Southeast Asian diversity: first insights into the complex mtDNA structure of Laos

<p>Abstract</p> <p>Background</p> <p>Vast migrations and subsequent assimilation processes have shaped the genetic composition of Southeast Asia, an area of close contact between several major ethnic groups. To better characterize the genetic variation of this region, we analyzed the entire mtDNA control region of 214 unrelated donors from Laos according to highest forensic quality standards. To detail the phylogeny, we inspected selected SNPs from the mtDNA coding region. For <it>a posteriori </it>data quality control, quasi-median network constructions and autosomal STR typing were performed. In order to describe the mtDNA setup of Laos more thoroughly, the data were subjected to population genetic comparisons with 16 East Asian groups.</p> <p>Results</p> <p>The Laos sample exhibited ample mtDNA diversity, reflecting the huge number of ethnic groups listed. We found several new, so far undescribed mtDNA lineages in this dataset and surrounding populations. The Laos population was characteristic in terms of haplotype composition and genetic structure, however, genetic comparisons with other Southeast Asian populations revealed limited, but significant genetic differentiation. Notable differences in the maternal relationship to the major indigenous Southeast Asian ethnolinguistic groups were detected.</p> <p>Conclusions</p> <p>In this study, we portray the great mtDNA variety of Laos for the first time. Our findings will contribute to clarify the migration history of the region. They encourage setting up regional and subpopulation databases, especially for forensic applications. The Laotian sequences will be incorporated into the collaborative EMPOP mtDNA database <url>http://www.empop.org</url> upon publication and will be available as the first mtDNA reference data for this country.</p

A scoping study of interventions to increase the uptake of physical activity (PA) amongst individuals with mild-to-moderate depression (MMD)

Background - Depression is the largest contributor to disease burden globally. The evidence favouring physical activity as a treatment for mild-to-moderate depression is extensive and relatively uncontested. It is unclear, however, how to increase an uptake of physical activity amongst individuals experiencing mild-to-moderate depression. This leaves professionals with no guidance on how to help people experiencing mild-to-moderate depression to take up physical activity. The purpose of this study was to scope the evidence on interventions to increase the uptake of physical activity amongst individuals experiencing mild-to-moderate depression, and to develop a model of the mechanisms by which they are hypothesised to work. Methods - A scoping study was designed to include a review of primary studies, grey literature and six consultation exercises; two with individuals with experience of depression, two pre-project consultations with physical activity, mental health and literature review experts, one with public health experts, and one with community engagement experts. Results - Ten papers met the inclusion criteria and were included in the review. Consultation exercises provided insights into the mechanisms of an uptake of physical activity amongst individuals experiencing mild-to-moderate depression; evidence concerning those mechanisms is (a) fragmented in terms of design and purpose; (b) of varied quality; (c) rarely explicit about the mechanisms through which the interventions are thought to work. Physical, environmental and social factors that may represent mediating variables in the uptake of physical activity amongst people experiencing mild-to-moderate depression are largely absent from studies. Conclusions - An explanatory model was developed. This represents mild-to-moderate depression as interfering with (a) the motivation to take part in physical activity and (b) the volition that it is required to take part in physical activity. Therefore, both motivational and volitional elements are important in any intervention to increase physical activity in people with mild-to-moderate depression. Furthermore, mild-to-moderate depression-specific factors need to be tackled in any physical activity initiative, via psychological treatments such as Cognitive Behavioural Therapy. We argu

