Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights

Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-Ancestry and African-Ancestry populations and identified substantial predictive power using European-derived models in a non-European target population.We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

Introduction to AMUSES: AKARI survey with a window of opportunity

With advancement of infrared space telescopes during the past decade, infrared wavelength regime has been a focal point to study various properties of galaxies with respect to evolution of galaxies. Polycyclic Aromatic Hydrocarbons (PAHs) have emerged as one of the most important features since these features dominate the mid-infrared spectra of galaxies. These PAH features provide a great handle to calibrate star formation rates and diagnose ionized states of grains. However, the PAH 3.3 μm feature has not been studied as much as other PAH features since it is weaker than others and resides outside of Spitzer capability, although it will be the only PAH feature accessible by JWST for high-z galaxies. AKARI mJy Unbiased Survey of Extragalactic Sources in 5MUSES (AMUSES) intends to take advantage of AKARI capability of spectroscopy in the 2 ~ 5   μm to provide an unbiased library of 44 sample galaxies selected from a parent sample of 5MUSES, one of Spitzer legacy projects. For these 3.6 μm flux limited sample galaxies whose redshifts range between 0 < z < 1, AMUSES will calibrate PAH 3.3 μm as a star formation rate (SFR) indicator while measuring ratios between PAH features. We present preliminary results of AMUSES

Histamine and TNF-α release by rat peritoneal mast cells stimulated with Trichomonas vaginalis

Mast cells have been reported to be predominant in the vaginal smears of patients infected with T. vaginalis. In this study, we investigated whether T. vaginalis could induce mast cells to migrate and to produce TNF-α and histamine. Rat peritoneal mast cells (RPMC), a primary mast cell, were used for the study. T. vaginalis induced an increase in chemotactic migration of the mast cells toward excretory and secretory product (ESP) of T. vaginalis, and the mast cells activated with T. vaginalis showed an increased release of histamine and TNF-α. Therefore, mast cells may be involved in the inflammatory response caused by T. vaginalis

Histamine and TNF-α release by rat peritoneal mast cells stimulated with

Mast cells have been reported to be predominant in the vaginal smears of patients infected with T. vaginalis. In this study, we investigated whether T. vaginalis could induce mast cells to migrate and to produce TNF-α and histamine. Rat peritoneal mast cells (RPMC), a primary mast cell, were used for the study. T. vaginalis induced an increase in chemotactic migration of the mast cells toward excretory and secretory product (ESP) of T. vaginalis, and the mast cells activated with T. vaginalis showed an increased release of histamine and TNF-α. Therefore, mast cells may be involved in the inflammatory response caused by T. vaginalis

Solar Assisted Cooling Systems for Building Climatization - Koordination der Project Definition Phase fuer Task 25 des IEA Solar Heating and Cooling Programme. Economic Study of Solar Assisted Cooling Systems Final report

This study indicates that several technologies for solar assisted air conditioning are market available. Different components and systems are being produced that allow to build air conditioning systems driven by (solar) thermal energy. Absorption chillers are well introduced into the market for applications where a cheap heat source is available. Adsorption chillers are available, but they are not competitive concerning costs until now. Their specific field of application is limited to cold production with very low temperature heat in the range of about 60 C to 80 C. For higher available temperatures absorption chillers show a better performance. Desiccant cooling systems employing rotating dehumidifier wheels are market available as well. These systems attained increased attention after the discussion on ozone depleting refrigerants became important. In general they are also installed if a low temperature heat source during summer is available. Solar thermal collectors which serve as thermal heat source in solar assisted air conditioning systems are market available as well. Though evacuated tube collectors for 'high' temperatures are still quite expensive, new developments promise decreasing costs for this technology in the future. Flat plate collectors which are today mainly applied for domestic hot water production showed a continuous price decrease during the last years. Solar air collectors exhibit a limited field of application mainly for heating in spring and autumn in commercial buildings until now. Often no load for their use during summer is available. Therefore cooling is a very interesting option for the application of solar air collectors during the time with highest solar radiation and the study showed that the combination with a desiccant cooling system is technically feasible. In this study the energy and economy related peformance of solar assisted air conditioning was investigated on the basis of a conventional ventilation system for a reference office building. This air conditioning system was not optimized in terms of comfort and energy performance for the given building. However, it gives a reasonable cooling load time series which allows to compare different systems to satisfy the given cooling load. (orig.)SIGLEAvailable from TIB Hannover: F99B1728 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman

Solar unterstuetzte Klimatisierung von Gebaeuden mit Niedertemperaturverfahren

Der Workshop 'Solar unterstuetzte Klimatisierung von Gebaeuden mit Niedertemperaturverfahren' wurde am 3. und 4. Juli 1995 gemeinsam vom Forschungsverbund Sonnenenergie und dem Fraunhofer-Institut fuer Solare Energiesysteme ISE in Munzingen bei Freiburg durchgefuehrt. Die Vorbereitung erfolgte in Abstimmung mit den Mitgliedseinrichtungen des Forschungsverbundes und dem BMBF/Projekttraeger BEO. Ziel des Workshops war es, den Stand der Technik der Gebaeudeklimatisierung mit Niedertemperaturverfahren darzustellen, die Moeglichkeit der Integration von thermischer Solarenergie in diese Verfahren zu beleuchten und wichtige Forschungs- und Entwicklungsziele zu identifizieren. In einzelnen sollten die folgenden Fragestellungen im Rahmen der Veranstaltung bearbeitet werden und finden sich in der Struktur des vorliegenden Bandes wieder: - Wie gross ist das Potential fuer solar unterstuetzte Klimatisierung in Deutschland und Europa?- Wie sehen die Betriebserfahrungen mit ausgefuehrten Systemen aus? - Welche Neuentwicklungen gibt es im Bereich der Komponenten, d.h. der Kaeltemaschinen, der offenen Systeme (Desiccant Cooling Technik) und der Solarkollektoren? - Fragen der Systemauslegung, Komponentendimensionierung, Planungshilfen und -tools. Alle 17 Vortraege, die im Rahmen des Workshops vorgestellt wurden, wurden analysiet und bearbeitet. (orig./HW)Potential for solar-supported air conditioning in Germany/Europe Operating experience with completed systems. New developments in the area of components, system design, component dimensioning and help in planning. All 17 lectures, which were given in the context of the workshop, were analysed and processed. (orig./HW)SIGLEAvailable from FIZ Karlsruhe / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman