Wildlife Trade and Human Health in Lao PDR: An Assessment of the Zoonotic Disease Risk in Markets.

Although the majority of emerging infectious diseases can be linked to wildlife sources, most pathogen spillover events to people could likely be avoided if transmission was better understood and practices adjusted to mitigate risk. Wildlife trade can facilitate zoonotic disease transmission and represents a threat to human health and economies in Asia, highlighted by the 2003 SARS coronavirus outbreak, where a Chinese wildlife market facilitated pathogen transmission. Additionally, wildlife trade poses a serious threat to biodiversity. Therefore, the combined impacts of Asian wildlife trade, sometimes termed bush meat trade, on public health and biodiversity need assessing. From 2010 to 2013, observational data were collected in Lao PDR from markets selling wildlife, including information on volume, form, species and price of wildlife; market biosafety and visitor origin. The potential for traded wildlife to host zoonotic diseases that pose a serious threat to human health was then evaluated at seven markets identified as having high volumes of trade. At the seven markets, during 21 observational surveys, 1,937 alive or fresh dead mammals (approximately 1,009 kg) were observed for sale, including mammals from 12 taxonomic families previously documented to be capable of hosting 36 zoonotic pathogens. In these seven markets, the combination of high wildlife volumes, high risk taxa for zoonoses and poor biosafety increases the potential for pathogen presence and transmission. To examine the potential conservation impact of trade in markets, we assessed the status of 33,752 animals observed during 375 visits to 93 markets, under the Lao PDR Wildlife and Aquatic Law. We observed 6,452 animals listed by Lao PDR as near extinct or threatened with extinction. The combined risks of wildlife trade in Lao PDR to human health and biodiversity highlight the need for a multi-sector approach to effectively protect public health, economic interests and biodiversity

Bioaccumulation of metals in juvenile rainbow trout 1 (oncorhynchus mykiss) via dietary exposure to blue mussels

The potential for metals to bioaccumulate in aquatic species, such as fish, via trophic level transfer was investigated. An in vivo experiment was set up in a flow-through system in which juvenile rainbow trout were fed blue mussels collected from a Class A pristine site and an effluent-impacted river estuary, over a period of 28 days. Selected elements (As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Mo, Ni, Se, Sn, V, Zn) were determined in the mussels and fish tissues (muscle and skin) collected at 0, 14 and 28 days. This study reveals the occurrence of metals in mussels sampled in the Irish marine environment and highlights the bioaccumulation potential of metals in fish tissues via trophic transfer. All 14 monitored metals were determined in the mussels collected from both sites and mussels collected from the effluent-impacted site contained three times more Co, Mo, Sn and V than the mussels collected from the Class A site. Following a 28-day dietary exposure, concentrations of As and Se (fish muscle), and Pb, Se and Zn (fish skin), were significantly greater in fish feeding on contaminated mussels compared to those with a regular fish feed diet. The significance of metal detection and bioaccumulation in the mussel and fish tissues, highlights the potential for metal exposure to humans through the food chain. As fish are recommended as a healthy and nutritious food source, it is important to fully understand metal bioaccumulation in commercially important aquatic species and ensure the safety of human consumers

Millisecond Timescale Motions Connect Amino Acid Interaction Networks in Alpha Tryptophan Synthase

Tryptophan synthase is a model system for understanding allosteric regulation within enzyme complexes. Amino acid interaction networks were previously delineated in the isolated alpha subunit (αTS) in the absence of the beta subunit (βTS). The amino acid interaction networks were different between the ligand-free enzyme and the enzyme actively catalyzing turnover. Previous X-ray crystallography studies indicated only minor localized changes when ligands bind αTS, and so, structural changes alone could not explain the changes to the amino acid interaction networks. We hypothesized that the network changes could instead be related to changes in conformational dynamics. As such, we conducted nuclear magnetic resonance relaxation studies on different substrate- and products-bound complexes of αTS. Specifically, we collected 15N R2 relaxation dispersion data that reports on microsecond-to-millisecond timescale motion of backbone amide groups. These experiments indicated that there are conformational exchange events throughout αTS. Substrate and product binding change specific motional pathways throughout the enzyme, and these pathways connect the previously identified network residues. These pathways reach the αTS/βTS binding interface, suggesting that the identified dynamic networks may also be important for communication with the βTS subunit

Common mental disorders and mortality in the West of Scotland Twenty-07 Study: comparing the General Health Questionnaire and the Hospital Anxiety and Depression Scale

Background While various measures of common mental disorders (CMD) have been found to be associated with mortality, a comparison of how different measures predict mortality may improve our understanding of the association. This paper compares how the Hospital Anxiety and Depression Scale (HADS) and the 30-item General Health Questionnaire (GHQ-30) predict all cause and cause-specific mortality. Methods Data on 2547 men and women from two cohorts, aged approximately 39 and 55 years, from the West of Scotland Twenty-07 Study who were followed up for mortality over an average of 18.9 (SD 5.0) years. Scores were calculated for HADS depression (HADS-D), HADS Anxiety (HADS-A) and GHQ-30. Cox Proportional Hazards Models were used to determine how each CMD measure predicted mortality. Results After adjusting for serious physical illness, smoking, social class, alcohol, obesity, pulse rate and living alone, HRs (95% CI) per SD increase in score for all-cause mortality were: 1.15 (1.07 to 1.25) for HADSD; 1.13 (1.04 to 1.23) for GHQ-30 and 1.05 (0.96 to 1.14) for HADS-A. After the same adjustments, cardiovascular disease mortality was also related to HADS-D (HR 1.24 (1.07 to 1.43)), to GHQ-30 (HR 1.24 (1.11 to 1.40)) and to HADS-A (HR 1.15 (1.01 to 1.32)); respiratory mortality to GHQ-30 (HR 1.33 (1.13 to 1.55)) and mortality from other causes, excluding injuries, to HADS-D (HR 1.28 (1.05 to 1.55)). Conclusions There were associations between CMD and both all-cause and cause-specific mortality which were broadly similar for GHQ-30 and HADS-D and were still present after adjustment for important confounders and mediators

