Heterogeneity of cell surface glutamate and GABA receptor expression in Shank and CNTN4 autism mouse models

Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study we used mutant/knock-out mice of Shank2 (Shank2-/-), Shank3 (Shank3αβ-/-), and Cntn4 (Cntn4-/-) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of classical several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and NR1GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2-/- and Shank3αβ-/- mice exhibit reduced levels of several cell surface glutamate receptors in most of the analyzed brain regions – especially in the striatum and thalamus – when compared to wildtype controls. Interestingly, even though Cntn4-/- mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4-/- mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions

An X-ray Spectral Survey of Radio-Loud AGN With ASCA

We present a uniform and systematic analysis of the 0.6-10 keV X-ray spectra of radio-loud active galactic nuclei (AGN) observed by ASCA. The sample 10 BLRGs, 5 QSRs, 9 NLRGs, and 10 RGs. At soft X-rays, about half of the NLRGs and all of the RGs exhibit a thermal plasma component, with a bimodal distribution of temperatures and luminosities, suggesting an origin either in a surrounding cluster or loose group or in a hot corona. At energies above 2 keV, a hard power-law component is detected in 90% of cases. The power-law photon indices and luminosities in BLRGs, QSRs, and NLRGs are similar, consistent with orientation-based unification schemes. Significant excess cold absorption is detected in most NLRGs, but also in some BLRGS and QSRs, which was somewhat unexpected. In contrast to Seyfert galaxies, only one object showss the signature of a warm absorber. The nuclear X-ray luminosity is correlated with the luminosity of the [O III] emission line, the FIR emission at 12 microns, and the lobe radio power at 5 GHz. The Fe K line is detected in 50% of BLRGs, one QSR, and a handful of NLRGs. This sample also includes 6 Weak Line Radio Galaxies (WLRGs). Their spectra WLRGs can be generally decomposed into a soft thermal component with hard absrorbed power-law component, which is significantly flatter than any other radio-loud AGNs. Their intrinsic luminosities are two orders of magnitude lower than in other sources of the sample. An interesting possibility is that WLRGs represent an extreme population of radio galaxies in which the central black hole is accreting at a rate well below the Eddington rate.Comment: To appear in the Astrophysical Journal. 72 pages, including many tables and figures. Fig 1 is separate, in TIFF format. Postscript version of fig 1 and postscript version of entire preprint can be obtained from http://www.astro.psu.edu/users/mce/preprint_index.htm

Ethics, Nanobiosensors and Elite Sport: The Need for a New Governance Framework

Individual athletes, coaches and sports teams seek continuously for ways to improve performance and accomplishment in elite competition. New techniques of performance analysis are a crucial part of the drive for athletic perfection. This paper discusses the ethical importance of one aspect of the future potential of performance analysis in sport, combining the field of biomedicine, sports engineering and nanotechnology in the form of ‘Nanobiosensors’. This innovative technology has the potential to revolutionise sport, enabling real time biological data to be collected from athletes that can be electronically distributed. Enabling precise real time performance analysis is not without ethical problems. Arguments concerning (1) data ownership and privacy; (2) data confidentiality; and (3) athlete welfare are presented alongside a discussion of the use of the Precautionary Principle in making ethical evaluations. We conclude, that although the future potential use of Nanobiosensors in sports analysis offers many potential benefits, there is also a fear that it could be abused at a sporting system level. Hence, it is essential for sporting bodies to consider the development of a robust ethically informed governance framework in advance of their proliferated use

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P&lt;5×10 - 8 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care. </p

Comparative Analysis of Expressed Sequence Tag (EST) Libraries in the Seagrass Zostera marina Subjected to Temperature Stress

Global warming is associated with increasing stress and mortality on temperate seagrass beds, in particular during periods of high sea surface temperatures during summer months, adding to existing anthropogenic impacts, such as eutrophication and habitat destruction. We compare several expressed sequence tag (EST) in the ecologically important seagrass Zostera marina (eelgrass) to elucidate the molecular genetic basis of adaptation to environmental extremes. We compared the tentative unigene (TUG) frequencies of libraries derived from leaf and meristematic tissue from a control situation with two experimentally imposed temperature stress conditions and found that TUG composition is markedly different among these conditions (all P < 0.0001). Under heat stress, we find that 63 TUGs are differentially expressed (d.e.) at 25°C compared with lower, no-stress condition temperatures (4°C and 17°C). Approximately one-third of d.e. eelgrass genes were characteristic for the stress response of the terrestrial plant model Arabidopsis thaliana. The changes in gene expression suggest complex photosynthetic adjustments among light-harvesting complexes, reaction center subunits of photosystem I and II, and components of the dark reaction. Heat shock encoding proteins and reactive oxygen scavengers also were identified, but their overall frequency was too low to perform statistical tests. In all conditions, the most abundant transcript (3–15%) was a putative metallothionein gene with unknown function. We also find evidence that heat stress may translate to enhanced infection by protists. A total of 210 TUGs contain one or more microsatellites as potential candidates for gene-linked genetic markers. Data are publicly available in a user-friendly database at http://www.uni-muenster.de/Evolution/ebb/Services/zostera

Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p <1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.Peer reviewe

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±