PenQuest Volume 1, Number 2

Table of Contents for this Volume: Untitled by Julie Ambrose Night by Judith Gallo Untitled by Judy Gozdur the shamans by Charles Riddles Untitled by Jerry Connell Untitled by Laura Woods Untitled by LEMA Wicked Bird by Laura Jo Last Untitled by Rick Dentos Untitled by Jeni Moody Untitled by Bettie W. Kwibs Untitled by Joann Stagg The Protector Stood by Laura Jo Last Visions of Salome by Charles Riddles Untitled by Thomas Tutten Kennesaw Line by Don Ova-Dunaway Stone Blood by Mary Ellen C. Wofford Untitled by Roger Whitt Jr. Untitled by C. Wingate Untitled by Doug Dorey Untitled by Karen Blumberg Untitled by Beverly Oviatt Untitled by Virginia Shrader The Crapulous Credo of Charles C. by Charles Riddles the brave and the true by David Reed Untitled by Charles Gutierrez Canoe Creek by Patricia Kraft Untitled by Linda Bobinger The Man in the Iron Lung by Patricia Kraft Untitled by Roger Whitt, Jr. Childish Things by Kathleen Gay Untitled by Joseph Avanzini The Lover by Mary S. Aken Untitled by Ann Harrington And He Taketh Away by David Reed Untitled by Mary Graham Untitled by Melody A. Cummons Untitled by Karen Blumberg To The Poets by Judith Gallo Untitled by Ann Harringto

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

Structural and kinetic differences between human and Aspergillus fumigatus D-glucosamine-6-phosphate N-acetyltransferase

International audienceAspergillus fumigatus is the causative agent of aspergillosis, a frequently invasive colonisation of the lungs of immunocompromised patients. Glucosamine-6-phosphate N-acetyltransferase (GNA1) catalyses the acetylation of glucosamine-6-phosphate (GlcN-6P) to N-acetylglucosamine-6-phosphate (GlcNAc-6P), a key intermediate in the UDP-GlcNAc biosynthetic pathway. Gene disruption of gna1 in yeast and Candida albicans has provided genetic validation of the enzyme as a potential target. An understanding of potential active site differences between the human and A. fumigatus enzymes is required to enable further work aimed at identifying selective inhibitors for the fungal enzyme. Here, we describe crystal structures of both human and A. fumigatus GNA1, as well as their kinetic characterization. The structures show significant differences in the sugar binding site, with in particular several non-conservative substitutions near the phosphate binding pocket. Mutagenesis targeting these differences revealed drastic effects on steady-state kinetics, suggesting that the differences could be exploitable with small molecule inhibitors