29 research outputs found

    Genetic mechanisms of critical illness in COVID-19.

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    Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

    Belief without Credence

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    One of the deepest ideological divides in contemporary epistemology concerns the relative importance of belief versus credence. A prominent consideration in favor of credence-based epistemology is the ease with which it appears to account for rational action. In contrast, cases with risky payoff structures threaten to break the link between rational belief and rational action. This threat poses a challenge to traditional epistemology, which maintains the theoretical prominence of belief. The core problem, we suggest, is that belief may not be enough to register all aspects of a subject’s epistemic position with respect to any given proposition. We claim this problem can be solved by introducing other doxastic attitudes—genuine representations—that differ in strength from belief. The resulting alternative picture, a kind of doxastic states pluralism, retains the central features of traditional epistemology—most saliently, an emphasis on truth as a kind of objective accuracy—while adequately accounting for rational action

    Teoria do valor: bases para um método

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    55Mn Electron Spin Echo ENDOR of Mn2+ Complexes

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    Revisiting the Peroxidase Oxidation of 2,4,6-Trihalophenols: ESR Detection of Radical Intermediates

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    The peroxidase oxidation of 2,4,6-trichlorophenol (TCP) has been clearly shown to result in 2,6-dichloro-1,4-benzoquinone (DCQ). DCQ is a 2-electron oxidation product of TCP that has undergone para dechlorination. Many peroxidases show similar oxidation of the substrate, TCP, to yield the quinone, DCQ. Depending on the substrate, peroxidases are thought to carry out both 1- and 2-electron oxidations; the mechanism can be confirmed by the detection of both enzyme and substrate intermediates. This article presents ESR evidence for the transient 2,4,6-trichlorophenoxyl radical intermediate (TCP•), which exists free in solution, i.e., is not enzyme associated. These data are best explained as a 1-electron peroxidase oxidation of TCP to form TCP•, followed by enzyme-independent radical reactions leading to the 2-electron oxidized product. Also presented are data for the peroxidase oxidation of 2,4,6-trifluorophenol and 2,6-dichloro-4-fluorophenol
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