Robust Network Stability of Mosquitoes and Human Pathogens of Medical Importance

Background: The exact number of mosquito species relevant to human health is unknown, posing challenges in understanding the scope and breadth of vector–pathogen relationships, and how resilient mosquito vector–pathogen networks are to targeted eradication of vectors. Methods: We performed an extensive literature survey to determine the associations between mosquito species and their associated pathogens of human medical importance. For each vector–pathogen association, we then determined the strength of the associations (i.e., natural infection, lab infection, lab dissemination, lab transmission, known vector). A network analysis was used to identify relationships among all pathogens and vectors. Finally, we examined how elimination of either random or targeted species affected the extinction of pathogens. Results: We found that 88 of 3578 mosquito species (2.5%) are known vectors for 78 human disease-causing pathogens; however, an additional 243 species (6.8%) were identified as potential or likely vectors, bringing the total of all mosquitos implicated in human disease to 331 (9.3%). Network analysis revealed that known vectors and pathogens were compartmentalized, with the removal of six vectors being enough to break the network (i.e., cause a pathogen to have no vector). However, the presence of potential or likely vectors greatly increased redundancies in the network, requiring more than 41 vectors to be eliminated before breaking the network. Conclusion: Although \u3c 10% of mosquitoes are involved in transmitting pathogens that cause human disease, our findings point to inherent robustness in global mosquito vector–pathogen networks

Identifying priority ecosystem services in tidal wetland restoration

Classification systems can be an important tool for identifying and quantifying the importance of relationships, assessing spatial patterns in a standardized way, and forecasting alternative decision scenarios to characterize the potential benefits (e.g., ecosystem services) from ecosystem restoration that improve human health and well-being. We present a top-down approach that systematically leverages ecosystem services classification systems to identify potential services relevant for ecosystem restoration decisions. We demonstrate this approach using the U.S. Environmental Protection Agency’s National Ecosystem Service Classification System Plus (NESCS Plus) to identify those ecosystem services that are relevant to restoration of tidal wetlands. We selected tidal wetland management documents from federal agencies, state agencies, wetland conservation organizations, and land stewards across three regions of the continental United States (northern Gulf of Mexico, Mid-Atlantic, and Pacific Northwest) to examine regional and organizational differences in identified potential benefits of tidal wetland restoration activities and the potential user groups who may benefit. We used an automated document analysis to quantify the frequencies at which different wetland types were mentioned in the management documents along with their associated beneficiary groups and the ecological end products (EEPs) those beneficiaries care about, as defined by NESCS Plus. Results showed that a top combination across all three regions, all four organizations, and all four tidal wetland types was the EEP naturalness paired with the beneficiary people who care (existence). Overall, the Mid-Atlantic region and the land steward organizations mentioned ecosystem services more than the others, and EEPs were mentioned in combination with tidal wetlands as a high-level, more general category than the other more specific tidal wetland types. Certain regional and organizations differences were statistically significant. Those results may be useful in identifying ecosystem services-related goals for tidal wetland restoration. This approach for identifying and comparing ecosystem service priorities is broadly transferrable to other ecosystems or decision-making contexts

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general

Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies: Liver and Kidney Specific Expression and Promoter Activity Predict Variation

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (−250 to +50 bp) and flanking 5′ sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (π) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes

OBJECTIVES: A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes. METHODS: Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset. RESULTS: Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2. CONCLUSION: Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk

No Differential Regulation of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) Binding in a Primate Model of Parkinson Disease

Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (rs = 0.83, rs = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion

Who wants a slimmer body? The relationship between body weight status, education level and body shape dissatisfaction among young adults in Hong Kong

Background: Body shape dissatisfaction has been thought to have an indispensable impact on weight control behaviors. We investigated the prevalence of body shape dissatisfaction (BSD) and explored its association with weight status, education level and other determinants among young adults in Hong Kong. Methods. Information on anthropometry, BSD, and socio-demographics was collected from a random sample of 1205 young adults (611 men and 594 women) aged 18-27 in a community-based household survey. BSD was defined as a discrepancy between current and ideal body shape based on a figure rating scale. Cross-tabulations, homogeneity tests and logistic regression models were applied. Results: The percentages of underweight men and women were 16.5% and 34.9% respectively, and the corresponding percentages of being overweight or obese were 26.7% and 13.2% for men and women respectively. Three-quarters of young adults had BSD. Among women, 30.9% of those underweight and 75.5% of those with normal weight desired a slimmer body shape. Overweight men and underweight women with lower education level were more likely to have a mismatch between weight status and BSD than those with higher education level. After controlling for other determinants, underweight women were found to have a higher likelihood to maintain their current body shapes than other women. Men were found to be less likely to have a mismatch between weight status and BSD than women. Conclusions: Overweight and obesity in men and underweight in women were prevalent among Hong Kong young adults. Inappropriate body shape desire might predispose individuals to unhealthy weight loss or gain behaviors. Careful consideration of actual weight status in body shape desire is needed in health promotion and education, especially for underweight and normal weight women and those with a low education level. © 2011 Cheung et al; licensee BioMed Central Ltd.published_or_final_versio