Differential Expression of Apoptosis Related Genes in Selected Strains of Aedes aegypti with Different Susceptibilities to Dengue Virus

Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain

Difficulties quitting for smokers with and without a respiratory disease and use of a tailored intervention for smoking cessation – a qualitative study

Introduction: Smokers with respiratory diseases are less likely to quit than those without impaired lung function, yet few studies have investigated the effectiveness of smoking cessation interventions with this population, and none have used a computer-tailored approach. Aims: This paper aims to fill this gap in the literature by exploring smokers’ experiences when trying to quit and their perceptions of a computer-tailored intervention. Methods: Semi-structured interviews were conducted with 26 smokers recruited from six GP practices in North London. Thematic analysis was conducted to examine participants’ previous experiences of quitting and their perceptions of receiving personal tailored feedback reports to aid smoking cessation. Results: Participants discussed how their positive smoking experiences coupled with their negative cessation experiences led to conflicts with quitting smoking. Although the computer-tailored intervention was key in prompting quit attempts and participants valued its personal approach; it was not sufficient as a stand-alone intervention. Conclusion: The results highlight the difficulties that smokers experience when quitting and the need for a more personalised stop smoking service in smokers with respiratory diseases. The study also demonstrates the application and potential for computer tailored intervention as part of a wider programme of long-term smoking cessation

Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass

Background: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. Methods: We used data from a population-based cohort of 4950 Swedish women (55–85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. Results: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. Conclusions: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.Peer reviewe

Protein network analyses of pulmonary endothelial cells in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. Dysfunction of endothelial cells is involved in CTEPH. The present study describes for the first time the molecular processes underlying endothelial dysfunction in the development of the CTEPH. The advanced analytical approach and the protein network analyses of patient derived CTEPH endothelial cells allowed the quantitation of 3258 proteins. The 673 differentially regulated proteins were associated with functional and disease protein network modules. The protein network analyses resulted in the characterization of dysregulated pathways associated with endothelial dysfunction, such as mitochondrial dysfunction, oxidative phosphorylation, sirtuin signaling, inflammatory response, oxidative stress and fatty acid metabolism related pathways. In addition, the quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach

Parental transfer of the antimicrobial protein LBP/BPI protects Biomphalaria glabrata eggs against oomycete infections

Copyright: © 2013 Baron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by ANR (ANR-07-BLAN-0214 and ANR-12-EMMA-00O7-01), CNRS and INRA. PvW was financially supported by the BBSRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Determinants of anxiety in elite athletes:a systematic review and meta-analysis

OBJECTIVE: To identify and quantify determinants of anxiety symptoms and disorders experienced by elite athletes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Five online databases (PubMed, SportDiscus, PsycINFO, Scopus and Cochrane) were searched up to November 2018 to identify eligible citations. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Articles were included if they were published in English, were quantitative studies and measured a symptom-level anxiety outcome in competing or retired athletes at the professional (including professional youth), Olympic or collegiate/university levels. RESULTS AND SUMMARY: We screened 1163 articles; 61 studies were included in the systematic review and 27 of them were suitable for meta-analysis. Overall risk of bias for included studies was low. Athletes and non-athletes had no differences in anxiety profiles (d=-0.11, p=0.28). Pooled effect sizes, demonstrating moderate effects, were identified for (1) career dissatisfaction (d=0.45; higher anxiety in dissatisfied athletes), (2) gender (d=0.38; higher anxiety in female athletes), (3) age (d=-0.34; higher anxiety for younger athletes) and (4) musculoskeletal injury (d=0.31; higher anxiety for injured athletes). A small pooled effect was found for recent adverse life events (d=0.26)-higher anxiety in athletes who had experienced one or more recent adverse life events. CONCLUSION: Determinants of anxiety in elite populations broadly reflect those experienced by the general population. Clinicians should be aware of these general and athlete-specific determinants of anxiety among elite athletes