High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.(1) completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10(-5)). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect

Corticosteroid transdermal delivery significantly improves arthritis pain and functional disability

Arthritis is characterized by pain and functional limitation affecting the patients’ quality of life. We performed a clinical study to investigate the efficacy of a betamethasone valerate medicated plaster (Betesil) in improving pain and functional disability in patients with arthritis and osteoarthritis. We enrolled 104 patients affected by osteoarthritis (n = 40) or arthritis (n = 64) in different joints. Patients received diclofenac sodium cream (2 g, four times a day) or a 2.25-mg dose of Betesil applied to the painful joint every night before bedtime for 10 days. Pain and functional disability were assessed, by the Visual Analogue Scale (VAS) and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) scores. Redness was assessed by clinical inspection, and edema by the Bfovea sign^ method. C-reactive protein (CRP) was also measured; CRP can be used to cost-effectively monitor the pharmacological treatment efficacy and is increased during the acute-phase response, returning to physiological values after tissue recovery and functional restoration. All measurements were at baseline and at 10-day follow-up. At 10-day follow-up, a greater improvement in VAS and WOMAC pain and WOMAC stiffness and functional limitation scores from baseline was observed in patients treated with Betesil compared with diclofenac (all p < 0.01). At 10-day follow-up, improvement in redness, edema, and CRP levels from baseline was also greater in patients treated with Betesil compared with diclofenac (all p < 0.01). This study demonstrates the safety and efficacy of transdermal delivery of betamethasone valerate in patients affected by arthritis and osteoarthritis

Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study

Type 1 diabetes is the product of a complex interplay between genetic susceptibility and exposure to environmental factors. Existing bacterial profiling studies focus on people who are most at risk at the time of diagnosis; there are limited data on the gut microbiota of people with long-standing Type 1 diabetes. This study compared the gut microbiota of patients with Type 1 diabetes and good glycaemic control and high levels of physical-fitness with that of matched controls without diabetes.Ten males with Type 1 diabetes and ten matched controls without diabetes were recruited; groups were matched for gender, age, BMI, peak oxygen uptake (VO2max ), and exercise habits. Stool samples were analysed using next-generation sequencing of the 16S rRNA gene to obtain bacterial profiles from each individual. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was implemented to predict the functional content of the bacterial operational taxonomic units.Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were typically the most abundant members of the community in both patients with Type 1 diabetes and controls, and were present in every sample in the cohort. Each bacterial profile was relatively individual and no significant difference was reported between the bacterial profiles or the Shannon diversity indices of Type 1 diabetes compared with controls. The functional profiles were more conserved and the Type 1 diabetes group were comparable with the control group.We show that both gut microbiota and resulting functional bacterial profiles from patients with long-standing Type 1 diabetes in good glycaemic control and high physical fitness levels are comparable with those of matched people without diabetes. This article is protected by copyright. All rights reserved

Flavor of quiver-like realizations of effective supersymmetry

We present a class of supersymmetric models which address the flavor puzzle and have an inverted hierarchy of sfermions. Their construction involves quiver-like models with link fields in generic representations. The magnitude of Standard-Model parameters is obtained naturally and a relatively heavy Higgs boson is allowed without fine tuning. Collider signatures of such models are possibly within the reach of LHC in the near future.Comment: LaTeX, 17 pages, 3 figures. V2: reference adde

Socioeconomic Gradient in Childhood Obesity and Hypertension: A Multilevel Population-Based Study in a Chinese Community

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Eating well, living well and weight management: A co-produced semi-qualitative study of barriers and facilitators experienced by adults with intellectual disabilities

Adults with intellectual disabilities in England experience health inequalities. They are more likely than their non-disabled peers to be obese and at risk of serious medical conditions such as heart disease, stroke and type 2 diabetes. This semi-qualitative study engaged adults with intellectual disabilities in a co-production process to explore their perceived barriers and facilitators to eating well, living well and weight management. Nineteen participants with intellectual disabilities took part in four focus groups and one wider group discussion. They were supported by eight of their carers or support workers. Several barriers were identified including personal income restrictions, carers’ and support workers’ unmet training needs, a lack of accessible information, inaccessible services and societal barriers such as the widespread advertising of less healthy foodstuffs. A key theme of frustration with barriers emerged from analysis of participants’ responses. Practical solutions suggested by participants included provision of clear and accessible healthy lifestyle information, reasonable adjustments to services, training, ‘buddying’ support systems or schemes and collaborative working to improve policy and practice

Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

A Brownian particle in a microscopic periodic potential

We study a model for a massive test particle in a microscopic periodic potential and interacting with a reservoir of light particles. In the regime considered, the fluctuations in the test particle's momentum resulting from collisions typically outweigh the shifts in momentum generated by the periodic force, and so the force is effectively a perturbative contribution. The mathematical starting point is an idealized reduced dynamics for the test particle given by a linear Boltzmann equation. In the limit that the mass ratio of a single reservoir particle to the test particle tends to zero, we show that there is convergence to the Ornstein-Uhlenbeck process under the standard normalizations for the test particle variables. Our analysis is primarily directed towards bounding the perturbative effect of the periodic potential on the particle's momentum.Comment: 60 pages. We reorganized the article and made a few simplifications of the conten

Two-loop RGEs with Dirac gaugino masses

The set of renormalisation group equations to two loop order for general supersymmetric theories broken by soft and supersoft operators is completed. As an example, the explicit expressions for the RGEs in a Dirac gaugino extension of the (N)MSSM are presented.Comment: 10 pages + 24 pages of RGEs in appendix; no figure

A slice of AdS_5 as the large N limit of Seiberg duality

A slice of AdS_5 is used to provide a 5D gravitational description of 4D strongly-coupled Seiberg dual gauge theories. An (electric) SU(N) gauge theory in the conformal window at large N is described by the 5D bulk, while its weakly coupled (magnetic) dual is confined to the IR brane. This framework can be used to construct an N = 1 MSSM on the IR brane, reminiscent of the original Randall-Sundrum model. In addition, we use our framework to study strongly-coupled scenarios of supersymmetry breaking mediated by gauge forces. This leads to a unified scenario that connects the extra-ordinary gauge mediation limit to the gaugino mediation limit in warped space.Comment: 47 Pages, axodraw4j.st