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

Chemokines and their receptors in ovarian cancer

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SDF1 controls pituitary cell proliferation through the activation of ERK1/2 and the Ca2+-dependent cytosolic tyrosine kinase, Pyk2.

Stromal cell-derived factor-1 (SDF-1) is a chemokine of the CXC subfamily that exerts its effects via CXCR4, a G-protein-coupled receptor. CXCR4 is often expressed. by tumor cells, and its activation causes tumor cell proliferation. Using GH4C1 cells, here we show that SDF-1 induced cell proliferation in a dose-dependent manner. Thus, we evaluated the intracellular signaling involved in this effect. SDF-1 increased cytosolic [Ca2+] and activated Pyk2, ERK1/2, and BKCa, channels. To correlate these intracellular effectors with the proliferative activity of SDF-1, we inhibited their activity using BAPTA-AM (Ca2+ chelator), PD98059 (MEK inhibitor), salicylate (Pyk2 inhibitor), and TEA (K+ channel blocker). All these compounds reverted SDF-1-induced proliferation, suggesting the involvement of multiple intracellular pathways. To identify a possible crosstalk and a molecular ordering among these pathways, we tested these antagonists on SDF-1-dependent activation of ERK1/2, Pyk2, and BKCa channels. We report that the inhibition of [Ca2+](i) increase or the blockade of BKCa channel activity did not affect ERK1/2 activation by SDF-1; Pyk2 activation was purely Ca2+ dependent, not involving ERK1/2 or BKCa channels; and BKCa channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that SDF-1-dependent increase of [Ca2+](i) activates Pyk2, which, in turn, regulates BKCa channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF-1 induces proliferation of GH4C1 cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for pituitary cell proliferation which may contribute to pituitary adenoma development

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

International audienceWe present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results