Modeling the Seasonal Variability of the Plasma Environment in Saturn's Magnetosphere between Main Rings and Mimas

The detection of O2+ and O+ ions over Saturn's main rings by the Cassini INMS and CAPS instruments at Saturn orbit insertion (SOI) in 2004 confirmed the existence of the ring atmosphere and ionosphere. The source mechanism was suggested to be primarily photolytic decomposition of water ice producing neutral O2 and H2 (Johnson et al., 2006). Therefore, we predicted that there would be seasonal variations in the ring atmosphere and ionosphere due to the orientation of the ring plane to the sun (Tseng et al., 2010). The atoms and molecules scattered out of the ring atmosphere by ion-molecule collisions are an important source for the inner magnetosphere (Johnson et al., 2006; Martens et al. 2008; Tseng et al., 2010 and 2011). This source competes with water products from the Enceladus' plumes, which, although possibly variable, do not appear to have a seasonal variability (Smith et al., 2010). Recently, we found that the plasma density, composition and temperature in the region from 2.5 to 3.5 RS exhibited significant seasonal variation between 2004 and 2010 (Elrod et al., 2011). Here we present a one-box ion chemistry model to explain the complex and highly variable plasma environment observed by the CAPS instrument on Cassini. We combine the water products from Enceladus with the molecules scattered from a corrected ring atmosphere, in order to describe the temporal changes in ion densities, composition and temperature detected by CAPS. We found that the observed temporal variations are primarily seasonal, due to the predicted seasonal variation in the ring atmosphere, and are consistent with a compressed magnetosphere at SOI.Comment: This is submitted to P&S

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

DNA Methylation Signatures of Chronic Low-Grade Inflammation Are Associated with Complex Diseases

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P \u3c 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P \u3c 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P \u3c 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P \u3c 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P \u3c 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation

Helminth burden and ecological factors associated with alterations in wild host gastrointestinal microbiota

Infection by gastrointestinal helminths of humans, livestock and wild animals is common, but the impact of such endoparasites on wild hosts and their gut microbiota represents an important overlooked component of population dynamics. Wild host gut microbiota and endoparasites occupy the same physical niche spaces with both affecting host nutrition and health. However, associations between the two are poorly understood. Here we used the commonly parasitized European shag (Phalacrocorax aristotelis) as a model wild host. Forty live adults from the same colony were sampled. Endoscopy was employed to quantify helminth infection in situ. Microbiota from the significantly distinct proventriculus (site of infection), cloacal and faecal gastrointestinal tract microbiomes were characterised using 16S rRNA gene-targeted high-throughput sequencing. We found increasingly strong associations between helminth infection and microbiota composition progressing away from the site of infection, observing a pronounced dysbiosis in microbiota when samples were partitioned into high- and low-burden groups. We posit this dysbiosis is predominately explained by helminths inducing an anti-inflammatory environment in the proventriculus, diverting host immune responses away from themselves. This study, within live wild animals, provides a vital foundation to better understand the mechanisms that underpin the three-way relationship between helminths, microbiota and hosts

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies

Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies

Semi-field evaluation of the cumulative effects of a "lethal House Lure" on malaria mosquito mortality

Background: There is growing interest in the potential to modify houses to target mosquitoes with insecticides or repellents as they search for human hosts. One version of this 'Lethal House Lure' approach is the In2Care® EaveTube, which consists of a section of polyvinyl chloride (PVC) pipe fitted into a closed eave, with an insert comprising electrostatic netting treated with insecticide powder placed inside the tube. Preliminary evidence suggests that when combined with screening of doors and windows, there is a reduction in entry of mosquitoes and an increase in mortality. However, the rate of overnight mortality remains unclear. The current study used a field enclosure built around experimental huts to investigate the mortality of cohorts of mosquitoes over multiple nights. Methods: Anopheles gambiae sensu lato mosquitoes were collected from the field as larvae and reared through to adult. Three-to-five days old adult females were released inside an enclosure housing two modified West African style experimental huts at a field site in M'be, Côte d'Ivoire. Huts were either equipped with insecticide-treated tubes at eave height and had closed windows (treatment) or had open windows and open tubes (controls). The number of host-seeking mosquitoes entering the huts and cumulative mortality were monitored over 2 or 4 days. Results: Very few (0-0.4%) mosquitoes were able to enter huts fitted with insecticide-treated tubes and closed windows. In contrast, mosquitoes continually entered the control huts, with a cumulative mean of 50-80% over 2 to 4 days. Baseline mortality with control huts was approximately 2-4% per day, but the addition of insecticide-treated tubes increased mortality to around 25% per day. Overall cumulative mortality was estimated to be up to 87% over 4 days when huts were fitted with tubes. Conclusion: Only 20-25% of mosquitoes contacted insecticide-treated tubes or entered control huts in a given night. However, mosquitoes continue to host search over sequential nights, and this can lead to high cumulative mortality over 2 to 4 days. This mortality should contribute to community-level reduction in transmission assuming sufficient coverage of the intervention