Predicting Raccoon, Procyon lotor, Occurrence Through the Use of Microhabitat Variables

Recent increases in Raccoon (Procyon lotor) abundance have been implicated for decreased nesting success of songbirds and transmission of rabies. Understanding the relationship between occurrence and microhabitat factors should be helpful in managing this species, though our current understanding of this relationship is inadequate. Therefore, we conducted a study in western Tennessee during 2000–2002 to determine this association. Occurrence (capture) data were assessed from results of live trapping at 176 and 112 trap sites during winter and summer, respectively, at three sites. A maximum of 26 habitat variables were measured at each trap location; all grids were combined for statistical analyses to account for varying relationships between occurrence and microhabitat factors across different landscapes. Univariate and stepwise logistic-regression analyses were used to assess associations among microhabitat variables and occurrence. Resulting models were validated through the jackknife procedure. Predictive equations were constructed from logistic-regression models to compute capture probabilities. Univariate analyses yielded numerous significant variables with those representing forest characteristics and proximity to water generally the most significant. Strong concordance was observed between winter and summer seasons for most variables though several differed (number of large hardwood snags, ground dens, and plant food species, distance to potential water and roads). Such temporal variability was expected due to seasonal differences in habitat components and biological needs of Raccoons. Variables included in derived models were similar to those scoring highest in univariate analyses; classification rates for models (winter = 72%; summer = 78%) were among the highest recorded for generalist species. By accounting for landscape attributes and replicating across sites, more accurate and useful models were developed. Such models should provide the information required to effectively manage this species

Release of Pen-reared Bobwhites: Potential Consequences to the Genetic Integrity of Resident Wild Populations

In response to low encounter rates with wild northern bobwhite (Colinus virginianus; hereafter bobwhite) during bird dog field trials at Ames Plantation in Tennessee, a large-scale release program of pen-reared bobwhites was implemented in fall 2002. To evaluate genetic effects of pen-reared releases on wild populations, we monitored survival of pen-reared and wild bobwhites from fall release of pen-reared bobwhites through the breeding season and collected feather samples from wild, pen-reared, and free-ranging juvenile bobwhites following the first breeding season after the initial release. We used genotypes from 6 polymorphic microsatellite loci to measure genetic diversity and conduct population assignment tests. Wild bobwhites experienced greater fallspring and annual survival than pen-reared bobwhites; however, pen-reared bobwhites experienced greater fall-spring and annual survival than reported in most other studies. Genetic diversity, number of alleles, and allelic richness were greatest in the wild, intermediate in the F1 generation, and lowest in the pen-reared populations. Likelihood analysis and cluster analysis indicated 20.4% and 33.6%, respectively, of juveniles captured after the first breeding season following release were ambiguous in population assignment; suggesting successful reproduction between wild and pen-reared individuals. These results suggest that large-scale releases of pen-reared bobwhite may result in negative impacts on genetic integrity of resident wild populations

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells

Cross-presentation of cellular antigens is crucial for priming CD8<sup>+</sup> T cells, and generating immunity to intracellular pathogens—particularly viruses. It is unclear which intestinal phagocytes perform this function in vivo. To address this, we examined dendritic cells (DCs) from the intestinal lymph of IFABP-tOVA 232-4 mice, which express ovalbumin in small intestinal epithelial cells (IECs). Among lymph DCs (LDCs) only CD103<sup>+</sup> CD11b<sup>−</sup> CD8α<sup>+</sup> DCs cross-present IEC-derived ovalbumin to CD8<sup>+</sup> OT-I T cells. Similarly, in the mesenteric lymph nodes (MLNs), cross-presentation of IEC–ovalbumin was limited to the CD11c<sup>+</sup> MHCII<sup>hi</sup> CD8α<sup>+</sup> migratory DCs, but absent from all other subsets, including the resident CD8α<sup>hi</sup> DCs. Crucially, delivery of purified CD8α<sup>+</sup> LDCs, but not other LDC subsets, into the MLN subcapsular lymphatic sinus induced proliferation of ovalbumin-specific, gut-tropic CD8<sup>+</sup> T cells <i>in vivo</i>. Finally, in 232-4 mice treated with R848, CD8α<sup>+</sup> LDCs were uniquely able to cross-prime interferon γ-producing CD8<sup>+</sup>T cells and drive their migration to the intestine. Our results clearly demonstrate that migrating CD8α<sup>+</sup> intestinal DCs are indispensable for cross-presentation of cellular antigens and, in conditions of inflammation, for the initial differentiation of effector CD8<sup>+</sup> T cells. They may therefore represent an important target for the development of antiviral vaccinations

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 hospitalization2–4 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

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

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