An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina

In the outer retina, G protein-coupled receptor (GPCR) signaling mediates phototransduction and synaptic transmission between photoreceptors and ON bipolar cells. In contrast, the functions of modulatory GPCR signaling networks in the inner retina are less well understood. We addressed this question by determining the consequences of augmenting modulatory Gi/o signaling driven by endogenous transmitters. This was done by analyzing the effects of genetically ablating the R7 RGS-binding protein (R7BP), a membrane-targeting protein and positive allosteric modulator of R7-RGS (regulator of the G protein signaling 7) family that deactivates Gi/oα subunits. We found that R7BP is expressed highly in starburst amacrine cells and retinal ganglion cells (RGCs). As indicated by electroretinography and multielectrode array recordings of adult retina, ablation of R7BP preserved outer retina function, but altered the firing rate and latency of ON RGCs driven by rods and cones but not rods alone. In developing retina, R7BP ablation increased the burst duration of glutamatergic waves whereas cholinergic waves were unaffected. This effect on glutamatergic waves did not result in impaired segregation of RGC projections to eye-specific domains of the dorsal lateral geniculate nucleus. R7BP knockout mice exhibited normal spatial contrast sensitivity and visual acuity as assessed by optomotor reflexes. Taken together these findings indicate that R7BP-dependent regulation of R7-RGS proteins shapes specific aspects of light-evoked and spontaneous activity of RGCs in mature and developing retina

Isoform-Level Transcriptome-Wide Association Uncovers Genetic Risk Mechanisms for Neuropsychiatric Disorders in the Human Brain

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits

Second cohomology for finite groups of Lie type

Let $G$ be a simple, simply-connected algebraic group defined over $\mathbb{F}_p$. Given a power $q = p^r$ of $p$, let $G(\mathbb{F}_q) \subset G$ be the subgroup of $\mathbb{F}_q$-rational points. Let $L(\lambda)$ be the simple rational $G$-module of highest weight $\lambda$. In this paper we establish sufficient criteria for the restriction map in second cohomology $H^2(G,L(\lambda)) \rightarrow H^2(G(\mathbb{F}_q),L(\lambda))$ to be an isomorphism. In particular, the restriction map is an isomorphism under very mild conditions on $p$ and $q$ provided $\lambda$ is less than or equal to a fundamental dominant weight. Even when the restriction map is not an isomorphism, we are often able to describe $H^2(G(\mathbb{F}_q),L(\lambda))$ in terms of rational cohomology for $G$. We apply our techniques to compute $H^2(G(\mathbb{F}_q),L(\lambda))$ in a wide range of cases, and obtain new examples of nonzero second cohomology for finite groups of Lie type.Comment: 29 pages, GAP code included as an ancillary file. Rewritten to include the adjoint representation in types An, B2, and Cn. Corrections made to Theorem 3.1.3 and subsequent dependent results in Sections 3-4. Additional minor corrections and improvements also implemente

First cohomology for finite groups of Lie type: simple modules with small dominant weights

Let $k$ be an algebraically closed field of characteristic $p > 0$, and let $G$ be a simple, simply connected algebraic group defined over $\mathbb{F}_p$. Given $r \geq 1$, set $q=p^r$, and let $G(\mathbb{F}_q)$ be the corresponding finite Chevalley group. In this paper we investigate the structure of the first cohomology group $H^1(G(\mathbb{F}_q),L(\lambda))$ where $L(\lambda)$ is the simple $G$-module of highest weight $\lambda$. Under certain very mild conditions on $p$ and $q$, we are able to completely describe the first cohomology group when $\lambda$ is less than or equal to a fundamental dominant weight. In particular, in the cases we consider, we show that the first cohomology group has dimension at most one. Our calculations significantly extend, and provide new proofs for, earlier results of Cline, Parshall, Scott, and Jones, who considered the special case when $\lambda$ is a minimal nonzero dominant weight.Comment: 24 pages, 5 figures, 6 tables. Typos corrected and some proofs streamlined over previous versio

Extracellular dsRNA induces a type I interferon response mediated via class A scavenger receptors in a novel Chinook salmon derived spleen cell line

