place in the CRISTAL project whose aim is to retrieve from bilingual comparable corpora the contexts that are the most relevant for translation and to provide them to users through a CAT tool

Is there any relationship between physical activity level and patterns, and physical performance in children?

<p>Abstract</p> <p>Background</p> <p>It is often assumed that physical activity (PA) and physical performance during childhood and adolescence are beneficial for health during adulthood, but a positive relationship between PA and physical performance has not been precisely clarified in children. The lack or the weakness of the relationships between PA and physical performance could be due to the measure of PA. If the use of accelerometry is considered as an objective and common measure of PA, the real patterns of children's habitual PA must be reflected. The aim of this study was to investigate the relationship between the levels and patterns of PA assessed with high frequency accelerometry and physical performance in young children.</p> <p>Methods</p> <p>Eighty-six boys and 101 girls aged 6-12 years participated in this study. Physical activity was measured over a 7-day period, using a 5-s epoch. Physical performance was assessed by means of EUROFIT tests (anthropometrics, standing broad jump, the 10 × 5 meter shuttle run, the sit-and-reach, the handgrip, the number of sit-ups in 30 seconds, the 20-meter shuttle run).</p> <p>Results</p> <p>No relationship was found between PA and physical performance. In boys only, body fatness was negatively associated with vigorous PA (r = -0.38, p < 0.001) and very high PA (r = -0.35, p < 0.01), in contrast to light PA (r = 0.28, p < 0.01), which was positively related to body fatness.</p> <p>Conclusion</p> <p>In 6- to- 12 year- old children, the more active children were not the fittest. Our results also underline the need for uniformity in approach to measurement of PA, body composition and health-related fitness between studies.</p

Using comparable corpora to characterize knowledge-rich contexts for various kinds of users: preliminary steps

V International Conference on Corpus Linguistics (CILC2013)International audienceThe paper presents the early stage of the CRISTAL project, an original French project involving linguists, computer researchers and a firm specializing in multilingual text management. What is at stake from a linguistic point of view is a deeper analysis of the notion of Knowledge Rich Context proposed by Meyer (2001). Using comparable corpora, it analyzes how the notion of KRC can vary according to text genre and/or type of users

Combined Mutation And Rearrangement Screening by Quantitative PCR High-Resolution Melting: Is It Relevant for Hereditary Recurrent Fever Genes?

The recent identification of genes implicated in hereditary recurrent fevers has allowed their specific diagnosis. So far however, only punctual mutations have been identified and a significant number of patients remain with no genetic confirmation of their disease after routine molecular approaches such as sequencing. The possible involvement of sequence rearrangements in these patients has only been examined in familial Mediterranean fever and was found to be unlikely. To assess the existence of larger genetic alterations in 3 other concerned genes, MVK (Mevalonate kinase), NLRP3 (Nod like receptor family, pyrin domain containing 3) and TNFRSF1A (TNF receptor superfamily 1A), we adapted the qPCR-HRM method to study possible intragenic deletions and duplications. This single-tube approach, combining both qualitative (mutations) and quantitative (rearrangement) screening, has proven effective in Lynch syndrome diagnosis. Using this approach, we studied 113 unselected (prospective group) and 88 selected (retrospective group) patients and identified no intragenic rearrangements in the 3 genes. Only qualitative alterations were found with a sensitivity similar to that obtained using classical molecular techniques for screening punctual mutations. Our results support that deleterious copy number alterations in MVK, NLRP3 and TNFRSF1A are rare or absent from the mutational spectrum of hereditary recurrent fevers, and demonstrate that a routine combined method such as qPCR-HRM provides no further help in genetic diagnosis. However, quantitative approaches such as qPCR or SQF-PCR did prove to be quick and effective and could still be useful after non contributory punctual mutation screening in the presence of clinically evocative signs

From the pathophysiology of the human lung alveolus to epigenetic editing: Congress 2018 highlights from ERS Assembly 3 "Basic and Translational Science."

The European Respiratory Society (ERS) International Congress is the largest respiratory congress and brings together leading experts in all fields of respiratory medicine and research. ERS Assembly 3 shapes the basic and translational science aspects of this congress, aiming to combine cutting-edge novel developments in basic research with novel clinical findings. In this article, we summarise a selection of the scientific highlights from the perspective of the three groups within Assembly 3. In particular, we discuss new insights into the pathophysiology of the human alveolus, novel tools in organoid development and (epi)genome editing, as well as insights from the presented abstracts on novel therapeutic targets being identified for idiopathic pulmonary fibrosis.S

CXCR3A promotes the secretion of the anti-fibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts

CXCR3A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodelling and fibroblast motility. IL‑13 is a pro‑fibrotic cytokine implicated in the pathogenies of inflammatory and fibro-proliferative conditions. Previous work from our lab has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Rα2. This study investigates the regulation of fibroblast phenotype, function and downstream IL-13 signalling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A-/- lung fibroblastswere isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodelling following acute lung injury was assessed in vivo using wild type (WT) and CXCR3-/- mice challenged with IL-13. CXCR3 and IL‑13Rα2 displayed a reciprocal relationship following stimulation with either IL-13 or CXCR3 ligands. CXCR3A reduced expression of fibroblast activation makers, soluble collagen production and proliferation. CXCR3A enhanced the basal expression of pERK1/2 while inducing IL-13 mediated down‑regulation of NFκB‑p65. CXCR3A-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and α‑smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Rα2 levels in lungs and broncho‑alveolar lavage fluid (BALF) of WT mice, this response was absent in CXCR3-/- mice. Alveolar macrophage accumulation and expression of genes involved in lung remodelling was increased in CXCR3-/- mice. We conclude that CXCR3A is a central anti-fibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing ECM production. Therefore targeting of CXCR3A may be a novel approach to regulate fibroblast activity in lung fibrosis and remodelling

Membrane estrogen receptor-α contributes to female protection against high-fat diet-induced metabolic disorders

BackgroundEstrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified.MethodsMale and female C451A-ERα mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (WT-ERα) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice.ResultsC451A-ERα genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed C451A-ERα female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure.ConclusionBesides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse

TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup

Tours et détours en bibliothèque. Carnet de voyage

Une bibliothèque pour faire quoi ? 19 écrivains et 1 plasticienne répondent, à leur manière – pour faire un tour, pour regarder un film, pour donner RDV, pour se mettre au chaud, pour lire, pour mettre le feu, pour parler de Flaubert, pour photographier le chantier, pour faire le ménage, pour être seul avec d'autres, pour travailler, pour dormir... Dans des styles différents, entre récits, nouvelles ou témoignages, les auteurs ont composé un portrait à multiples facettes de ce lieu public, et de ses passagers. Leurs textes reflètent aussi les grandes tendances de la littérature contemporaine, tournés pour certains vers le politique ou le social, pour d'autres vers le poétique ou le biographique. De son côté, en photographe, Aurélie Pétrel donne un ancrage visuel à ce Carnet de voyage