Genetic mechanisms of critical illness in COVID-19.

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

Stable N-functionalised 'pincer' bis carbene ligands and their ruthenium complexes; synthesis and catalytic studies

Deprotonation of 2,6-bis(arylimidazolium)pyridine dibromide with KN(SiMe3)(2) gave thermally stable 2,6-bis(arylimidazol-2-ylidene)pyridine, which was further used to prepare ruthenium 'pincer' complexes; the latter show catalytic activity in transfer hydrogenation of carbonyl compounds

Molecular N2 complexes of iron stabilised by N-heterocyclic 'pincer' dicarbene ligands

The first N2 complex stabilised by N-heterocyclic carbene ligands, Fe(C–N–C)(N2)2, has been obtained by the reduction of Fe(C–N–C)Br2 where C–N–C = 2,6-bis(aryl-imidazol-2-ylidene)pyridine, aryl = 2,6-Pri2C6H3, with Na(Hg); it serves as a convenient precursor for other iron NHC 'pincer' complexes of the type Fe(C–N–C)(N2)L where L = C2H4, PMe3 and Fe(C–N–C)(CO)2

N-heterocyclic 'pincer' dicarbene complexes of cobalt(I), cobalt(II), and cobalt(III)

The complex Co(C-N-C)Br-2 (C-N-C = 2,6-bis(aryl-imidazol-2-ylidene)pyridine, aryl = 2,6-(Pr2C6H3)-C-i), prepared by aminolysis of Co[N(SiMe3)(2)](2) with the corresponding imidazolium salt, (CH-N-CH)Br-2, was methylated to the square-planar Co(C-N-C-)(CH3) and oxidized with BrN(SiMe3)(2) to give Co(C-N-C)Br-3. The new Co(II), Co(III), and Co(I) complexes show no ethylene polymerization activity