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

El uso de una tecnología interactiva de videodisco para la enseñanza en el lenguaje por señas americano y en inglés escrito

La simultaneidad de códigos y lenguajes es una de las potencialidades más sugerentes del ordenador y su uso resulta decisivo en las didácticas de segundos lenguajes o de sistemas de comunicación alternativos

Body as subject.

The notion of subject in human language has a privileged status relative to other arguments. This special status is manifested in the behavior of subjects at the morphological, syntactic, semantic and discourse levels. Here we present evidence that subjects have a privileged status at the lexical level as well, by analyzing lexicalization patterns of verbs in three different sign languages. Our analysis shows that the sub-lexical structure of iconic signs denoting states of affairs in these languages manifests an inherent pattern of form-meaning correspondence : the signer's body consistently represents one argument of the verb, the subject. The hands, moving in relation to the body, represent all other components of the event -including all other arguments. This analysis shows that sign languages provide novel evidence in support of the centrality of the notion of subject in human language. It also solves a typological puzzle about the apparent primacy of object in sign language verb agreement, a primacy not usually found in spoken languages, in which subject agreement generally ranks higher. Our analysis suggests that the subject argument is represented by the body and is part of the lexical structure of the verb. Because it is always inherently represented in the structure of the sign, the subject is more basic than the object, and tolerates the omission of agreement morphology. [1] We thank Malka Rappaport-Hovav for very helpful discussion, and Yehuda Falk and two anonymous JL referees for thoughtful comments

Les enfants sourds et l'alphabétisation /

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