Exact Wave Solutions to 6D Gauged Chiral Supergravity

We describe a broad class of time-dependent exact wave solutions to 6D gauged chiral supergravity with two compact dimensions. These 6D solutions are nontrivial warped generalizations of 4D pp-waves and Kundt class solutions and describe how a broad class of previously-static compactifications from 6D to 4D (sourced by two 3-branes) respond to waves moving along one of the uncompactified directions. Because our methods are generally applicable to any higher dimensional supergravity they are likely to be of use for finding the supergravity limit of time-dependent solutions in string theory. The 6D solutions are interesting in their own right, describing 6D shock waves induced by high energy particles on the branes, and as descriptions of the near-brane limit of the transient wavefront arising from a local bubble-nucleation event on one of the branes, such as might occur if a tension-changing phase transition were to occur.Comment: 22 pages, 1 figure. Minor clarifications added. Accepted in JHE

An efficient and robust approach to Mendelian randomization with measured pleiotropic effects in a high-dimensional setting.

Valid estimation of a causal effect using instrumental variables requires that all of the instruments are independent of the outcome conditional on the risk factor of interest and any confounders. In Mendelian randomization studies with large numbers of genetic variants used as instruments, it is unlikely that this condition will be met. Any given genetic variant could be associated with a large number of traits, all of which represent potential pathways to the outcome which bypass the risk factor of interest. Such pleiotropy can be accounted for using standard multivariable Mendelian randomization with all possible pleiotropic traits included as covariates. However, the estimator obtained in this way will be inefficient if some of the covariates do not truly sit on pleiotropic pathways to the outcome. We present a method that uses regularization to identify which out of a set of potential covariates need to be accounted for in a Mendelian randomization analysis in order to produce an efficient and robust estimator of a causal effect. The method can be used in the case where individual-level data are not available and the analysis must rely on summary-level data only. It can be used where there are any number of potential pleiotropic covariates up to the number of genetic variants less one. We show the results of simulation studies that demonstrate the performance of the proposed regularization method in realistic settings. We also illustrate the method in an applied example which looks at the causal effect of urate plasma concentration on coronary heart disease

First record of an Odontaspidid shark in Ascension Island waters

The occurrence of the poorly understood shark species Odontapsis ferox is reported at an oceanic seamount in the central south Atlantic, within the Exclusive Economic Zone of Ascension Island. The presence of the species at this location is confirmed by the discovery of a tooth embedded in scientific equipment, and footage of at least one animal on autonomous underwater video. The new record of this shark species at this location demonstrates the knowledge gaps which still exist at many remote, oceanic structures and their candidacy for status as important conservation areas.info:eu-repo/semantics/publishedVersio

Noise-augmented directional clustering of genetic association data identifies distinct mechanisms underlying obesity.

Funder: NIHR Cambridge Biomedical Research CentreClustering genetic variants based on their associations with different traits can provide insight into their underlying biological mechanisms. Existing clustering approaches typically group variants based on the similarity of their association estimates for various traits. We present a new procedure for clustering variants based on their proportional associations with different traits, which is more reflective of the underlying mechanisms to which they relate. The method is based on a mixture model approach for directional clustering and includes a noise cluster that provides robustness to outliers. The procedure performs well across a range of simulation scenarios. In an applied setting, clustering genetic variants associated with body mass index generates groups reflective of distinct biological pathways. Mendelian randomization analyses support that the clusters vary in their effect on coronary heart disease, including one cluster that represents elevated body mass index with a favourable metabolic profile and reduced coronary heart disease risk. Analysis of the biological pathways underlying this cluster identifies inflammation as potentially explaining differences in the effects of increased body mass index on coronary heart disease

Altered Oxygen Utilisation in Rat Left Ventricle and Soleus after 14 Days, but Not 2 Days, of Environmental Hypoxia.

The effects of environmental hypoxia on cardiac and skeletal muscle metabolism are dependent on the duration and severity of hypoxic exposure, though factors which dictate the nature of the metabolic response to hypoxia are poorly understood. We therefore set out to investigate the time-dependence of metabolic acclimatisation to hypoxia in rat cardiac and skeletal muscle. Rats were housed under normoxic conditions, or exposed to short-term (2 d) or sustained (14 d) hypoxia (10% O2), after which samples were obtained from the left ventricle of the heart and the soleus for assessment of metabolic regulation and mitochondrial function. Mass-corrected maximal oxidative phosphorylation was 20% lower in the left ventricle following sustained but not short-term hypoxia, though no change was observed in the soleus. After sustained hypoxia, the ratio of octanoyl carnitine- to pyruvate- supported respiration was 11% and 12% lower in the left ventricle and soleus, respectively, whilst hexokinase activity increased by 33% and 2.1-fold in these tissues. mRNA levels of PPARα targets fell after sustained hypoxia in both tissues, but those of PPARα remained unchanged. Despite decreased Ucp3 expression after short-term hypoxia, UCP3 protein levels and mitochondrial coupling remained unchanged. Protein carbonylation was 40% higher after short-term but not sustained hypoxic exposure in the left ventricle, but was unchanged in the soleus at both timepoints. Our findings therefore demonstrate that 14 days, but not 2 days, of hypoxia induces a loss of oxidative capacity in the left ventricle but not the soleus, and a substrate switch away from fatty acid oxidation in both tissues.JAH received a PhD Studentship from the Biotechnology and Biological Sciences Research Council (Grant number: BB/F016581/1, www.bbsrc.ac.uk (http://www.bbsrc.ac.uk/). SLB received no specific funding for this work. HY received a Departmental Summer Studentship Bursary from Imperial College, London (www.imperial.ac.uk (http://www.imperial.ac.uk/)). AJM received an academic fellowship from the Research Councils UK (www.rcuk.ac.uk (http://www.rcuk.ac.uk/)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.013856

Pleiotropy robust methods for multivariable Mendelian randomization

Abstract: Mendelian randomization is a powerful tool for inferring the presence, or otherwise, of causal effects from observational data. However, the nature of genetic variants is such that pleiotropy remains a barrier to valid causal effect estimation. There are many options in the literature for pleiotropy robust methods when studying the effects of a single risk factor on an outcome. However, there are few pleiotropy robust methods in the multivariable setting, that is, when there are multiple risk factors of interest. In this article we introduce three methods which build on common approaches in the univariable setting: MVMR‐Robust; MVMR‐Median; and MVMR‐Lasso. We discuss the properties of each of these methods and examine their performance in comparison to existing approaches in a simulation study. MVMR‐Robust is shown to outperform existing outlier robust approaches when there are low levels of pleiotropy. MVMR‐Lasso provides the best estimation in terms of mean squared error for moderate to high levels of pleiotropy, and can provide valid inference in a three sample setting. MVMR‐Median performs well in terms of estimation across all scenarios considered, and provides valid inference up to a moderate level of pleiotropy. We demonstrate the methods in an applied example looking at the effects of intelligence, education and household income on the risk of Alzheimer's disease

Rapid kinetics of changes in oxygen consumption rate in thrombin-stimulated platelets measured by high-resolution respirometry.

Platelet activation plays a key role in normal haemostasis and pathological thrombosis. Platelet activation is rapid; within minutes of stimulation, platelets generate bioactive phospholipids, secrete their granule contents, activate integrins and aggregate together to form a haemostatic plug. These events are dependent on ATP synthesis. Mitochondrial function in platelets from healthy volunteers and patients with a range of diseases indicate an important role for oxygen consumption in oxidative phosphorylation in normal and pathological function. Platelets also consume oxygen during oxidation reactions, such as cyclooxygenase-dependent thromboxane A2 synthesis. In this study, we used high-resolution respirometry to investigate rapid changes in oxygen consumption during platelet activation. We demonstrated a rapid, transient increase in oxygen consumption rate within minutes of platelet stimulation by the physiological activator, thrombin. This was partly inhibited by aspirin and by oligomycin. This shows that high resolution respirometry can provide information regarding rapid and dynamic changes in oxygen consumption during platelet activation

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.</p

The evolution of embryonic creek systems in a recently inundated large open coast managed realignment site

Managed realignment (MR) schemes are being implemented to compensate for the degradation of coastal habitats. However, evidence suggests that MR sites have lower biodiversity than anticipated, which has been linked to poor drainage. Despite creek networks playing an important role in enhancing site drainage in natural intertidal environments, there remains a shortage of data on the formation and evolution of creeks within MR sites. This study evaluates creek development at the Medmerry Managed Realignment Site, UK. Creek development is investigated using differential global positioning system(dGPS) data, supported by sedimentological analyses and a high-resolution digital surface model (DSM) derived from images taken using a small unmanned aerial vehicle. Measurements indicated that creeks will develop relatively quickly, but are influenced by differences in the sub-surface sedimentological conditions. A suitable level of agreement was found between the DSM and dGPS measurements, demonstrating the appropriateness of this method to study creek development within intertidal environments at a higher resolution than traditional surveying techniques. These results are used to propose the collapseof sub-surface piping as the primary creek formation mechanism. Findings are discussed in terms of increasing the success of MR schemes and enhancing site design to maximise the ecosystem services provided