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.dci.2018.08.010 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/Despite increased global interest in Chinook salmon aquaculture, little is known of their viral immune defenses. This study describes the establishment and characterization of a continuous cell line derived from Chinook salmon spleen, CHSS, and its use in innate immune studies. Optimal growth was seen at 14–18 °C when grown in Leibovitz's L-15 media with 20% fetal bovine serum. DNA analyses confirmed that CHSS was Chinook salmon and genetically different from the only other available Chinook salmon cell line, CHSE-214. Unlike CHSE-214, CHSS could bind extracellular dsRNA, resulting in the rapid and robust expression of antiviral genes. Receptor/ligand blocking assays confirmed that class A scavenger receptors (SR-A) facilitated dsRNA binding and subsequent gene expression. Although both cell lines expressed three SR-A genes: SCARA3, SCARA4, and SCARA5, only CHSS appeared to have functional cell-surface SR-As for dsRNA. Collectively, CHSS is an excellent cell model to study dsRNA-mediated innate immunity in Chinook salmon.Natural Sciences and Engineering Research Council of CanadaCanada Research Counci

Brain Cell-Type Shifts in Alzheimer’s Disease, Autism, and Schizophrenia Interrogated Using Methylomics and Genetics

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer\u27s disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer\u27s disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer\u27s disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders

Identification of the population density of a species model with nonlocal diffusion and nonlinear reaction

The identification of the population density of a logistic equation backwards in time associated with nonlocal diffusion and nonlinear reaction, motivated by biology and ecology fields, is investigated. The diffusion depends on an integral average of the population density whilst the reaction term is a global or local Lipschitz function of the population density. After discussing the ill-posedness of the problem, we apply the quasi-reversibility method to construct stable approximation problems. It is shown that the regularized solutions stemming from such method not only depend continuously on the final data, but also strongly converge to the exact solution in L²-norm. New error estimates together with stability results are obtained. Furthermore, numerical examples are provided to illustrate the theoretical results

N=2 supergravity and supercurrents

We address the problem of classifying all N=2 supercurrent multiplets in four space-time dimensions. For this purpose we consider the minimal formulation of N=2 Poincare supergravity with a tensor compensator, and derive its linearized action in terms of three N=2 off-shell multiplets: an unconstrained scalar superfield, a vector multiplet, and a tensor multiplet. Such an action was ruled out to exist in the past. Using the action constructed, one can derive other models for linearized N=2 supergravity by applying N=2 superfield duality transformations. The action depends parametrically on a constant non-vanishing real isotriplet g^{ij}=g^{ji} which originates as an expectation value of the tensor compensator. Upon reduction to N=1 superfields, we show that the model describes two dually equivalent formulations for the massless multiplet (1,3/2)+(3/2,2) depending on a choice of g^{ij}. In the case g^{11}=g^{22}=0, the action describes (i) new minimal N=1 supergravity; and (ii) the Fradkin-Vasiliev-de Wit-van Holten gravitino multiplet. In the case g^{12}=0, on the other hand, the action describes (i) old minimal N=1 supergravity; and (ii) the Ogievetsky-Sokatchev gravitino multiplet.Comment: 40 pages; v2: added references, some comments, new appendi

Spinolaminar line test as a screening tool for C1 stenosis.

Study Design Retrospective cohort. Objective To clarify the sensitivity of C3–C2 spinolaminar line test as a screening tool for the stenosis of C1 space available for the cord (SAC). Methods Spine clinic records from April 2005 to August 2011 were reviewed. The C1 SAC was measured on lateral radiographs, and the relative positions between a C1 posterior arch and the C3–C2 spinolaminar line were examined and considered positive when the C1 ring lay ventral to the line. Computed tomography (CT) scans and magnetic resonance imaging (MRI) were utilized to measure precise diameters of C1 and C2 SAC and to check the existence of spinal cord compression. Results Four hundred eighty-seven patients were included in this study. There were 246 men and 241 women, with an average age of 53 years (range: 18 to 86). The mean SAC at C1 on radiographs was 21.2 mm (range: 13.5 to 28.2). Twenty-one patients (4.3%) were positive for the spinolaminar line test; all of these patients had C1 SAC of 19.4 mm or less. Eight patients (1.6%) had C1 SAC smaller than C2 on CT examination; all of these patients had a positive spinolaminar test, with high sensitivity (100%) and specificity (97%). MRI analysis revealed that two of the eight patients with a smaller C1 SAC had spinal cord compression at the C1 level. Conclusion Although spinal cord compression at the level of atlas without instability is a rare condition, the spinolaminar line can be used as a screening of C1 stenosis.OAIID:oai:osos.snu.ac.kr:snu2016-01/102/0000004226/3ADJUST_YN:NEMP_ID:A079510DEPT_CD:801FILENAME:2016_spinolaminar line test as a screening tool for c1 stenosis.pdfDEPT_NM:의학과CONFIRM: