Two-stage clustering in genotype-by-environment analyses with missing data

Cluster analysis has been commonly used in genotype-by-environment (G x E) analyses, but current methods are inadequate when the data matrix is incomplete. This paper proposes a new method, referred to as two-stage clustering, which relies on a partitioning of squared Euclidean distance into two independent components, the G x E interaction and the genotype main effect. These components are used in the first and second stages of clustering respectively. Two-stage clustering forms the basis for imputing missing values in the G x E matrix so that a more complete data array is available for other GxE analyses. Imputation for a given genotype uses information from genotypes with similar interaction profiles. This imputation method is shown to improve on an existing nearest cluster method that confounds the G x E interaction and the genotype main effect

Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin protein, leading to progressive muscle weakness and premature death due to respiratory and/or cardiac complications. Cardiac involvement is characterized by progressive dilated cardiomyopathy, decreased fractional shortening and metabolic dysfunction involving reduced metabolism of fatty acids—the major cardiac metabolic substrate. Several mouse models have been developed to study molecular and pathological consequences of dystrophin deficiency, but do not recapitulate all aspects of human disease pathology and exhibit a mild cardiac phenotype. Here we demonstrate that Cmah (cytidine monophosphate-sialic acid hydroxylase)-deficient mdx mice (Cmah−/−;mdx) have an accelerated cardiac phenotype compared to the established mdx model. Cmah−/−;mdx mice display earlier functional deterioration, specifically a reduction in right ventricle (RV) ejection fraction and stroke volume (SV) at 12 weeks of age and decreased left ventricle diastolic volume with subsequent reduced SV compared to mdx mice by 24 weeks. They further show earlier elevation of cardiac damage markers for fibrosis (Ctgf), oxidative damage (Nox4) and haemodynamic load (Nppa). Cardiac metabolic substrate requirement was assessed using hyperpolarized magnetic resonance spectroscopy indicating increased in vivo glycolytic flux in Cmah−/−;mdx mice. Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic genes (Pdk1, Pdk4, Ppara), also denote disturbed cardiac metabolism and shift towards glucose utilization in Cmah−/−;mdx mice. Moreover, we show long-term treatment with peptide-conjugated exon skipping antisense oligonucleotides (20-week regimen), resulted in 20% cardiac dystrophin protein restoration and significantly improved RV cardiac function. Therefore, Cmah−/−;mdx mice represent an appropriate model for evaluating cardiac benefit of novel DMD therapeutics

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model

Integrating social protection and climate change adaptation: a review

Policymakers are increasingly interested in how social protection is evolving in the context of climate change. This review assesses what the literature tells us about its role in facilitating adaptation in lower income countries. It also explores how far thinking on an integrated “adaptive social protection” (ASP) agenda considers transforming the socioeconomic and political contexts where vulnerability to climate change originates. The review finds that research to date focuses on how instruments such as cash or asset transfers can protect the poor from shocks and stresses, prevent households from falling into poverty as a result of climate change, and promote climate-resilient livelihoods. However, it cautions that such interventions must go beyond helping households to cope against shocks over short time horizons; they should enable the adoption of forward-looking strategies for long-lasting adaptation. Much less attention in the literature is given to whether social protection measures might have transformational effects for recipients. This is despite the fact that the earliest proponents of ASP favored a rights-based approach to social protection to address issues of inequality and marginalization which are at the root of poverty and vulnerability to climate change. Although the role of social protection should not be overstated, it holds promise as a tool for building adaptive capacity. However, the potential of ASP to be truly transformational for its recipients by tackling the structural causes of vulnerability to climate change is not yet harnessed by policymakers. This constitutes a missed opportunity for the agenda to deliver on the international community's promise to “leave no one behind.”. This article is categorized under: Climate and Development > Sustainability and Human Well-Being Vulnerability and Adaptation to Climate Change > Values-Based Approach to Vulnerability and Adaptation

USA and RXTE Observations of a Variable Low-Frequency QPO in XTE J1118+480

The USA experiment on ARGOS and RXTE have exensively observed the X-ray transient XTE J1118+480 during its recent outburst in 2000 April--June. We present detailed monitoring of the evolution of a low frequency QPO which drifts from 0.07 Hz to 0.15 Hz during the outburst. We examine possible correlations of the QPO frequency with the flux and spectral characteristics of the source, and compare this QPO to low frequency QPOs observed in other black hole candidates.Comment: Accepted by ApJ Letters, reference added, minor revisions, 6 page

USA Observation of Spectral and Timing Evolution During the 2000 Outburst of XTE J1550-564