I Going Away. I Going Home. : Austin Clarke\u27s Leaving this Island Place

Austin Clarke’s “Leaving This Island Place” is one of scores of Caribbean autobiographical works that focus on a bright, young, lower-class islander leaving his/her small island place and setting out on “Eldorado voyages.” The narrative of that journey away from home to Europe or Canada or the United States and the later efforts to return may be said to be the Caribbean story, as suggested in the subtitle of Wilfred Cartey’s study of Caribbean literature, Whispers from the Caribbean: I Going Away, I Going Home, which argues that while in Caribbean literature there is much movement away, there is also a body of literature in which “the notion of ‘away’ and images of movement out are replaced by images of return” (xvi). Traditionally, however, the first autobiographical works, such as George Lamming’s In the Castle of My Skin, V. S. Naipaul’s A House for Mr. Biswas, Merle Hodge’s Crick Crack, Monkey, Jamaica Kincaid’s Annie John, Michelle Cliff’s No Telephone to Heaven, Edwidge Danticat’s Breath, Eyes, Memory, and Elizabeth Nunez’s Beyond the Limbo Silence, have focused on the childhood in the Caribbean and the journey away—or at least the preparation for that journey. Such is the case with Clarke’s “Leaving This Island Place.

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Genome-Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels

IL-17 Expression in the Time Course of Acute Anti-Thy1 Glomerulonephritis

Background Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti- thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. Methods Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. Results Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-β1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-β1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). Conclusions The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions

Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin—an insight from molecular dynamics simulations with classical and ab initio force fields

In the field of enzymatic catalysis, creating activity from a non catalytic scaffold is a daunting task. Introduction of a catalytically active moiety within a protein scaffold offers an attractive means for the creation of artificial metalloenzymes. With this goal in mind, introduction of a biotinylated d6-piano-stool complex within streptavidin (SAV) affords enantioselective artificial transfer-hydrogenases for the reduction of prochiral ketones. Based on an X-ray crystal structure of a highly selective hybrid catalyst, displaying significant disorder around the biotinylated catalyst [η6-(p-cymene)Ru(Biot-p-L)Cl], we report on molecular dynamics simulations to shed light on the protein–cofactor interactions and contacts. The results of these simulations with classical force field indicate that the SAV-biotin and SAV-catalyst complexes are more stable than ligand-free SAV. The point mutations introduced did not affect significantly the overall behavior of SAV and, unexpectedly, the P64G substitution did not provide additional flexibility to the protein scaffold. The metal-cofactor proved to be conformationally flexible, and the S112K or P64G mutants proved to enhance this effect in the most pronounced way. The network of intermolecular hydrogen bonds is efficient at stabilizing the position of biotin, but much less at fixing the conformation of an extended biotinylated ligand. This leads to a relative conformational freedom of the metal-cofactor, and a poorly localized catalytic metal moiety. MD calculations with ab initio potential function suggest that the hydrogen bonds alone are not sufficient factors for full stabilization of the biotin. The hydrophobic biotin-binding pocket (and generally protein scaffold) maintains the hydrogen bonds between biotin and protein

Investigating International Time Trends in the Incidence and Prevalence of Atopic Eczema 1990-2010: A Systematic Review of Epidemiological Studies

The prevalence of atopic eczema has been found to have increased greatly in some parts of the world. Building on a systematic review of global disease trends in asthma, our objective was to study trends in incidence and prevalence of atopic eczema. Disease trends are important for health service planning and for generating hypotheses regarding the aetiology of chronic disorders. We conducted a systematic search for high quality reports of cohort, repeated cross-sectional and routine healthcare database-based studies in seven electronic databases. Studies were required to report on at least two measures of the incidence and/or prevalence of atopic eczema between 1990 and 2010 and needed to use comparable methods at all assessment points. We retrieved 2,464 citations, from which we included 69 reports. Assessing global trends was complicated by the use of a range of outcome measures across studies and possible changes in diagnostic criteria over time. Notwithstanding these difficulties, there was evidence suggesting that the prevalence of atopic eczema was increasing in Africa, eastern Asia, western Europe and parts of northern Europe (i.e. the UK). No clear trends were identified in other regions. There was inadequate study coverage worldwide, particularly for repeated measures of atopic eczema incidence. Further epidemiological work is needed to investigate trends in what is now one of the most common long-term disorders globally. A range of relevant measures of incidence and prevalence, careful use of definitions and description of diagnostic criteria, improved study design, more comprehensive reporting and appropriate interpretation of these data are all essential to ensure that this important field of epidemiological enquiry progresses in a scientifically robust manner

Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP