259 research outputs found

    Extraterritorial Jurisdiction Over Acts of Terrorism Committed Abroad Omnibus Diplomatic Security and Antiterrorism Act of 1986

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    Impact of more intensive grazing on nitrogen and phosphorus in shallow aquifers of the Southern Perth Basin

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    This study reports on the nutrient content, pH and salinity of groundwater samples collected from the watertable and within the Superficial and the upper Leederville Aquifers from the Southern Perth Basin, south of Pinjarra, Western Australia. Sampling was undertaken to determine the impact of intensification of broadscale grazing on groundwater nutrients in the area

    Low-Tech Riparian and Wet Meadow Restoration Increases Vegetation Productivity and Resilience Across Semiarid Rangelands

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    Restoration of riparian and wet meadow ecosystems in semiarid rangelands of the western United States is a high priority given their ecological and hydrological importance in the region. However, traditional restoration approaches are often intensive and costly, limiting the extent over which they can be applied. Practitioners are increasingly trying new restoration techniques that are more cost‐effective, less intensive, and can more practically scale up to the scope of degradation. Unfortunately, practitioners typically lack resources to undertake outcome‐based evaluations necessary to judge the efficacy of these techniques. In this study, we use freely available, satellite remote sensing to explore changes in vegetation productivity (normalized difference vegetation index) of three distinct, low‐tech, riparian and wet meadow restoration projects. Case studies are presented that range in geographic location (Colorado, Oregon, and Nevada), restoration practice (Zeedyk structures, beaver dam analogs, and grazing management), and time since implementation. Restoration practices resulted in increased vegetation productivity of up to 25% and increased annual persistence of productive vegetation. Improvements in productivity with time since restoration suggest that elevated resilience may further enhance wildlife habitat and increase forage production. Long‐term, documented outcomes of conservation are rare; we hope our findings empower practitioners to further monitor and explore the use of low‐tech methods for restoration of ecohydrologic processes at meaningful spatial scales

    Next-Generation NAMPT Inhibitors Identified by Sequential High-Throughput Phenotypic Chemical and Functional Genomic Screens

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    Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. Tandem high-throughput screening using chemical and ultracomplex shRNA libraries, therefore, provides a rapid chemical genetics approach for seamless progression from small-molecule lead identification to target discovery and validation

    Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study

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    BACKGROUND AND HYPOTHESIS: Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. STUDY DESIGN: We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. STUDY RESULTS: Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. CONCLUSIONS: This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia

    Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

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    Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

    Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

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    Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
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