We report on timing and spectral observations of the 2000 outburst of XTE J1550-564 made by the Unconventional Stellar Aspect (USA) Experiment on board the Advanced Research and Global Observation Satellite (ARGOS). We observe a low-frequency quasi-periodic oscillation (LFQPO) with a centroid frequency that tends to increase with increasing flux and a fractional rms amplitude which is correlated with the hardness ratio. The evolution of the hardness ratio (4--16 keV/1--4 keV) with time and source flux is examined. The hardness-intensity diagram (HID) shows a cyclical movement in the clockwise direction and possibly indicates the presence of two independent accretion flows. We observe a relationship between the USA 4--16 keV count rate and radio observations and discuss this in the context of previously observed correlations between X-ray, radio, optical and IR data. We examine our results in the context of models invoking two accretion flows: a thin disk and a hot sub-Keplerian flow.Comment: 11 pages, 2 figure

Effects of drinking patterns on prospective memory performance in college students [pre-print]

OBJECTIVE: Traditional college students are at a critical juncture in the development of prospective memory (PM). Their brains are vulnerable to the effects of alcohol. METHOD: There were 123 third and fourth year college students, 19-23 years old, who completed the Self-Rating Effects of Alcohol (SREA), Modified Timeline Follow-back (TFLB), Brief Young Adult Alcohol Consequences Scale (BYAACS), and Alcohol Effects Questionnaire (AEQ) once per month on a secure online database, as reported elsewhere (Dager et al., 2013). Data from the 6 months immediately before memory testing were averaged. In a single testing session participants were administered the Mini International Neuropsychiatric Interview-Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition-Text Revision (MINI-DSM-IV-TR), measures of PM (event-based and time-based), and retrospective memory (RM). Based on the average score of six consecutive monthly responses to the SREA, TLFB, and AEQ, students were classified as nondrinkers, light drinkers, or heavy drinkers (as defined previously; Dager et al., 2013). Alcohol-induced amnesia (blackout) was measured with the BYAACS. RESULTS: We found a relationship between these alcohol use classifications and time-based PM, such that participants who were classified as heavier drinkers were more likely to forget to perform the time-based PM task. We also found that self-reported alcohol-induced amnesia (blackouts) during the month immediately preceding memory testing was associated with lower performance on the event-based PM task. Participants\u27 ability to recall the RM tasks suggested the PM items were successfully encoded even when they were not carried out, and we observed no relationship between alcohol use and RM performance. CONCLUSION: Heavy alcohol use in college students may be related to impairments in PM. (PsycINFO Database Recor

Heavy Drinking in College Students Is Associated with Accelerated Gray Matter Volumetric Decline over a 2 Year Period

Background: Heavy and/or harmful alcohol use while in college is a perennial and significant public health issue. Despite the plethora of cross-sectional research suggesting deleterious effects of alcohol on the brain, there is a lack of literature investigating the longitudinal effects of alcohol consumption on the adolescent brain. We aim to probe the longitudinal effects of college drinking on gray matter change in students during this crucial neurodevelopmental period.Methods: Data were derived from the longitudinal Brain and Alcohol Research in College Students (BARCS) study of whom a subset underwent brain MRI scans at two time points 24 months apart. Students were young adults with a mean age at baseline of about 18.5 years. Based on drinking metrics assessed at both baseline and followup, subjects were classified as sustained abstainers/light drinkers (N = 45) or sustained heavy drinkers (N = 84) based on criteria established in prior literature. Gray matter volumetric change (GMV-c) maps were derived using the longitudinal DARTEL pipeline as implemented in SPM12. GMV-c maps were then subjected to a 1-sample and 2-sample t-test in SPM12 to determine within- and between-group GMV-c differences in drinking groups. Supplementary between-group differences were also computed at baseline only.Results: Within-group analysis revealed significant decline in GMV in both groups across the 2 year followup period. However, tissue loss in the sustained heavy drinking group was more significant, larger per region, and more widespread across regions compared to abstainers/light drinkers. Between-group analysis confirmed the above and showed a greater rate of GMV-c in the heavy drinking group in several brain regions encompassing inferior/medial frontal gyrus, parahippocampus, and anterior cingulate. Supplementary analyses suggest that some of the frontal differences existed at baseline and progressively worsened.Conclusion: Sustained heavy drinking while in college was associated with accelerated GMV decline in brain regions involved with executive functioning, emotional regulation, and memory, which are critical to everyday life functioning. Areas of significant GMV decreases also overlapped largely with brain reward and stress systems implicated in addictive behavior

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults