Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Regionalism in Hellenistic and Roman Asia Minor

La notion de région a depuis fort longtemps été un concept de base de l'analyse historique du monde grec. Cependant, ce concept n'a pas toujours été clairement défini. Les contributions de ce volume n'esquivent pas la question et s'efforcent de mettre en évidence les implications de la notion selon différentes perspectives d'analyse, en prenant pour cadre de référence l'Asie Mineure hellénistique et romaine. Qu'elles examinent la culture, le monnayage ou les institutions politiques, les contributions de ce volume s'attachent à explorer les différentes facettes des identités régionales. De même, elles prennent en considération les moyens par lesquels ces identités pouvaient rester tendanciellement stables ou au contraire évoluer au fil du temps, et définissent leur type d'interaction avec les puissances hégémoniques. Parfois aussi, elles n'hésitent pas à mettre en cause l'utilité de l'approche régionale. Enfin, la question de l'"ethnicité" n'est pas négligée. Ce volume intéressera les spécialistes de l'Asie Mineure, aussi bien que tous ceux qui s'intéressent à la conceptualisation de la notion de région dans le monde méditerranéen.Regions and regionalism have been staples of historical analysis for the Greek world for a very long time. What is meant by a region, however, is not always obvious. The contributions in this volume seek to address the question of defining regions and working out the implications of regionalism along different dimensions of analysis for Asia Minor in the Hellenistic and Roman periods. Looking at culture, coinage, political institutions, the papers explore different markers of regional identity, consider ways in which these identities may remain stable or change over time, review the character of the interaction between regional entities and hegemonic powers, and challenge the usefulness in some cases of regional analysis. Questions of ethnicity are also addressed. This volume will be of interest to historians working in Asia Minor and also to anyone concerned with the conceptual questions around regions and regionalism in the Mediterranean world

Mechanisms and modeling of bake-hardening steels : Part I. Uniaxial tension

International audienceA physically based model for bake-hardening (BH) steels is developed suitable to predict the BH as well as the macroscopic behavior of strain-aged steels in tensile tests, such as the lower yield stress and the yield point elongation or Lüders strain. A description of the strain aging kinetics is given by considering two aging steps: Cottrell atmospheres formation and precipitation of coherent carbides. The modeling includes the effect of solute carbon content, aging time, temperature, and prestrain. Then, a numerical approach of Lüders phenomenon using finite element (FE) method codes is conducted. The strain aging model is eventually coupled with the previous numerical study thanks to a local mechanical behavior that schematically describes the local dislocation behavior. Simulations of tensile tests are performed and agree well with experiments carried out on aluminum-killed (AlK) and ULC BH steels, in terms of lower yield stress and yield point elongation. Effects of aging treatment, grain size, and strain rate on the macroscopic behavior are particularly enlightened