2,049 research outputs found

    Effect of the Chandler Act Upon General Assignments and Compositions

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    Impaired nutrient signaling and body weight control in a Na⁺ neutral amino acid cotransporter (Slc6a19)-deficient mouse

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    Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter BᴼAT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na⁺ -dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking BᴼAT1 showed a reduced body weight. When adapted to a standard 20% protein diet, BᴼAT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.This work was supported by National Health and Medical Research Council Grant 525415, Australian Research Council Grant DP0877897, University of Sydney Bridging Grant RIMS2009-02579), and by an anonymous foundatio

    Antarctic Ocean and Sea Ice Response to Ozone Depletion: A Two-Time-Scale Problem

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    The response of the Southern Ocean to a repeating seasonal cycle of ozone loss is studied in two coupled climate models and is found to comprise both fast and slow processes. The fast response is similar to the interannual signature of the southern annular mode (SAM) on sea surface temperature (SST), onto which the ozone hole forcing projects in the summer. It comprises enhanced northward Ekman drift, inducing negative summertime SST anomalies around Antarctica, earlier sea ice freeze-up the following winter, and northward expansion of the sea ice edge year-round. The enhanced northward Ekman drift, however, results in upwelling of warm waters from below the mixed layer in the region of seasonal sea ice. With sustained bursts of westerly winds induced by ozone hole depletion, this warming from below eventually dominates over the cooling from anomalous Ekman drift. The resulting slow time-scale response (years to decades) leads to warming of SSTs around Antarctica and ultimately a reduction in sea ice cover year-round. This two-time-scale behavior—rapid cooling followed by slow but persistent warming—is found in the two coupled models analyzed: one with an idealized geometry and the other with a complex global climate model with realistic geometry. Processes that control the time scale of the transition from cooling to warming and their uncertainties are described. Finally the implications of these results are discussed for rationalizing previous studies of the effect of the ozone hole on SST and sea ice extent.United States. National Aeronautics and Space Administration. Modeling, Analysis, and Prediction Program (Grant)National Science Foundation (U.S.) (Frontiers in Earth System Dynamics Project

    Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

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    Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

    Wildland fire deficit and surplus in the western United States, 1984–2012

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    Wildland fire is an important disturbance agent in the western US and globally. However, the natural role of fire has been disrupted in many regions due to the influence of human activities, which have the potential to either exclude or promote fire, resulting in a ‘‘fire deficit’’ or ‘‘fire surplus’’, respectively. In this study, we developed a model of expected area burned for the western US as a function of climate from 1984 to 2012.We then quantified departures from expected area burned to identify geographic regions with fire deficit or surplus. We developed our model of area burned as a function of several climatic variables from reference areas with low human influence; the relationship between climate and fire is strong in these areas. We then quantified the degree of fire deficit or surplus for all areas of the western US as the difference between expected (as predicted with the model) and observed area burned from 1984 to 2012. Results indicate that many forested areas in the western US experienced a fire deficit from 1984 to 2012, likely due to fire exclusion by human activities. We also found that large expanses of non-forested regions experienced a fire surplus, presumably due to introduced annual grasses and the prevalence of anthropogenic ignitions. The heterogeneity in patterns of fire deficit and surplus among ecoregions emphasizes fundamentally different ecosystem sensitivities to human influences and suggests that largescale adaptation and mitigation strategies will be necessary in order to restore and maintain resilient, healthy, and naturally functioning ecosystems

    Wildland fire deficit and surplus in the western United States, 1984–2012

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    Wildland fire is an important disturbance agent in the western US and globally. However, the natural role of fire has been disrupted in many regions due to the influence of human activities, which have the potential to either exclude or promote fire, resulting in a ‘‘fire deficit’’ or ‘‘fire surplus’’, respectively. In this study, we developed a model of expected area burned for the western US as a function of climate from 1984 to 2012.We then quantified departures from expected area burned to identify geographic regions with fire deficit or surplus. We developed our model of area burned as a function of several climatic variables from reference areas with low human influence; the relationship between climate and fire is strong in these areas. We then quantified the degree of fire deficit or surplus for all areas of the western US as the difference between expected (as predicted with the model) and observed area burned from 1984 to 2012. Results indicate that many forested areas in the western US experienced a fire deficit from 1984 to 2012, likely due to fire exclusion by human activities. We also found that large expanses of non-forested regions experienced a fire surplus, presumably due to introduced annual grasses and the prevalence of anthropogenic ignitions. The heterogeneity in patterns of fire deficit and surplus among ecoregions emphasizes fundamentally different ecosystem sensitivities to human influences and suggests that largescale adaptation and mitigation strategies will be necessary in order to restore and maintain resilient, healthy, and naturally functioning ecosystems

    Aliskiren, enalapril, or aliskiren and enalapril in heart failure

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    BACKGROUND Among patients with chronic heart failure, angiotensin-converting–enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. METHODS After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure. RESULTS After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001). CONCLUSIONS In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapri

    Wildland fire deficit and surplus in the western United States, 1984-2012

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    Wildland fire is an important disturbance agent in the western US and globally. However, the natural role of fire has been disrupted in many regions due to the influence of human activities, which have the potential to either exclude or promote fire, resulting in a fire deficit or fire surplus, respectively. In this study, we developed a model of expected area burned for the western US as a function of climate from 1984 to 2012. We then quantified departures from expected area burned to identify geographic regions with fire deficit or surplus. We developed our model of area burned as a function of several climatic variables from reference areas with low human influence; the relationship between climate and fire is strong in these areas. We then quantified the degree of fire deficit or surplus for all areas of the western US as the difference between expected (as predicted with the model) and observed area burned from 1984 to 2012. Results indicate that many forested areas in the western US experienced a fire deficit from 1984 to 2012, likely due to fire exclusion by human activities. We also found that large expanses of non-forested regions experienced a fire surplus, presumably due to introduced annual grasses and the prevalence of anthropogenic ignitions. The heterogeneity in patterns of fire deficit and surplus among ecoregions emphasizes fundamentally different ecosystem sensitivities to human influences and suggests that large scale adaptation and mitigation strategies will be necessary in order to restore and maintain resilient, healthy, and naturally functioning ecosystems
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