A non-apoptotic role for caspase-9 in muscle differentiation

Caspases, a family of cysteine proteases most often investigated for their roles in apoptosis, have also been demonstrated to have functions that are vital for the efficient execution of cell differentiation. One such role that has been described is the requirement of caspase-3 for the differentiation of skeletal myoblasts into myotubes but, as yet, the mechanism leading to caspase-3 activation in this case remains elusive. Here, we demonstrate that caspase-9, an initiator caspase in the mitochondrial death pathway, is responsible for the activation of caspase-3 in differentiating C2C12 cells. Reduction of caspase-9 levels, using an shRNA construct, prevented caspase-3 activation and inhibited myoblast fusion. Myosin-heavy-chain expression, which accompanies myoblastic differentiation, was not caspase-dependent. Overexpression of Bcl-xL, a protein that inhibits caspase-9 activation, had the same effect on muscle differentiation as knockdown of caspase-9. These data suggest that the mitochondrial pathway is required for differentiation; however, the release of cytochrome c or Smac (Diablo) could not be detected, raising the possibility of a novel mechanism of caspase-9 activation during muscle differentiation.</jats:p

Three-dimensional analytical magnetohydrostatic equilibria of rigidly rotating magnetospheres in cylindrical geometry

We present three-dimensional solutions of the magnetohydrostatic equations in the co-rotating frame of reference outside a magnetized rigidly rotating cylinder. We make no symmetry assumption for the magnetic field, but to be able to make analytical progress we neglect outflows and specify a particular form for the current density. The magnetohydrostatic equations can then be reduced to a single linear partial differential equation for a pseudo-potential $U$, from which the magnetic field can be calculated by differentiation. The equation for $U$ can be solved by standard methods. The solutions can also be used to determine the plasma pressure, density and temperature as functions of all three spatial coordinates. Despite the obvious limitations of this approach, it can for example be used as a simple tool to create three-dimensional models for the closed field line regions of rotating magnetospheres without rotational symmetry.Comment: 13 pages, 2 figures, accepted for publication by Geophysical and Astrophysical Fluid Dynamic

The Two Roads to "Intrinsic Charm" in B Decays

We describe two complementary ways to show the presence of higher order effects in the 1/m_Q expansion for inclusive B decays that have been dubbed "Intrinsic Charm". Apart from the lessons they can teach us about QCD's nonperturbative dynamics their consideration is relevant for precise extractions of |V_{cb}|: for they complement the estimate of the potential impact of 1/m_Q^4 contributions. We draw semiquantitative conclusions for the expected scale of Weak Annihilation in semileptonic B decays, both for its valence and non-valence components.Comment: 17 pages, 3 figure

A sequence analysis of behaviors in immersive virtual reality for indoor earthquake and post-earthquake evacuation

Behavioral sequence analysis (BSA) gives insights to understand and model individual behaviors. The present study uses BSA for a virtual earthquake. The virtual earthquake drill was facilitated by a head-mounted display (HMD)-based immersive virtual reality (IVR) system. Eighty-three participants experienced a full earthquake and post-earthquake evacuation in a virtual hospital building. Concurrent verbal protocol analysis (VPA) and retrospective video analysis of the footage of participants’ in-IVR behaviors have been conducted to identify the behavioral sequence of participants. As a result, behavioral transition diagrams are generated, showing the progression of behaviors exhibited in the virtual earthquake drill. A variety of behavioral paths for each individual participant is presented using a visual analytics approach. The behavioral transition diagrams and behavioral paths expose the full picture of human behaviors in an earthquake emergency, which are vital to developing behavior-oriented strategies for earthquake emergencies.Publishe

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease. Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n(DM) = 178,691, n(noDM) = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.Peer reviewe

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Supersymmetric Vacua in Random Supergravity

We determine the spectrum of scalar masses in a supersymmetric vacuum of a general N=1 supergravity theory, with the Kahler potential and superpotential taken to be random functions of N complex scalar fields. We derive a random matrix model for the Hessian matrix and compute the eigenvalue spectrum. Tachyons consistent with the Breitenlohner-Freedman bound are generically present, and although these tachyons cannot destabilize the supersymmetric vacuum, they do influence the likelihood of the existence of an `uplift' to a metastable vacuum with positive cosmological constant. We show that the probability that a supersymmetric AdS vacuum has no tachyons is formally equivalent to the probability of a large fluctuation of the smallest eigenvalue of a certain real Wishart matrix. For normally-distributed matrix entries and any N, this probability is given exactly by P = exp(-2N^2|W|^2/m_{susy}^2), with W denoting the superpotential and m_{susy} the supersymmetric mass scale; for more general distributions of the entries, our result is accurate when N >> 1. We conclude that for |W| \gtrsim m_{susy}/N, tachyonic instabilities are ubiquitous in configurations obtained by uplifting supersymmetric vacua.Comment: 26 pages, 6 figure

Lorentz Violation in Warped Extra Dimensions

Higher dimensional theories which address some of the problematic issues of the Standard Model(SM) naturally involve some form of $D=4+n$-dimensional Lorentz invariance violation (LIV). In such models the fundamental physics which leads to, e.g., field localization, orbifolding, the existence of brane terms and the compactification process all can introduce LIV in the higher dimensional theory while still preserving 4-d Lorentz invariance. In this paper, attempting to capture some of this physics, we extend our previous analysis of LIV in 5-d UED-type models to those with 5-d warped extra dimensions. To be specific, we employ the 5-d analog of the SM Extension of Kostelecky et. al. ~which incorporates a complete set of operators arising from spontaneous LIV. We show that while the response of the bulk scalar, fermion and gauge fields to the addition of LIV operators in warped models is qualitatively similar to what happens in the flat 5-d UED case, the gravity sector of these models reacts very differently than in flat space. Specifically, we show that LIV in this warped case leads to a non-zero bulk mass for the 5-d graviton and so the would-be zero mode, which we identify as the usual 4-d graviton, must necessarily become massive. The origin of this mass term is the simultaneous existence of the constant non-zero $AdS_5$ curvature and the loss of general co-ordinate invariance via LIV in the 5-d theory. Thus warped 5-d models with LIV in the gravity sector are not phenomenologically viable.Comment: 14 pages, 4 figs; discussion added, algebra repaire