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Publications and source records attributed to St.

4 recordsLinked to original sources

Widespread occurrence of bovine-like and new viruses in wild deer across the United States

Over the past several decades, deer populations in North America have grown considerably, resulting in frequent contact with humans and livestock, and increased potential for pathogen spillover. Despite the importance of pathogen spillover among humans, wildlife, and livestock, the diversity of viruses present in deer remains largely unknown. Using a metagenomic high-throughput sequencing approach, we characterized viral communities in the upper respiratory tracts of live mule deer (Odocoileus hemionus) and white-tailed deer (Odocoileus virginianus) captured at fourteen study sites in nine states across the United States. We identified vertebrate-infecting viruses in both deer species at all but two of the study sites, located in Illinois and Utah. Viral richness did not vary among species or study sites. However, viral community composition was different across study sites but not among deer species. Amongst the detected viral sequences, several originate from or were closely related to viruses previously described in humans (e.g., severe acute respiratory syndrome coronavirus 2) and livestock (e.g., bovine-like coronavirus). We also documented viruses recently discovered in deer, such as CHeRI orbivirus 1. Finally, we identified several new putative viruses in the Picornaviridae, Rhabdoviridae and Tobaniviridae families, including a novel Aphthovirus related to bovine rhinitis A virus in both deer species, across seven states and nine study sites. Our findings expand the understanding of viral diversity in two deer species across the United States, providing important insights for managing pathogens at the wildlife, livestock, and human interface.

microbiology↗

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗

Multi-omics profiling of Earth's biomes reveals that microbial and metabolite composition are shaped by the environment

As our understanding of the structure and diversity of the microbial world grows, interpreting its function is of critical interest for understanding and managing the many systems microbes influence. Despite advances in sequencing, lack of standardization challenges comparisons among studies that could provide insight into the structure and function of microbial communities across multiple habitats on a planetary scale. Technical variation among distinct studies without proper standardization of approaches prevents robust meta-analysis. Here, we present a multi-omics, meta-analysis of a novel, diverse set of microbial community samples collected for the Earth Microbiome Project. We include amplicon (16S, 18S, ITS) and shotgun metagenomic sequence data, and untargeted metabolomics data (liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry), centering our description on relationships and co-occurrences of microbially-related metabolites and microbial taxa across environments. Standardized protocols and analytical methods for characterizing microbial communities, including assessment of molecular diversity using untargeted metabolomics, facilitate identification of shared microbial and metabolite features, permitting us to explore diversity at extraordinary scale. In addition to a reference database for metagenomic and metabolomic data, we provide a framework for incorporating additional studies, enabling the expansion of existing knowledge in the form of a community resource that will become more valuable with time. To provide examples of applying this database, we outline important ecological questions that can be addressed, and test the hypotheses that every microbe and metabolite is everywhere, but the environment selects. Our results show that metabolite diversity exhibits turnover and nestedness related to both microbial communities and the environment. The relative abundances of microbially-related metabolites vary and co-occur with specific microbial consortia in a habitat-specific manner, and highlight the power of certain chemistry - in particular terpenoids - in distinguishing Earths environments.

ecology↗

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

genetics↗