Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk

<p>Abstract</p> <p>Background</p> <p>Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease.</p> <p>Method</p> <p>The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population.</p> <p>Results</p> <p>In both samples, odds ratios (ORs) increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49). The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59).</p> <p>Conclusions</p> <p>These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk.</p

The application of robotics to a mobility aid for the elderly blind

In this paper we describe a novel application of mobile robot technology to the construction of a mobility for the frail blind. The robot mobility aid discussed in this paper physically supports the person walking behind it and provides obstacle avoidance to ensure safer travel. As in all Assistive Technology projects, a clear understanding of the user's needs is vital and we summarise the main user requirements for our device. We then describe the mechanical design, the user interface, the software and hardware architectures of our robot. We describe the results of evaluations carried out by both mobility experts and users and finally we outline our plans for further development

FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption

Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter, a model of bile acid malabsorption. Treatment of Asbt-/- mice with either a synthetic FXR agonist or FGF15 downregulates hepatic cholesterol 7alpha-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption

Indirect bounds on heavy scalar masses of the two-Higgs-doublet model in light of recent Higgs boson searches

We study an upper bound on masses of additional scalar bosons from the electroweak precision data and theoretical constraints such as perturbative unitarity and vacuum stability in the two Higgs doublet model taking account of recent Higgs boson search results. If the mass of the Standard-Model-like Higgs boson is rather heavy and is outside the allowed region by the electroweak precision data, such a discrepancy should be compensated by contributions from the additional scalar bosons. We show the upper bound on masses of the additional scalar bosons to be about 2 $(1)$ TeV for the mass of the Standard-Model-like Higgs boson to be 240 $(500)$ GeV.Comment: 11 pages, 5 eps file

Light Gauginos - a Solution to More than the EDMs?

In this talk I want to present questions that remained unclear to me in the last years. These questions concern the Electric Dipole Moments of electron and neutron and the way people exclude regions of parameter space.Comment: 7 pages, 2 eps-figues included, uses espcrc2.sty, submitted to conference proceedings for SUSY30; one error in dimensions correcte

MSSM Higgs-Boson Production at Hadron Colliders with Explicit CP Violation

Gluon fusion is the main production mechanism for Higgs bosons with masses up to several hundred GeV in $pp$ collisions at the CERN Large Hadron Collider. We investigate the effects of the CP-violating phases on the fusion process including both the sfermion-loop contributions and the one-loop induced CP-violating scalar-pseudoscalar mixing in the minimal supersymmetric standard model. With a universal trilinear parameter assumed, every physical observable involves only the sum of the phases of the universal trilinear parameter $A$ and the higgsino mass parameter $\mu$. The phase affects the lightest Higgs-boson production rate significantly through the neutral Higgs-boson mixing and, for the masses around the lightest stop-pair threshold, it also changes the production rate of the heavy Higgs bosons significantly through both the stop and sbottom loops and the neutral Higgs-boson mixing.Comment: 28 pages, 8 figures. Some references and comments added. Typos corrected. To appear in Phys. Rev.

Vagus nerve stimulation paired with upper limb rehabilitation after chronic stroke

Background and Purpose: We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods: We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results: All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post–in-clinic therapy (difference, 2.3 points; CI, −1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, −1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS (P&lt;0.05). Conclusions: VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified

CCR5 Chemokine Receptor Mediates Recruitment of MHC Class II-Positive Langerhans Cells in the Mouse Corneal Epithelium

PURPOSE. To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-α, on the recruitment of MHC class II+Langerhans cells (LCs) in the corneal epithelium. METHODS. A standard model for corneal LC recruitment, application of cautery to the central corneal surface was used, and the differential gene expression levels of a panel of chemokines and chemokine receptors were determined by RNase protection assay. Chemokine receptor-knockout mice were used to evaluate the recruitment of MHC class II+LCs to the corneal epithelium. To determine the sensitivity of selected chemokines to IL-1 and TNF-a stimulation, the chemokine gene expression pattern was analyzed after blockade of IL-1 and TNF receptors. RESULTS. CCR1, -2, and -5 were overexpressed in corneas after cauterization. Topical administration of soluble TNF receptor I and IL-1 receptor antagonist, which abrogated corneal LC recruitment, significantly suppressed the gene transcription levels of the ligands of CCR1 and/or -5, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, and MIP-1β. The recruitment of major histocompatibility complex (MHC) class II+LC was significantly suppressed in CCR5-/-mice and blockade of RANTES and MIP-1β, but not in CCRI-/-, CCR2-/-/MIP-1α-/-, or MIP-1α-/-mice. The evaluation of epithelial CD11c+LC cells by confocal microscopy revealed coexpression for CCR5 primarily among B7-(CD80-/CD86 ) subsets of these LCs but not among the mature B7+subsets of CD1 1c+LCs. CONCLUSIONS. These data suggest that CCR5 plays a critical role in mediating recruitment and mobilization of MHC class II+LCs into the corneal epithelium. Targeting CCR5 and its ligands may be a new strategy for modulating immunity

Digital behavioural signatures reveal trans-diagnostic clusters of schizophrenia and Alzheimer's disease patients

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.</p