Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach

Since the advent of genome-wide small interfering RNA screening, large numbers of cellular cofactors important for viral infection have been discovered at a rapid pace, but the viral targets and the mechanism of action for many of these cofactors remain undefined. One such cofactor is cyclophilin A (CyPA), upon which hepatitis C virus (HCV) replication critically depends. Here we report a new genetic selection scheme that identified a major viral determinant of HCV's dependence on CyPA and susceptibility to cyclosporine A. We selected mutant viruses that were able to infect CyPA-knockdown cells which were refractory to infection by wild-type HCV produced in cell culture. Five independent selections revealed related mutations in a single dipeptide motif (D316 and Y317) located in a proline-rich region of NS5A domain II, which has been implicated in CyPA binding. Engineering the mutations into wild-type HCV fully recapitulated the CyPA-independent and CsA-resistant phenotype and four putative proline substrates of CyPA were mapped to the vicinity of the DY motif. Circular dichroism analysis of wild-type and mutant NS5A peptides indicated that the D316E/Y317N mutations (DEYN) induced a conformational change at a major CyPA-binding site. Furthermore, nuclear magnetic resonance experiments suggested that NS5A with DEYN mutations adopts a more extended, functional conformation in the putative CyPA substrate site in domain II. Finally, the importance of this major CsA-sensitivity determinant was confirmed in additional genotypes (GT) other than GT 2a. This study describes a new genetic approach to identifying viral targets of cellular cofactors and identifies a major regulator of HCV's susceptibility to CsA and its derivatives that are currently in clinical trials

Biomarqueurs de toxicité et anomalies métaboliques dans les principales intoxications graves. Symptomatologie clinique et toxique. Le prélèvement conservatoire.

Les membres du groupe de travail pluridisciplinaire « Toxicologie et biologie clinique » appartenant à la Société française de biologie clinique (SFBC), à la Société française de toxicologie analytique (SFTA), à la Société de toxicologie clinique (STC), proposent une aide méthodologique à l’intention des biologistes non spécialistes en toxicologie. Ils formulent également pour respecter les bonnes pratiques de laboratoire un certain nombre de recommandations. Trois documents de synthèse ont été élaborés. Ils concernent d’une part, les biomarqueurs de toxicité et les anomalies métaboliques dans les principales intoxications graves et, d’autre part, les symptômes cliniques essentiels correspondant à ces intoxications, enfin des recommandations sur le prélèvement conservatoire. Pour les biomarqueurs de toxicité, le tableau de synthèse concerne une cinquantaine de xénobiotiques : les principaux symptômes, les méthodes d’identification ou de dosage disponibles en urgence, les marqueurs biologiques utiles, la décision clinique correspondante, les dosages éventuels nécessaires à la prise en charge du patient, ainsi que l’antidote lorsque celui-ci existe. En ce qui concerne les techniques, le groupe propose un certain nombre de recommandations relatives au domaine clinique et médico-légal. Le groupe insiste également sur la nécessité de procéder dans certains cas à des prélèvements biologiques conservatoires dès la prise en charge du malade, prélèvements qui seront ou ne seront pas analysés en fonction du contexte et/ou de l’évolution de l’intoxication

Cyclosporin C Is the Main Antifungal Compound Produced by Acremonium Luzulae

A strain of Acremonium luzulae (Fuckel) W. Gams was selected in screening new microorganisms for biological control of fruit postharvest diseases, especially gray and blue mold diseases on apples and strawberries. This strain manifests a very strong activity against a large number of phytopathogenic fungi. In this work, the product responsible for this antifungal activity was isolated from modified Sabouraud dextrose broth cultures of A. luzulae. It was purified to homogeneity by reverse-phase column chromatography. On the basis of UV, infrared, and 1H and 13C nuclear magnetic resonance spectra, mass spectral analysis, and the amino acid composition of the acid hydrolysates, the antibiotic was determined to be cyclosporin C. Cyclosporin C showed a broad-spectrum activity against filamentous phytopathogenic fungi but no activity against bacteria or yeasts. Its antifungal activity is only fungistatic. In contrast to Tolypocladium inflatum, another cyclosporin-producing strain, A. luzulae, did not produce additional cyclosporins. This was confirmed by in vivo-directed biosynthesis

Dépistage, prise en charge et suivi des personnes potentiellement surexposées à l’arsenic inorganique du fait de leur lieu de résidence

International audienceBackground and objectives. - The French national authority for health (Haute Autorite de sante: HAS) and the French clinical toxicology society (Societe de toxicologie clinique: STC) received a formal request from the French ministry for heath to elaborate recommendations for the screening of environmental overexposure to inorganic arsenic (iAs), for the medical management of overexposed patients and for the medical surveillance of exposed population.Methods. - The method used for the elaboration was the Clinical practice guidelines method recommended by HAS in this situation (HAS, 2010).Results. - The recommendations are presented in the present article. They concern: a) identification of those sites with a high risk of iAs overexposure for the residents (using bioaccessible concentrations in soils); the target population for Asi overexposure screening and screening modalities (using measurement of iAs and its metabolites in urine); b) the biomonitoring indications and modalities for overexposed individuals; c) the fraction of the population with iAs environmental exposure which should be the target for the detection and the diagnosis of complications, and the modalities of these operations; d) the treatment and prevention of iAs environmental overexposure. (C) 2020 Elsevier Masson SAS. All rights reserved.RésuméContexte et objectifsÀ la demande de la Direction générale de la santé, la Haute Autorité de santé (HAS), en partenariat avec la Société de toxicologie clinique (STC) et avec la collaboration de la Société française de médecine du travail (SFMT), la Société française de santé publique (SFSP), la Société française de toxicologie analytique (SFTA) et la Société francophone de santé-environnement (SFSE) a élaboré des recommandations pour le dépistage des surexpositions environnementales à l’arsenic inorganique (Asi) et la prise en charge des populations concernées.MéthodeLa méthode d’élaboration utilisée est celle des Recommandations pour la pratique clinique (RPC) de la HAS (HAS, 2010).RésultatsLes recommandations élaborées identifient : les sites susceptibles d’entraîner des surexpositions environnementales, à partir de la concentration d’Asi dans leur sol ; la fraction des résidents qui constitue la population cible du dépistage ; les modalités de ce dépistage qui utilise le dosage de l’Asi et de ses métabolites dans les urines. En fonction des résultats du primo-dépistage, elles précisent les indications et le déroulement de la surveillance biométrologique. Elles indiquent la fraction de la population exposée qui constitue la cible de la recherche de complications de la surexposition environnementale à l’Asi. Elles précisent les modalités de cette recherche. Enfin, elles proposent des mesures pour le traitement et la prévention des contaminations par l’Asi de l’environnement