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

Theoretical Calculations Of The Proton Affinities Of N-alkylamines Using The Oniom Method [cálculos Teóricos De Afinidades Por Próton De N-alquilaminas Usando O Método Oniom]

The ONIOM method was used to calculate the proton affinities (PA) of n-alkylamines (CnH2n+1NH2, n = 3 to 6, 8, 10, 12, 14, 16 and 18). The calculations were carried out at several levels (HF, MP2, B3LYP, QCISD(T), ...) using Pople basis sets and at the QCISD(T) level using basis sets developed by the generator coordinate method (GCM) and adapted to effective core potentials. PAs were also obtained through the GCM and high level methods, like ONIOM[QCISD(T)/6-31+G(2df,p):MP2/6-31G+G(d,p))//ONIOM[MP2/6-31+G(d,p):HF/6-31G]. The average error using the GCM, with respect to experimental data, was 3.4 kJ mol -1.292187193Svensson, M., Humbel, S., Froese, R.D.J., Matsubara, T., Sieber, S., Morokuma, K., (1996) J. Phys. Chem., 100, p. 19357Urban, M., Noga, J., Cole, S.J., Bartlett, R.J., (1985) J. Chem. Phys., 83, p. 4041Pople, J.A., Head-Gordon, M., Raghavachari, K., (1987) J. Chem. Phys., 87, p. 5968Froese, R.D.J., Morokuma, K., (1999) J. Phys. Chem. 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Descriptions Of Crystalline Structures Of Zeolites [descrições Estruturais Cristalinas De Zeólitos]

Crystalline structures of zeolites can be studied using different representations: the internal symmetry obtained by X-Ray or neutron diffraction crystallography techniques or a systematic analysis of the basic structural units which can be arranged to build the geometries of each kind of zeolite. In this work the basic concepts of three building units, SBU (Secondary Building Units), SSU (Structural SubUnits) and PBU (Periodic Building Units) are presented. The properties of the resulting crystalline structures are discussed (pores, cavities, channels), describing the influence of each one of these properties in processes of physical-chemical interest. Representative case studies of known zeolite crystalline structures are also discussed in terms of their space group classification.301178188Sherman, J.D., (1999) Proc. Natl. Acad. Sci. U.S.A, 96, p. 3471Fujikawa, T., Chiyouda, O., Tsukagoshi, M., Idei, K., Takehara, S., (1998) Catal. 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