25 research outputs found

    Meta-analysis of type 2 Diabetes in African Americans Consortium

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    Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

    New insights into the genetic etiology of Alzheimer's disease and related dementias

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    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele

    Losses and transport of odd nitrogen species over the Western Atlantic Ocean during CASE/WATOX

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    Aircraft and shipboard measurements of mixing ratios for odd nitrogen species (N0y) were made over the western Atlantic Ocean during the summer of 1988. N0y in boundary layer air ranged from 4.8 ppbv near the U.S. east coast to 1.7 ppbv near a research ship 160 km from the coast. A vertical N0y gradient was observed near shore; mixing ratios decreased with altitude from 3.0 ppbv at 150 m to 1.3 ppbv at 2600 m. A smaller N0y gradient was observed near the ship, with mixing ratios also decreasing with altitude. During the observation period of this experiment, a high-pressure system over the mid-Atlantic limited advection of polluted continental air to a band just along the coast, thus preserving less polluted conditions to the east of the band. Loss rates for N0y advected from the continent, based on 3 eastward flights from the U.S. east coast, were estimated to be 2.0 ± 1.5% hour−1. Measurements near Bermuda were in marine air with average mixing ratios near the surface of 0.8 ppbv for NOy and 0.3 ppbv for total NO3 −. No significant vertical gradient was observed for NOy near Bermuda, where the high-altitude N0y mixing ratio was 0.7 ppbv. Overall, N0y mixing ratios near Bermuda were higher than would be expected on the basis of either measurements or computer modeling for remote marine air, suggesting possible influence from local anthropogenic sources

    Long-term trends in aerosol and precipitation composition over the western North Atlantic Ocean at Bermuda

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    Since the 1980s, emissions of SO2 and NOx (NO + NO2) from anthropogenic sources in the United States (US), Canada, and Europe have decreased significantly suggesting that the export of oxidized S and N compounds from surrounding continents to the atmosphere overlying the North Atlantic Ocean (NAO) has also decreased. The chemical compositions of aerosols and precipitation sampled daily on Bermuda (32.27° N, 64.87° W) from 1989 to 1997 and from 2006 to 2009 were evaluated to quantify the magnitudes, significance, and implications of associated tends in atmospheric composition. The chemical data were stratified based on FLEXPART (FLEXible PARTicle dispersion model) retroplumes into four discrete transport regimes: westerly flow from eastern North America (NEUS/SEUS); easterly trade-wind flow from northern Africa and the subtropical NAO (Africa); long, open-ocean, anticyclonic flow around the Bermuda High (Oceanic); and transitional flow from the relatively clean open ocean to the polluted eastern North America (North). Based on all data, annual average concentrations of non-sea-salt (nss) SO42&ndash; associated with aerosols and annual volume-weighted-average (VWA) concentrations in precipitation decreased significantly (by 22% and 49%, respectively) whereas annual VWA concentrations of NH4+ in precipitation increased significantly (by 70%). Corresponding trends in aerosol and precipitation NO3&ndash; and of aerosol NH4+ were insignificant. Nss SO42&ndash; in precipitation under NEUS/SEUS and Oceanic flow decreased significantly (61% each) whereas corresponding trends in particulate nss SO42&ndash; under both flow regimes were insignificant. Trends in precipitation composition were driven in part by decreasing emissions of SO2 over upwind continents and associated decreases in anthropogenic contributions to nss SO42&ndash; concentrations. Under NEUS/SEUS and Oceanic flow, the ratio of anthropogenic to biogenic contributions to nss SO42&ndash; in the column scavenged by precipitation were relatively greater than those in near surface aerosol, which implies that, for these flow regimes, precipitation is a better indicator of overall anthropogenic impacts on the lower troposphere. Particulate nss SO42&ndash; under African flow also decreased significantly (34%) whereas the corresponding decrease in nss SO42&ndash; associated with precipitation was insignificant. We infer that these trends were driven in part by reductions in the emissions and transport of oxidized S compounds from Europe. The lack of significant trends in NO3&ndash; associated with aerosols and precipitation under NEUS/SEUS flow is notable in light of the large decrease (37%) in NOx emissions in the US and Canada over the period of record. Rapid chemical processing of oxidized N in marine air contributed to this lack of correspondence. Decreasing ratios of nss SO42&ndash; to NH4+ and the significant decreasing trend in precipitation acidity (37%) indicate that the total amount of acidity in the multiphase gas–aerosol system in the western NAO troposphere decreased over the period of record. Decreasing aerosol acidities would have shifted the phase partitioning of total NH3 (NH3 + particulate NH4+ towards the gas phase thereby decreasing the atmospheric lifetime of total NH3 against wet plus dry deposition. The trend of increasing NH4+ in precipitation at Bermuda over the period of record suggests that NH3 emissions from surrounding continents also increased. Decreasing particulate nss SO42&ndash; in near-surface air under NEUS/SEUS flow over the period of record implies that the corresponding shortwave scattering and absorption by nss S and associated aerosols constituents also decreased. These changes in radiative transfer suggest a corresponding lower limit for net warming over the period in the range of 0.1–0.3 W m&ndash;2

    Inorganic nitrogen over the Western North Atlantic Ocean

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    The concentrations of the reactive nitrogen species NO2, NOx(= NO + NO2), NOy (the sum of all compounds of nitrogen and oxygen with the exception of N2O), particulate NO3 −, and volatile NO3 − were measured from ship and aircraft platforms over the western North Atlantic Ocean as part of the GCE/CASE/WATOX experiment. Air masses sampled were divided into continentally influenced and typical marine on the basis of trajectories, and radon and black carbon measurements. From the NO3 − measurements on size separated aerosol and the altitude variations of volatile NO3 − and particulate NO3 −, a significant interaction between volatile NO3 − and sea salt aerosol was indicated. The average marine concentrations measured were: 18 nmol m−3 for NO2, 29 nmol m−3 for NOx, 46 nmol m−3 for NOy, and 10 nmol m−3 for total inorganic NO3 −. The reactive nitrogen species were present at concentrations some 40 times those encountered in the remote Pacific Ocean, whereas the inorganic NO3 − was only 3 times higher

    Thymidine Analogs Are Transferred from Prelabeled Donor to Host Cells in the Central Nervous System After Transplantation: A Word of Caution

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    Thymidine analogs, including bromodeoxyuridine, chlorodeoxyuridine, iododeoxyuridine, and tritiated thymidine, label dividing cells by incorporating into DNA during S phase of cell division and are widely employed to identify cells transplanted into the central nervous system. However, the potential for transfer of thymidine analogs from grafted cells to dividing host cells has not been thoroughly tested. We here demonstrate that graft-derived thymidine analogs can become incorporated into host neural precursors and glia. Large numbers of labeled neurons and glia were found 3–12 weeks after transplantation of thymidine analog-labeled live stem cells, suggesting differentiation of grafted cells. Remarkably, however, similar results were obtained after transplantation of dead cells or labeled fibroblasts. Our findings reveal for the first time that thymidine analog labeling may not be a reliable means of identifying transplanted cells, particularly in highly proliferative environments such as the developing, neurogenic, or injured brain
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