An Efficient Representation of Euclidean Gravity I

We explore how the topology of spacetime fabric is encoded into the local structure of Riemannian metrics using the gauge theory formulation of Euclidean gravity. In part I, we provide a rigorous mathematical foundation to prove that a general Einstein manifold arises as the sum of SU(2)_L Yang-Mills instantons and SU(2)_R anti-instantons where SU(2)_L and SU(2)_R are normal subgroups of the four-dimensional Lorentz group Spin(4) = SU(2)_L x SU(2)_R. Our proof relies only on the general properties in four dimensions: The Lorentz group Spin(4) is isomorphic to SU(2)_L x SU(2)_R and the six-dimensional vector space of two-forms splits canonically into the sum of three-dimensional vector spaces of self-dual and anti-self-dual two-forms. Consolidating these two, it turns out that the splitting of Spin(4) is deeply correlated with the decomposition of two-forms on four-manifold which occupies a central position in the theory of four-manifolds.Comment: 31 pages, 1 figur

Reward-Related Behavioral Paradigms for Addiction Research in the Mouse: Performance of Common Inbred Strains

The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touchscreen-based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research

The search for transient astrophysical neutrino emission with IceCube-DeepCore

We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (-5 degrees < delta < 90 degrees) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae

Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice

Lisofylline (LSF), is the R-(−) enantiomer of the metabolite M1 of pentoxifylline, and is currently under development for the treatment of type 1 diabetes. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of LSF in mice and to perform simulations in order to predict LSF concentrations in human serum and tissues following intravenous and oral administration. The concentrations of LSF in serum, brain, liver, kidneys, lungs, muscle, and gut were determined at different time points over 60 min by a chiral HPLC method with UV detection following a single intravenous dose of LSF to male CD-1 mice. A PBPK model was developed to describe serum pharmacokinetics and tissue distribution of LSF using ADAPT II software. All pharmacokinetic profiles were fitted simultaneously to obtain model parameters. The developed model characterized well LSF disposition in mice. The estimated intrinsic hepatic clearance was 5.427 ml/min and hepatic clearance calculated using the well-stirred model was 1.22 ml/min. The renal clearance of LSF was equal to zero. On scaling the model to humans, a good agreement was found between the predicted by the model and presented in literature serum LSF concentration–time profiles following an intravenous dose of 3 mg/kg. The predicted LSF concentrations in human tissues following oral administration were considerably lower despite the twofold higher dose used and may not be sufficient to exert a pharmacological effect. In conclusion, the mouse is a good model to study LSF pharmacokinetics following intravenous administration. The developed PBPK model may be useful to design future preclinical and clinical studies of this compound

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Low-molecular-weight heparin reduces hyperoxia-augmented ventilator-induced lung injury via serine/threonine kinase-protein kinase B

<p>Abstract</p> <p>Background</p> <p>High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce the release of cytokines, including high-mobility group box-1 (HMGB1), oxygen radicals, neutrophil infiltration, and the disruption of epithelial and endothelial barriers. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between high tidal volume and hyperoxia are unclear. We hypothesized that subcutaneous injections of enoxaparin would decrease the effects of hyperoxia on high-tidal-volume ventilation-induced HMGB1 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway.</p> <p>Methods</p> <p>Male C57BL/6, either wild type or Akt^+/-, aged between 6 and 8 weeks, weighing between 20 and 25 g, were exposed to high-tidal-volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 2 to 8 hours with or without 4 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet-to-dry weight ratio, free radicals, myeloperoxidase, Western blot of Akt, and gene expression of HMGB1 were measured. The expression of HMGB1 was studied by immunohistochemistry.</p> <p>Results</p> <p>High-tidal-volume ventilation using hyperoxia induced microvascular permeability, Akt activation, HMGB1 mRNA expression, neutrophil infiltration, oxygen radicals, HMGB1 production, and positive staining of Akt in bronchial epithelium. Hyperoxia-induced augmentation of ventilator-induced lung injury was attenuated with Akt deficient mice and pharmacological inhibition of Akt activity by enoxaparin.</p> <p>Conclusion</p> <p>These data suggest that enoxaparin attenuates hyperoxia-augmented high-tidal-volume ventilation-induced neutrophil influx and HMGB1 production through inhibition of the Akt pathway. Understanding the protective mechanism of enoxaparin related with the reduction of HMGB1 may help further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.</p

Peer role-play and standardised patients in communication training: a comparative study on the student perspective on acceptability, realism, and perceived effect

<p>Abstract</p> <p>Background</p> <p>To assess the student perspective on acceptability, realism, and perceived effect of communication training with peer role play (RP) and standardised patients (SP).</p> <p>Methods</p> <p>69 prefinal year students from a large German medical faculty were randomly assigned to one of two groups receiving communication training with RP (N = 34) or SP (N = 35) in the course of their paediatric rotation. In both groups, training addressed major medical and communication problems encountered in the exploration and counselling of parents of sick children. Acceptability and realism of the training as well as perceived effects and applicability for future parent-physician encounters were assessed using six-point Likert scales.</p> <p>Results</p> <p>Both forms of training were highly accepted (RP 5.32 ± .41, SP 5.51 ± .44, n.s.; 6 = very good, 1 = very poor) and perceived to be highly realistic (RP 5.60 ± .38, SP 5.53 ± .36, n.s.; 6 = highly realistic, 1 = unrealistic). Regarding perceived effects, participation was seen to be significantly more worthwhile in the SP group (RP 5.17 ± .37, SP 5.50 ± .43; p < .003; 6 = totally agree, 1 = don't agree at all). Both training methods were perceived as useful for training communication skills (RP 5.01 ± .68, SP 5.34 ± .47; 6 = totally agree; 1 = don't agree at all) and were considered to be moderately applicable for future parent-physician encounters (RP 4.29 ± 1.08, SP 5.00 ± .89; 6 = well prepared, 1 = unprepared), with usefulness and applicability both being rated higher in the SP group (p < .032 and p < .009).</p> <p>Conclusions</p> <p>RP and SP represent comparably valuable tools for the training of specific communication skills from the student perspective. Both provide highly realistic training scenarios and warrant inclusion in medical curricula. Given the expense of SP, deciding which method to employ should be carefully weighed up. From the perspective of the students in our study, SP were seen as a more useful and more applicable tool than RP. We discuss the potential of RP to foster a greater empathic appreciation of the patient perspective.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente