Generalized Structured Component Analysis in candidate gene association studies: Applications and limitations [version 2; peer review: 3 approved]

Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing. Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9. Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects. Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis

Development and Application of a Functional Human Esophageal Mucosa Explant Platform to Eosinophilic Esophagitis.

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE

Relaxation Processes in Clouds of Trapped Bosons above the Bose-Einstein Condensation Temperature

We present a unified account of damping of low-lying collective modes and of relaxation of temperature anisotropies in a trapped Bose gas in the collisionless regime. By means of variational techniques, we show that the relaxation times for the two situations are closely related to the simplest variational estimate of the viscous relaxation time. We derive rather precise theoretical expressions for the characteristic relaxation times, and compare our results with experiment.Comment: 4 pages, revte

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Funding: This work was funded by a Marie Curie Career Integration Grant and by a Max Planck Research Group Grant both awarded to SCV. The work of the Newbury lab is funded by the Medical Research Council (G1000569/1 and MR/J003719/1). XSC, AG, CF and SEF were supported by the Max Planck Society. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust (090532/Z/09/Z). JH was supported by a scholarship from the Agency for Science, Technology, and Research, Singapore. The work of SDS is supported by the grant HD027802 from NIH.Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.Publisher PDFPeer reviewe

A comparison of course-related stressors in undergraduate problem-based learning (PBL) versus non-PBL medical programmes

Background: Medical students report high levels of stress related to their medical training as well as to other personal and financial factors. The aim of this study is to investigate whether there are differences in course-related stressors reported by medical students on undergraduate problem-based learning (PBL) and non-PBL programmes in the UK. Method: A cross-sectional study of second-year medical students in two UK medical schools (one PBL and one non-PBL programme) was conducted. A 16-question self-report questionnaire, derived from the Perceived Medical Student Stress Scale and the Higher Education Stress Inventory, was used to measure course-related stressors. Following univariate analysis of each stressor between groups, multivariate logistic regression was used to determine which stressors were the best predictors of each course type, while controlling for socio-demographic differences between the groups. Results: A total of 280 students responded. Compared to the non-PBL students (N = 197), the PBL students (N = 83) were significantly more likely to agree that: they did not know what the faculty expected of them (Odds Ratio (OR) = 0.38, p = 0.03); there were too many small group sessions facilitated only by students resulting in an unclear curriculum (OR = 0.04, p < 0.0001); and that there was a lack of opportunity to explore academic subjects of interest (OR = 0.40, p = 0.02). They were significantly more likely to disagree that: there was a lack of encouragement from teachers (OR = 3.11, p = 0.02); and that the medical course fostered a sense of anonymity and feelings of isolation amongst students (OR = 3.42, p = 0.008). Conclusion: There are significant differences in the perceived course-related stressors affecting medical students on PBL and non-PBL programmes. Course designers and student support services should therefore tailor their work to minimise, or help students cope with, the specific stressors on each course type to ensure optimum learning and wellbeing among our future doctors

A Mutation in Amino Acid Permease AAP6 Reduces the Amino Acid Content of the Arabidopsis Sieve Elements but Leaves Aphid Herbivores Unaffected.

The aim of this study was to investigate the role of the amino acid permease gene AAP6 in regulating phloem amino acid composition and then to determine the effects of this altered diet on aphid performance. A genotype of Arabidopsis thaliana (L.) was produced in which the function of the amino acid permease gene AAP6 (At5g49630) was abolished. Plants homozygous for the insertionally inactivated AAP6 gene had a significantly larger mean rosette width than the wild type and a greater number of cauline leaves. Seeds from the aap6 mutant were also significantly larger than those from the wild-type plants. Sieve element (SE) sap was collected by aphid stylectomy and the amino acids derivatized, separated, and quantified using Capillary Electrophoresis with Laser Induced Fluorescence (CE-LIF). In spite of the large variation across samples, the total amino acid concentration of SE sap of the aap6 mutant plants was significantly lower than that of the wild-type plants. The concentrations of lysine, phenylalanine, leucine, and aspartic acid were all significantly lower in concentration in the aap6 mutant plants compared with wild-type plants. This is the first direct demonstration of a physiological role for an amino acid transporter in regulating SE composition in vivo. The amino acid availability in sieve element sap is thought to be the major limiting factor for aphid growth and reproduction. Despite the changes in their diet, the aphid Myzus persicae(Sulzer) displayed only small changes in feeding behaviour on mutant plants when measured using the Electronic Penetration Graph (EPG) technique. Salivation by the aphid into the SE (E1 phase) was increased on mutant plants but there was no significant effect on other feeding EPG behaviours, or in the rate of honeydew production. Consistent with the small effect on aphid feeding behaviour, there was only a small effect of reduced sieve element amino acid concentration on aphid reproduction. The data are discussed in relation to the regulation of phloem composition and the role of phloem amino acids in regulating aphid performance

The SLAC high‐density 3He target polarized by spin‐exchange optical plumbing

A new high‐density 3He target polarized by spin exchange with optically pumped rubidium vapor has recently been used at the Stanford Linear Accelerator in an experiment to measure the longitudinal spin‐dependent structure function of the neutron. The 3He target operated at a density of 2.3×1020 atoms/cm3 in a 30 cm long scattering region with polarizations between 30% and 40% measured with NMR techniques. Target cells with several day spin‐relaxation times were developed in order to achieve these polarizations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87509/2/244_1.pd

A qualitative exploration of school-based staff's experiences of delivering an alcohol screening and brief intervention in the high school setting: findings from the SIPS JR-HIGH trial.

Background: Whilst underage drinking in the UK has been declining in recent years, prevalence is still higher than in most other Western European countries. Therefore, it is important to deliver effective interventions to reduce risk of harm. Methods: Semi-structured interviews with staff delivering an alcohol screening and brief intervention in the high-school setting. The analysis was informed by normalization process theory (NPT), interviews were open coded and then a framework applied based on the four components of NPT. Results: Five major themes emerged from the analysis. The majority of participants felt that the intervention could be useful, and that learning mentors were ideally suited to deliver it. However, there was a feeling that the intervention should have been targeted at young people who drink the most. Conclusions: The intervention was generally well received in schools and seen as an effective tool for engaging young people in a discussion around alcohol. However, in the future schools need to consider the level of staffing in place to deliver the intervention. Furthermore, the intervention could focus more on the long-term risks of initiating alcohol consumption at a young age

A qualitative account of young people's experiences of alcohol screening and brief interventions in schools: SIPS Jr-HIGH trial findings.

BACKGROUND: The United Kingdom (UK) has seen a decrease in the number of young people drinking alcohol. However, the UK prevalence of underage drinking still ranks amongst the highest in Western Europe. Whilst there is a wealth of evidence reporting on the effectiveness of both primary, and secondary interventions, there are few reports of the experiences of young people who receive them. METHODS: The present study reports findings from interviews with 33 young people who were involved in an alcohol screening and brief intervention randomized controlled trial in schools in England. All interviews were analysed using inductive applied thematic analysis. RESULTS: Three major themes were identified following the analysis process: 1) drinking identities and awareness of risk; 2) access to support and advice in relation to alcohol use; and 3) appraisal of the intervention and potential impact on alcohol use. CONCLUSIONS: There appeared to be a reluctance from participants to describe themselves as someone who drinks alcohol. Furthermore, those who did drink alcohol often did so with parental permission. There was variation amongst participants as to how comfortable they felt talking about alcohol issues with school staff. Overall participants felt the intervention was useful, but would be better suited to 'heavier' drinkers