61 research outputs found

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

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    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

    Specific induction of intracellular calcium oscillations by complement membrane attack on oligodendroglia

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    Original article can be found at: http://www.jneurosci.org/contents-by-date.0.shtml--Copyright The Society for Neuroscience.Peer reviewe

    Voltage-gated and agonist mediated rises in intracellular Ca in rat clonal pituitary cells (GH3) held under voltage clamp

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    ‘The definitive version is available at www.blackwell-synergy.com '. / PubMed Central Copyright The Physiological Society/ Blackwell Publishing [Full text of this article is not available in the UHRA]Peer reviewe

    ATP gated channels in vascular smooth muscle cells

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    ‘The definitive version is available at www.blackwell-synergy.com '. Copyright Blackwell Publishing. DOI: 10.1111/j.1749-6632.1990.tb37679.x [Full text of this record is not available in UHRA]Peer reviewe

    Tetrodotoxin resistant sodium channels in pain

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    Original article can be found at: http://www.sciencedirect.com/science/journal/14714892 Copyright Elsevier Ltd. DOI: 10.1016/S1471-4892(01)00015-7 [Full text of this article is not available in the UHRA]Peer reviewe

    ATP-activated channels gate calcium entry in single smooth muscle cells dissociated from rabbit ear artery

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    ‘The definitive version is available at www.blackwell-synergy.com '. / PubMed Central. Copyright Blackwell/ The Physiological Society [Full text of this article is not available in the UHRA]Peer reviewe

    Spontaneous transient outward currents in single visceral and vascular smooth muscle cells of rabbit

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    ‘The definitive version is available at www.blackwell-synergy.com '. / PubMed Central Copyright The Physiological Society / Blackwell Publishing [Full text of this article is not available in the UHRA]Peer reviewe
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