Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Trends in HIV counseling and testing uptake among married individuals in Rakai, Uganda.

BACKGROUND: Despite efforts to promote HIV counseling and testing (HCT) among couples, few couples know their own or their partners' HIV status. We assessed trends in HCT uptake among married individuals in Rakai district, southwestern Uganda. METHODS: We analysed data for 11,268 married individuals aged 15-49 years who were enrolled into the Rakai Community Cohort Study (RCCS) between 2003 and 2009. Married individuals were interviewed separately but were retrospectively linked to their partners at analysis. All participants had serologic samples obtained for HIV testing, and had the option of receiving HCT together (couples' HCT) or separately (individual HCT). Individuals were categorized as concordant HIV-positive if both partners had HIV; concordant HIV-negative if both did not have HIV; or HIV-discordant if only one of the partners had HIV. We used χ2 tests to assess linear trends in individual and couples' HCT uptake in the entire sample and conducted multinomial logistic regression on a sub-sample of 10,712 individuals to assess relative risk ratios (RRR) and 95% Confidence Intervals (95% CI) associated with individual and couples' HCT uptake. Analysis was done using STATA version 11.0. RESULTS: Uptake of couples' HCT was 27.2% in 2003/04, 25.1% in 2005/06, 28.5% in 2006/08 and 27.8% in 2008/09 (χ2 for trend = 2.38; P = 0.12). Uptake of individual HCT was 57.9% in 2003/04, 60.2% in 2005/06, 54.0% in 2006/08 and 54.4% in 2008/09 (χ2 for trend = 8.72; P = 0.003). The proportion of couples who had never tested increased from 14.9% in 2003/04 to 17.8% in 2008/09 (χ2 for trend = 18.16; P < 0.0001). Uptake of couples' HCT was significantly associated with prior HCT (Adjusted [Adj.] RRR = 6.80; 95% CI: 5.44, 8.51) and being 25-34 years of age (Adj. RRR = 1.81; 95% CI: 1.32, 2.50). Uptake of individual HCT was significantly associated with prior HCT (Adj. RRR = 6.26; 95% CI: 4.24, 9.24) and the female partner being HIV-positive (Adj. RRR = 2.46; 95% CI: 1.26, 4.80). CONCLUSION: Uptake of couples' HCT remained consistently low (below 30%) over the years, while uptake of individual HCT declined over time. These findings call for innovative strategies to increase demand for couples' HCT, particularly among younger couples and those with no prior HCT

Structure and Dynamics of Colliding Plasma Jets

Monoenergetic-proton radiographs of laser-generated, high-Mach-number plasma jets colliding at various angles shed light on the structures and dynamics of these collisions. The observations compare favorably with results from 2D hydrodynamic simulations of multistream plasma jets, and also with results from an analytic treatment of electron flow and magnetic field advection. In collisions of two noncollinear jets, the observed flow structure is similar to the analytic model’s prediction of a characteristic feature with a narrow structure pointing in one direction and a much thicker one pointing in the opposite direction. Spontaneous magnetic fields, largely azimuthal around the colliding jets and generated by the well-known ∇T[subscript e] × ∇n[subscript e] Biermann battery effect near the periphery of the laser spots, are demonstrated to be “frozen in” the plasma (due to high magnetic Reynolds number Re[subscript M] ~ 5 × 10[superscript 4]) and advected along the jet streamlines of the electron flow. These studies provide novel insight into the interactions and dynamics of colliding plasma jets.United States. Dept. of Energy (University of Rochester. Laboratory for Laser Energetics. National Laser User’s Facility DE-FG52-07NA28 059)United States. Dept. of Energy (University of Rochester. Laboratory for Laser Energetics. National Laser User’s Facility DE-FG03-03SF22691)Lawrence Livermore National Laboratory (B543881)Lawrence Livermore National Laboratory (LDRD-08-ER-062)University of Rochester. Laboratory for Laser Energetics (414090-G)University of Rochester. Fusion Science Center (412761-G

Time-resolved turbulent dynamo in a laser plasma

Understanding magnetic-field generation and amplification in turbulent plasma is essential to account for observations of magnetic fields in the universe. A theoretical framework attributing the origin and sustainment of these fields to the so-called fluctuation dynamo was recently validated by experiments on laser facilities in low-magnetic-Prandtl-number plasmas (Pm &lt; 1). However, the same framework proposes that the fluctuation dynamo should operate differently when Pm &amp; 1, the regime relevant to many astrophysical environments such as the intracluster medium of galaxy clusters. This paper reports an experiment that creates a laboratory Pm &amp; 1 plasma dynamo. We provide a time-resolved characterization of the plasma&apos;s evolution, measuring temperatures, densities, flow velocities, and magnetic fields, which allows us to explore various stages of the fluctuation dynamo&apos;s operation on seed magnetic fields generated by the action of the Biermann-battery mechanism during the initial drive-laser target interaction. The magnetic energy in structures with characteristic scales close to the driving scale of the stochastic motions is found to increase by almost three orders of magnitude and saturate dynamically. It is shown that the initial growth of these fields occurs at a much greater rate than the turnover rate of the driving-scale stochastic motions. Our results point to the possibility that plasma turbulence produced by strong shear can generate fields more efficiently at the driving scale than anticipated by idealized magnetohydrodynamics (MHD) simulations of the nonhelical fluctuation dynamo; this finding could help explain the large-scale fields inferred from observations of astrophysical systems

Enamel proteins reveal biological sex and genetic variability within southern African Paranthropus

The evolutionary relationships among extinct African hominin taxa are highly debated and largely unresolved, due in part to a lack of molecular data. Even within taxa, it is not always clear, based on morphology alone, whether ranges of variation are due to sexual dimorphism versus potentially undescribed taxonomic diversity. For Paranthropus robustus , a Pleistocene hominin found only in South Africa, both phylogenetic relationships to other taxa 1,2 and the nature of intraspecific variation 3–6 are still disputed. Here we report the mass spectrometric (MS) sequencing of enamel proteomes from four ca. 2 million year (Ma) old dental specimens attributed morphologically to P. robustus, from the site of Swartkrans. The identification of AMELY-specific peptides and semi-quantitative MS data analysis enabled us to determine the biological sex of all the specimens. Our combined molecular and morphometric data also provide compelling evidence of a significant degree of variation within southern African Paranthropus , as previously suggested based on morphology alone 6 . Finally, the molecular data also confirm the taxonomic placement of Paranthropus within the hominin clade. This study demonstrates the feasibility of recovering informative Early Pleistocene hominin enamel proteins from Africa. Crucially, it also shows how the analysis of these proteins can contribute to understanding whether hominin morphological variation is due to sexual dimorphism or to taxonomic differences. We anticipate that this approach can be widely applied to geologically-comparable sites within South Africa, and possibly more broadly across the continent