190 research outputs found

    Changes in ocean vertical heat transport with global warming

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    Heat transport between the surface and deep ocean strongly influences transient climate change. Mechanisms setting this transport are investigated using coupled climate models and by projecting ocean circulation into the temperature-depth diagram. In this diagram, a “cold cell” cools the deep ocean through the downwelling of Antarctic waters and upwelling of warmer waters and is balanced by warming due to a “warm cell,” coincident with the interhemispheric overturning and previously linked to wind and haline forcing. With anthropogenic warming, the cold cell collapses while the warm cell continues to warm the deep ocean. Simulations with increasingly strong warm cells, set by their mean Southern Hemisphere winds, exhibit increasing deep-ocean warming in response to the same anthropogenic forcing. It is argued that the partition between components of the circulation which cool and warm the deep ocean in the preindustrial climate is a key determinant of ocean vertical heat transport with global warming

    Overturning in the Subpolar North Atlantic Program: A New International Ocean Observing System

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    For decades oceanographers have understood the Atlantic meridional overturning circulation (AMOC) to be primarily driven by changes in the production of deep-water formation in the subpolar and subarctic North Atlantic. Indeed, current Intergovernmental Panel on Climate Change (IPCC) projections of an AMOC slowdown in the twenty-first century based on climate models are attributed to the inhibition of deep convection in the North Atlantic. However, observational evidence for this linkage has been elusive: there has been no clear demonstration of AMOC variability in response to changes in deep-water formation. The motivation for understanding this linkage is compelling, since the overturning circulation has been shown to sequester heat and anthropogenic carbon in the deep ocean. Furthermore, AMOC variability is expected to impact this sequestration as well as have consequences for regional and global climates through its effect on the poleward transport of warm water. Motivated by the need for a mechanistic understanding of the AMOC, an international community has assembled an observing system, Overturning in the Subpolar North Atlantic Program (OSNAP), to provide a continuous record of the transbasin fluxes of heat, mass, and freshwater, and to link that record to convective activity and water mass transformation at high latitudes. OSNAP, in conjunction with the Rapid Climate Change–Meridional Overturning Circulation and Heatflux Array (RAPID–MOCHA) at 26°N and other observational elements, will provide a comprehensive measure of the three-dimensional AMOC and an understanding of what drives its variability. The OSNAP observing system was fully deployed in the summer of 2014, and the first OSNAP data products are expected in the fall of 2017

    Generation of a genomic tiling array of the human Major Histocompatibility Complex (MHC) and its application for DNA methylation analysis

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    Background: The major histocompatibility complex (MHC) is essential for human immunity and is highly associated with common diseases, including cancer. While the genetics of the MHC has been studied intensively for many decades, very little is known about the epigenetics of this most polymorphic and disease-associated region of the genome.Methods: To facilitate comprehensive epigenetic analyses of this region, we have generated a genomic tiling array of 2 Kb resolution covering the entire 4 Mb MHC region. The array has been designed to be compatible with chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), array comparative genomic hybridization (aCGH) and expression profiling, including of non-coding RNAs. The array comprises 7832 features, consisting of two replicates of both forward and reverse strands of MHC amplicons and appropriate controls.Results: Using MeDIP, we demonstrate the application of the MHC array for DNA methylation profiling and the identification of tissue-specific differentially methylated regions (tDMRs). Based on the analysis of two tissues and two cell types, we identified 90 tDMRs within the MHC and describe their characterisation.Conclusion: A tiling array covering the MHC region was developed and validated. Its successful application for DNA methylation profiling indicates that this array represents a useful tool for molecular analyses of the MHC in the context of medical genomics

    Dysregulated Recruitment of the Histone Methyltransferase EZH2 to the Class II Transactivator (CIITA) Promoter IV in Breast Cancer Cells

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    One mechanism frequently utilized by tumor cells to escape immune system recognition and elimination is suppression of cell surface expression of Major Histocompatibility Class II (MHC II) molecules. Expression of MHC II is regulated primarily at the level of transcription by the Class II Transactivator, CIITA, and decreased CIITA expression is observed in multiple tumor types. We investigate here contributions of epigenetic modifications to transcriptional silencing of CIITA in variants of the human breast cancer cell line MDA MB 435. Significant increases in histone H3 lysine 27 trimethylation upon IFN-Îł stimulation correlate with reductions in transcription factor recruitment to the interferon-Îł inducible CIITA promoter, CIITApIV, and with significantly increased CIITApIV occupancy by the histone methyltransferase enhancer of zeste homolog 2 (EZH2). Most compelling is evidence that decreased expression of EZH2 in MDA MB 435 variants results in significant increases in CIITA and HLA-DRA mRNA expression, even in the absence of interferon-Îł stimulation, as well as increased cell surface expression of MHC II. Together, these data add mechanistic insight to prior observations of increased EZH2 expression and decreased CIITA expression in multiple tumor types

    Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment

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    Current quality of life and its determinants among opiate-dependent individuals five years after starting methadone treatment

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    This study explores the current QoL of opiate-dependent individuals who started outpatient methadone treatment at least 5 years ago and assesses the influence of demographic, psychosocial, drug and health-related variables on individuals' QoL. Participants (n = 159) were interviewed about their current QoL, psychological distress and severity of drug-related problems, using the Lancashire Quality of Life Profile, the Brief Symptom Inventory and the Addiction Severity Index. Potential determinants of QoL were assessed in a multiple linear regression analysis. Five years after the start of methadone treatment, opiate-dependent individuals report low QoL scores on various domains. No association was found between drug-related variables and QoL, but a significant negative impact of psychological distress was identified. Severity of psychological distress, taking medication for psychological problems and the inability to change one's living situation were associated with lower QoL. Having at least one good friend and a structured daily activity had a significant, positive impact on QoL. Opiate-dependent individuals' QoL is mainly determined by their psychological well-being and a number of psychosocial variables. These findings highlight the importance of a holistic approach to treatment and support in methadone maintenance treatment, which goes beyond fixing the negative physical consequences of opiate dependence

    Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

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    OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)
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