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

Effect of Nozzle Port Angle on Transient Flow and Surface Slag Behavior During Continuous Steel-Slab Casting

Undesirable flow variations can cause severe instabilities at the interface between liquid mold flux and molten steel across the mold top-region during continuous steel casting, resulting in surface defects in the final products. A three-dimensional Large Eddy Simulation (LES) model using the volume of fluid method for the slag and molten steel phases is validated with plant measurements, and applied to gain new insights into the effects of nozzle port angle on transient flow, top slag/steel interface movement, and slag behavior during continuous slab casting under nominally steady conditions. Upward-angled ports produce a single-roll flow pattern with lower surface velocity, due to rapid momentum dissipation of the spreading jet. However, strong jet wobbling from the port leads to greater interface variations. Severe level drops allow easy entrapment of liquid flux by the solidifying steel shell at the meniscus. Sudden level rises may also be detrimental, leading to overflow of the solidified meniscus region. Downward-angled ports produce a classic double-roll pattern with less jet turbulence and a more stable interface everywhere except near the narrow faces. Finally, the flow patterns, surface velocity, and level predicted from the validated LES model are compared with steady-state standard k-epsilon model predictions.11Nsciescopu

Children of Men\u27s ambient apocalyptic visions

Alfonso Cuarón\u27s Children of Men (2006) is part of the long stream of films that respond vividly to social crisis and the hovering threat of human annihilation and that have sought to reimagine the Judeo-Christian apocalyptic myth. But I will argue that it represents a unique take on this popular genre that I call the ambient apocalyptic. The film\u27s sense of pervasive crisis is not linked to a singular apocalyptic event and it redraws the tropes of many popular post-apocalyptic films. Cuarón intricately builds into nearly every scene referential signals to specific current political realities. He does this, however, without overburdening his film with either apocalyptic literalness or undisturbed certainty. He uses a layered referential style that seeks to create a kind of visionary realis