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

Proteomic profiling to identify potential biomarkers of alpha-particle radiation exposure in human lung epithelial cells

Of the radiation types, alpha-(α) particles are of particular interest as they are an environmental concern, predominately due to inhalation of radon and its daughter progeny. Furthermore, α-particle emitters like Americium-241, Plutonium-238 and Polonium-210 have been identified as probable isotopes to be used in radiological dispersal devices. Thus, the identification of potential biomarkers to α-particle radiation exposure would be useful for the development of field deployable bioassays which could be used for human risk assessment and public health protection. Human lung cells were exposed to α-particle radiation and assessed for modulations in protein expression using two-dimensional gel electrophoresis (2D-GE). Concurrently, cell culture supernatants were analyzed for cytokine secretion using a multiplex-27 bead array assay. Cell culture supernatants assessed for cytokine secretion expressed 8 statistically significant cytokines following α-particle exposure, among which VEGF was confirmed to be dose-responsive and not modulated in X-irradiated cells. Analysis of whole cell lysates using 2-D gel electrophoresis showed 15 upregulated and 1 downregulated protein spot, of which 4 were identified by mass spectrometry. These data suggest that α-particle exposure results in the alterations in expression-levels of specific proteins which may be potential biomarkers used further for the development of fast and reliable bioassays

Male genital mutilation:beyond the tolerable?

For liberals like Martha Nussbaum, Female Genital Mutilation (FGM) has come to mark the boundary of toleration. By impairing physical, sexual and psychological functioning, the likes of Nussbaum believe the non-western practice to fulfil, most clearly, the conditions for proscription according to the harm principle. However, those same liberals assume the western practice of male circumcision, generally, to be benign or, even, necessary. As there is seen to be no harm, there is no reason to intervene. I argue that this assumption is erroneous, highlighting evidence that suggests that, according to the criteria of sexual diminution, pain and coercion employed by liberals to criticize FGM, circumcision can be viewed as a harmful act of Male Genital Mutilation (MGM). I highlight the qualitative similarities in the harmfulness of FGM and MGM in order to establish in Nussbaum an empirical and, I argue, ethnocentric oversight in which the criteria of harm are inadequately applied to the latter. I then attempt to identify the obstacles to Nussbaum’s recognition of this harm, arguing that she is party to culturally constituted beliefs in the medical and sexual necessity of the practice and, importantly, the methodological tenet of gender oppression. Having attempted to explain obstacles to the recognition of harm, I then consider the possibility that Nussbaum’s inconsistency is grounded in toleration of religious obligation, arguing that MGM should stimulate certain liberals to reconsider their engagement with theology. My aim is to enable liberals to overcome, often justifiable, claims of ethnocentricity, in order to develop a consistent approach to harmful cultural practices