Impact of Maternal Thyroperoxidase Status on Fetal Body and Brain Size

The obstetric consequences of abnormal thyroid function during pregnancy have been established. Less understood is the influence of maternal thyroid autoantibodies on infant outcomes. The objective of this study was to examine the influence of maternal thyroperoxidase (TPO) status on fetal/infant brain and body growth. Six-hundred thirty-one (631) euthyroid pregnant women were recruited from prenatal clinics in Tampa Bay, Florida, and the surrounding area between November 2007 and December 2010. TPO status was determined during pregnancy and fetal/infant brain and body growth variables were assessed at delivery. Regression analysis revealed maternal that TPO positivity was significantly associated with smaller head circumference, reduced brain weight, and lower brain-to-body ratio among infants born to TPO+ white, non-Hispanic mothers only, distinguishing race/ethnicity as an effect modifier in the relationship. No significant differences were noted in body growth measurements among infants born to TPO positive mothers of any racial/ethnic group. Currently, TPO antibody status is not assessed as part of the standard prenatal care laboratory work-up, but findings from this study suggest that fetal brain growth may be impaired by TPO positivity among certain populations; therefore autoantibody screening among high-risk subgroups may be useful for clinicians to determine whether prenatal thyroid treatment is warranted

Ageing causes an aortic contractile dysfunction phenotype by targeting the expression of members of the extracellular signal-regulated kinase pathway

The extracellular signal-regulated kinase (ERK) pathway is a well-known regulator of vascular smooth muscle cell proliferation, but it also serves as a regulator of caldesmon, which negatively regulates vascular contractility. This study examined whether aortic contractile function requires ERK activation and if this activation is regulated by ageing. Biomechanical experiments revealed that contractile responses to the alpha1-adrenergic agonist phenylephrine are attenuated specifically in aged mice, which is associated with downregulation of ERK phosphorylation. ERK inhibition attenuates phenylephrine-induced contractility, indicating that the contractile tone is at least partially ERK-dependent. To explore the mechanisms of this age-related downregulation of ERK phosphorylation, we transfected microRNAs, miR-34a and miR-137 we have previously shown to increase with ageing and demonstrated that in A7r5 cells, both miRs downregulate the expression of Src and paxillin, known regulators of ERK signalling, as well as ERK phosphorylation. Further studies in aortic tissues transfected with miRs show that miR-34a but not miR-137 has a negative effect on mRNA levels of Src and paxillin. Furthermore, ERK phosphorylation is decreased in aortic tissue treated with the Src inhibitor PP2. Increases in miR-34a and miR-137 with ageing downregulate the expression of Src and paxillin, leading to impaired ERK signalling and aortic contractile dysfunction.NIA AGO53274 - NIH HHSPublished versio

Contribution of Intrinsic Reactivity of the HIV-1 Envelope Glycoproteins to CD4-Independent Infection and Global Inhibitor Sensitivity

Human immunodeficiency virus (HIV-1) enters cells following sequential activation of the high-potential-energy viral envelope glycoprotein trimer by target cell CD4 and coreceptor. HIV-1 variants differ in their requirements for CD4; viruses that can infect coreceptor-expressing cells that lack CD4 have been generated in the laboratory. These CD4-independent HIV-1 variants are sensitive to neutralization by multiple antibodies that recognize different envelope glycoprotein epitopes. The mechanisms underlying CD4 independence, global sensitivity to neutralization and the association between them are still unclear. By studying HIV-1 variants that differ in requirements for CD4, we investigated the contribution of CD4 binding to virus entry. CD4 engagement exposes the coreceptor-binding site and increases the “intrinsic reactivity” of the envelope glycoproteins; intrinsic reactivity describes the propensity of the envelope glycoproteins to negotiate transitions to lower-energy states upon stimulation. Coreceptor-binding site exposure and increased intrinsic reactivity promote formation/exposure of the HR1 coiled coil on the gp41 transmembrane glycoprotein and allow virus entry upon coreceptor binding. Intrinsic reactivity also dictates the global sensitivity of HIV-1 to perturbations such as exposure to cold and the binding of antibodies and small molecules. Accordingly, CD4 independence of HIV-1 was accompanied by increased susceptibility to inactivation by these factors. We investigated the role of intrinsic reactivity in determining the sensitivity of primary HIV-1 isolates to inhibition. Relative to the more common neutralization-resistant (“Tier 2-like”) viruses, globally sensitive (“Tier 1”) viruses exhibited increased intrinsic reactivity, i.e., were inactivated more efficiently by cold exposure or by a given level of antibody binding to the envelope glycoprotein trimer. Virus sensitivity to neutralization was dictated both by the efficiency of inhibitor/antibody binding to the envelope glycoprotein trimer and by envelope glycoprotein reactivity to the inhibitor/antibody binding event. Quantitative differences in intrinsic reactivity contribute to HIV-1 strain variability in global susceptibility to neutralization and explain the long-observed relationship between increased inhibitor sensitivity and decreased entry requirements for target cell CD4

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

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

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements