Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD

BACKGROUND: The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. METHODS: The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. RESULTS: The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. CONCLUSION: Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk

Widespread association between the ericoid mycorrhizal fungus Rhizoscyphus ericae and a leafy liverwort in the maritime and sub-Antarctic

A recent study identified a fungal isolate from the Antarctic leafy liverwort Cephaloziella varians as the ericoid mycorrhizal associate Rhizoscyphus ericae. However, nothing is known about the wider Antarctic distribution of R. ericae in C. varians, and inoculation experiments confirming the ability of the fungus to form coils in the liverwort are lacking. Using direct isolation and baiting with Vaccinium macrocarpon seedlings, fungi were isolated from C. varians sampled from eight sites across a 1875-km transect through sub- and maritime Antarctica. The ability of an isolate to form coils in aseptically grown C. varians was also tested. Fungi with 98–99% sequence identity to R. ericae internal transcribed spacer (ITS) region and partial large subunit ribosomal (r)DNA sequences were frequently isolated from C. varians at all sites sampled. The EF4/Fung5 primer set did not amplify small subunit rDNA from three of five R. ericae isolates, probably accounting for the reported absence of the fungus from C. varians in a previous study. Rhizoscyphus ericae was found to colonize aseptically-grown C. varians intracellularly, forming hyphal coils. This study shows that the association between R. ericae and C. varians is apparently widespread in Antarctica, and confirms that R. ericae is at least in part responsible for the formation of the coils observed in rhizoids of field-collected C. varians

The Suitability of 3D Data: 3D Digitisation of Human Remains

The use of 3D data in the analysis of skeletal and fossil materials has conveyed numerous advantages in many fields; however, as the availability and use of 3D scanning equipment are rapidly increasing, it is important for researchers to consider whether these methods are suitable for the proposed study. The issue of suitability has been largely overlooked in previous research; for instance, casts and reconstruction methods are frequently used to increase sample sizes, without sufficient assessment of the effect, this may have on the accuracy and reliability of results. Furthermore, the reliability of geometric morphometric methods and the implications of virtual curation have not received sufficient consideration. This paper discusses the suitability of 3D research with regard to the accuracy, reliability, and accessibility of methods and materials, as well as the effects of the current learning environment. Areas where future work will progress 3D research are proposed

The Spanish conquest and the Maya collapse: how ‘religious’ is change?

The phenomenon of the Spanish Conquest of the Maya region suggests strongly that, in the process of socio-cultural transformation, ‘religion’ has no meaning as a concept with its own particular dynamic. There is no such thing as ‘religious’ change that is not also tied to other sorts of changes and indeed to continuity. One dramatic change was the adoption by whole communities, or large segments of communities, of Christian burial practice in which the body was placed in the supine position, head to the west, facing east. Christian burial is seen to represent ‘religious conversion’ but it was one of a broad sweep of changes in how power was gained and wealth appropriated, and the way in which killing was socially sanctioned through warfare. Evidence is accumulating from sites in Belize that a significant change in burial practice also took place at time of the Maya collapse in the ninth and tenth centuries. The question that remains to be answered is whether or not the new interment practices were part of a pattern which, like the burials of the Conquest period, reflected broader socio-cultural transformations

Duration of shedding of respiratory syncytial virus in a community study of Kenyan children

Background: Our understanding of the transmission dynamics of respiratory syncytial virus (RSV) infection will be better informed with improved data on the patterns of shedding in cases not limited only to hospital admissions. Methods: In a household study, children testing RSV positive by direct immunofluorescent antibody test (DFA) were enrolled. Nasal washings were scheduled right away, then every three days until day 14, every 7 days until day 28 and every 2 weeks until a maximum of 16 weeks, or until the first DFA negative RSV specimen. The relationship between host factors, illness severity and viral shedding was investigated using Cox regression methods. Results: From 151 families a total of 193 children were enrolled with a median age of 21 months (range 1-164 months), 10% infants and 46% male. The rate of recovery from infection was 0.22/person/day (95% CI 0.19-0.25) equivalent to a mean duration of shedding of 4.5 days (95%CI 4.0-5.3), with a median duration of shedding of 4 days (IQR 2-6, range 1-14). Children with a history of RSV infection had a 40% increased rate of recovery i.e. shorter duration of viral shedding (hazard ratio 1.4, 95% CI 1.01-1.86). The rate of cessation of shedding did not differ significantly between males and females, by severity of infection or by age. Conclusion: We provide evidence of a relationship between the duration of shedding and history of infection, which may have a bearing on the relative role of primary versus re-infections in RSV transmission in the community

Effects of comorbidities on quality of life in Filipino people with tuberculosis.

BACKGROUND: We investigated health-related quality of life (HrQoL) in Filipino people undergoing TB treatment, and whether HrQoL was negatively impacted by comorbidity with undernutrition, diabetes (DM) and anaemia.METHODS: Adult participants were enrolled in public facilities in Metro Manila (three sites) and Negros Occidental (two sites). Multivariate linear regression was used to model the four correlated domain scores from a WHOQOL-BREF questionnaire (physical, psychological, social, environmental). A forward-stepwise approach was used to select a final multivariable model with inclusion based on global tests of significance at P < 0.1.RESULTS: In 446 people on drug-susceptible TB treatment, DM and moderate/severe anaemia were not associated with HrQoL. After adjustment for age, sex, education, food insecurity, treatment adherence, inflammation, Category I or II TB treatment, treatment phase, current side effects and inhibited ability to work, moderate/severe undernutrition (body mass index < 17 kg/m²) was associated with lower HrQoL (P = 0.003) with reduced psychological (coefficient: -1.02, 95% CI -1.54 to -0.51), physical (-0.62, 95% CI -1.14 to -0.09) and environmental domain scores (-0.45, 95% CI -0.88 to -0.01). In 225 patients with known HIV status in Metro Manila, HIV was associated with modestly reduced HrQoL (P = 0.014).CONCLUSION: Nutritional status and food insecurity represent modifiable risk factors for poor HrQoL that may be alleviated through interventions

Synthesis of novel thieno[3,2-b]thienobis(silolothiophene) based low bandgap polymers for organic photovoltaics

Thieno[3,2-b]thienobis(silolothiophene), a new electron rich hexacyclic monomer has been synthesized and incorporated into three novel donor–acceptor low-bandgap polymers. By carefully choosing the acceptor co-monomer, the energy levels of the polymers could be modulated and high power conversion efficiencies of 5.52% were reached in OPV devices

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups

Introducing a Peoples Academy into Higher Education: A coproduction approach to sustained wellbeing

Purpose: The introduction of a People’s Academy within the School of Health and Social Care at London South Bank University has created ripples across the pond that is Higher Education. Approach: Working as a coproduction innovation hub, the People’s Academy celebrates inclusion of those with a lived experience of health and social care services into the academic community as valued members of the teaching and learning team. In it’s second year the People’s Academy has gained attention and achieved a ‘highly commended’ status from external regulating bodies. Findings: In this paper we report on aspects arising from an entrepreneurial education approach. First, is the work based learning experience students achieve within the Higher Education Institution setting, preparing them for clinical placements and client encounters. Second are ripples of activity the People’s Academy workstreams have sent throughout the academic staff via critically creative working practices as a process of entrepreneurial education. Conclusions focus on a sustainable approach to recovery and resilience (whether physical or psychological) and overall wellbeing that People’s Academy members recognise as a raised level of compassion for sustainable health and wellbeing for all. Originality: The work and enthusiasm of the People’s Academy as an authentic social engagement process rippling across the ‘University’ experience; whether for students in the classroom or when working alongside academic staff, is identifiable in all aspects of academic activities. Most importantly is a positive gain in terms of knowledge, skills and confidence for the People’s Academy members themselves and their own wellbeing enhancement