105 research outputs found
Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation
Pericentric heterochromatin plays an important role in epigenetic gene regulation. We show that pericentric heterochromatin aggregates during myogenic differentiation. This clustering leads to the formation of large chromocenters and correlates with increased levels of the methyl CpG–binding protein MeCP2 and pericentric DNA methylation. Ectopic expression of fluorescently tagged MeCP2 mimicked this effect, causing a dose-dependent clustering of chromocenters in the absence of differentiation. MeCP2-induced rearrangement of heterochromatin occurred throughout interphase, did not depend on the H3K9 histone methylation pathway, and required the methyl CpG–binding domain (MBD) only. Similar to MeCP2, another methyl CpG–binding protein, MBD2, also increased during myogenic differentiation and could induce clustering of pericentric regions, arguing for functional redundancy. This MeCP2- and MBD2-mediated chromatin reorganization may thus represent a molecular link between nuclear genome topology and the epigenetic maintenance of cellular differentiation
The Chandra Source Catalog
The Chandra Source Catalog (CSC) is a general purpose virtual X-ray
astrophysics facility that provides access to a carefully selected set of
generally useful quantities for individual X-ray sources, and is designed to
satisfy the needs of a broad-based group of scientists, including those who may
be less familiar with astronomical data analysis in the X-ray regime. The first
release of the CSC includes information about 94,676 distinct X-ray sources
detected in a subset of public ACIS imaging observations from roughly the first
eight years of the Chandra mission. This release of the catalog includes point
and compact sources with observed spatial extents <~ 30''. The catalog (1)
provides access to the best estimates of the X-ray source properties for
detected sources, with good scientific fidelity, and directly supports
scientific analysis using the individual source data; (2) facilitates analysis
of a wide range of statistical properties for classes of X-ray sources; and (3)
provides efficient access to calibrated observational data and ancillary data
products for individual X-ray sources, so that users can perform detailed
further analysis using existing tools. The catalog includes real X-ray sources
detected with flux estimates that are at least 3 times their estimated 1 sigma
uncertainties in at least one energy band, while maintaining the number of
spurious sources at a level of <~ 1 false source per field for a 100 ks
observation. For each detected source, the CSC provides commonly tabulated
quantities, including source position, extent, multi-band fluxes, hardness
ratios, and variability statistics, derived from the observations in which the
source is detected. In addition to these traditional catalog elements, for each
X-ray source the CSC includes an extensive set of file-based data products that
can be manipulated interactively.Comment: To appear in The Astrophysical Journal Supplement Series, 53 pages,
27 figure
Statistical Characterization of the Chandra Source Catalog
The first release of the Chandra Source Catalog (CSC) contains ~95,000 X-ray
sources in a total area of ~0.75% of the entire sky, using data from ~3,900
separate ACIS observations of a multitude of different types of X-ray sources.
In order to maximize the scientific benefit of such a large, heterogeneous
data-set, careful characterization of the statistical properties of the
catalog, i.e., completeness, sensitivity, false source rate, and accuracy of
source properties, is required. Characterization efforts of other, large
Chandra catalogs, such as the ChaMP Point Source Catalog (Kim et al. 2007) or
the 2 Mega-second Deep Field Surveys (Alexander et al. 2003), while
informative, cannot serve this purpose, since the CSC analysis procedures are
significantly different and the range of allowable data is much less
restrictive. We describe here the characterization process for the CSC. This
process includes both a comparison of real CSC results with those of other,
deeper Chandra catalogs of the same targets and extensive simulations of
blank-sky and point source populations.Comment: To be published in the Astrophysical Journal Supplement Series (Fig.
52 replaced with a version which astro-ph can convert to PDF without issues.
Canada-Africa Relations in Changing Core-Periphery Dynamics: A Chance to "Come Back" Differently
The Department of Foreign Affairs Canada sees the dynamism at play across the African continent as calling out for Canadian engagement. Africa in the twenty-first century is no longer the continent emerging from colonial rule; it seeks new forms of relationships with international partners. The African Development Bank, for instance, has identified five priorities for inclusive growth on the continent. The challenges are huge, as is the potential for transformative change. But the conditions for international collaboration in achieving these goals have changed; African leaders are seeking new forms of associations and teamwork. Canada has an opportunity to "come back" differently if it can look beyond its narrow mining interests and become an active partner working with public authorities in need of new and bold international partnerships. Unfortunately, Trudeau's "Canada is back" campaign does not look set to change the status quo. And, in a world where the political economic power is moving east, African countries do not have much reason to listen to Canada
In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells
The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV
CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells
While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication
Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals
Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease
Tree-ring isotopes suggest atmospheric drying limits temperature–growth responses of treeline bristlecone pine
Altitudinally separated bristlecone pine populations in the White Mountains (California, USA) exhibit differential climate-growth responses as temperature and tree-water relations change with altitude. These populations provide a natural experiment to explore the ecophysiological adaptations of this unique tree species to the twentieth century climate variability. We developed absolutely dated annual ring-width chronologies, and cellulose stable carbon and oxygen isotope chronologies from bristlecone pine growing at the treeline (~3500 m) and ~200 m below for the period AD 1710-2010. These chronologies were interpreted in terms of ecophysiological adaptations to climate variability with a dual-isotope model and a leaf gas exchange model. Ring widths show positive tree growth anomalies at treeline and consistent slower growth below treeline in relation to the twentieth century warming and associated atmospheric drying until the 1980s. Growth rates of both populations declined during and after the 1980s when growing-season temperature and atmospheric vapour pressure deficit continued to increase. Our model-based interpretations of the cellulose stable isotopes indicate that positive treeline growth anomalies prior to the 1980s were related to increased stomatal conductance and leaf-level transpiration and photosynthesis. Reduced growth since the 1980s occurred with a shift to more conservative leaf gas exchange in both the treeline and below-treeline populations, whereas leaf-level photosynthesis continued to increase in response to rising atmospheric CO2 concentrations. Our results suggest that warming-induced atmospheric drying confounds positive growth responses of apparent temperature-limited bristlecone pine populations at treeline. In addition, the observed ecophysiological responses of attitudinally separated bristlecone pine populations illustrate the sensitivity of conifers to climate change
The genomics of heart failure: design and rationale of the HERMES consortium
Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction
The genomics of heart failure: design and rationale of the HERMES consortium
Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.</p
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