SLC6A1 variant pathogenicity, molecular function and phenotype: A genetic and clinical analysis

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/)

Le lemme fondamental pond\'er\'e pour le groupe m\'etaplectique

We state a variant of Arthur's weighted fundamental lemma for the metaplectic group of Weil, which will be an essential ingredient of the stable trace formula. Over a local field of large enough residual characteristic, we give a proof using the method of descent, which is conditional upon the weighted nonstandard fundamental lemma on Lie algebras. In view of the works of Chaudouard and Laumon, this condition is expected to hold.Comment: 41 page

Formal Education of Menominee Children at the High School Level: Teachers.

Training Center for Community Programs

An Experimental University Television Course on Native Americans: 1970-71.

Training Center for Community Programs

Junior High Indian Children in Minneapolis: A Study of One Problem School.

Training Center for Community Programs

Prospectives

Tiré de: Prospectives, vol. 6, no 3 (juin 1970)Titre de l'écran-titre (visionné le 24 janv. 2013

Collaborative Science to Enhance Coastal Resilience and Adaptation

Impacts from natural and anthropogenic coastal hazards are substantial and increasing significantly with climate change. Coasts and coastal communities are increasingly at risk. In addition to short-term events, long-term changes, including rising sea levels, increasing storm intensity, and consequent severe compound flooding events are degrading coastal ecosystems and threatening coastal dwellers. Consequently, people living near the coast require environmental intelligence in the form of reliable short-term and long-term predictions in order to anticipate, prepare for, adapt to, resist, and recover from hazards. Risk-informed decision making is crucial, but for the resulting information to be actionable, it must be effectively and promptly communicated to planners, decision makers and emergency managers in readily understood terms and formats. The information, critical to forecasts of extreme weather and flooding, as well as long-term projections of future risks, must involve synergistic interplay between observations and models. In addition to serving data for assimilation into models, the observations are also essential for objective validation of models via hind casts. Linked observing and modeling programs that involve stakeholder input and integrate engineering, environmental, and community vulnerability are needed to evaluate conditions prior to and following severe storm events, to update baselines, and to plan for future changes over the long term. In contrast to most deep-sea phenomena, coastal vulnerabilities are locally and regionally specific and prioritization of the most important observational data and model predictions must rely heavily on input from local and regional communities and decision makers. Innovative technologies and nature-based solutions are already helping to reduce vulnerability from coastal hazards in some localities but more focus on local circumstances, as opposed to global solutions, is needed. Agile and spatially distributed response capabilities will assist operational organizations in predicting, preparing for and mitigating potential community-wide disasters. This white paper outlines the rationale, synthesizes recent literature and summarizes some data-driven approaches to coastal resilience

CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV

Neutralizing antibodies protect mice against Venezuelan equine encephalitis virus aerosol challenge

Venezuelan equine encephalitis virus (VEEV) remains a risk for epidemic emergence or use as an aerosolized bioweapon. To develop possible countermeasures, we isolated VEEV-specific neutralizing monoclonal antibodies (mAbs) from mice and a human immunized with attenuated VEEV strains. Functional assays and epitope mapping established that potently inhibitory anti-VEEV mAbs bind distinct antigenic sites in the A or B domains of the E2 glycoprotein and block multiple steps in the viral replication cycle including attachment, fusion, and egress. A 3.2-Å cryo-electron microscopy reconstruction of VEEV virus-like particles bound by a human Fab suggests that antibody engagement of the B domain may result in cross-linking of neighboring spikes to prevent conformational requirements for viral fusion. Prophylaxis or postexposure therapy with these mAbs protected mice against lethal aerosol challenge with VEEV. Our study defines functional and structural mechanisms of mAb protection and suggests that multiple antigenic determinants on VEEV can be targeted for vaccine or antibody-based therapeutic development