Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

The association of cardioprotective medications with pneumonia-related outcomes

Introduction: Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes. Materials and Methods: We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events. Results: Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63-0.77), ACE inhibitors (OR 0.82, 95% CI 0.74-0.91), and ARBs (OR 0.58, 95% CI 0.44-0.77). However, none of the medications were significantly associated with decreased cardiovascular events. Discussion: While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects

The impact of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia

BACKGROUND: Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of ACE inhibitors on mortality for patients hospitalized with community-acquired pneumonia. METHODS: A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation. RESULTS: Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk. In the multivariable conditional logistic regression analysis, after adjusting for potential confounders, the use of ACE inhibitors at presentation (odds ratio 0.44, 95% confidence interval 0.22–0.89) was significantly associated with 30-day mortality. CONCLUSION: Prior outpatient use of an ACE inhibitor was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect

The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia

BACKGROUND: Recent studies suggest that HMG-CoA reductase inhibitors ("statins") may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of statins on mortality for patients hospitalized with community-acquired pneumonia. METHODS: A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation. RESULTS: Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk based on the pneumonia severity index. In the multivariable regression analysis, after adjusting for potential confounders including a propensity score, the use of statins at presentation (odds ratio 0.36, 95% confidence interval 0.14–0.92) was associated with decreased 30-day mortality. DISCUSSION: Prior outpatient statin use was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Disgust trumps lust:women’s disgust and attraction towards men is unaffected by sexual arousal

Mating is a double-edged sword. It can have great adaptive benefits, but also high costs, depending on the mate. Disgust is an avoidance reaction that serves the function of discouraging costly mating decisions, for example if the risk of pathogen transmission is high. It should, however, be temporarily inhibited in order to enable potentially adaptive mating. We therefore tested the hypothesis that sexual arousal inhibits disgust if a partner is attractive, but not if he is unattractive or shows signs of disease. In an online experiment, women rated their disgust towards anticipated behaviors with men depicted on photographs. Participants did so in a sexually aroused state and in a control state. The faces varied in attractiveness and the presence of disease cues (blemishes). We found that disease cues and attractiveness, but not sexual arousal, influenced disgust. The results suggest that women feel disgust at sexual contact with unattractive or diseased men independently of their sexual arousal

Charged-particle distributions at low transverse momentum in √s=13 13 TeV pp interactions measured with the ATLAS detector at the LHC

Measurements of distributions of charged particles produced in proton–proton collisions with a centre-of-mass energy of 13 TeV are presented. The data were recorded by the ATLAS detector at the LHC and correspond to an integrated luminosity of 151 μb −1 μb−1 . The particles are required to have a transverse momentum greater than 100 MeV and an absolute pseudorapidity less than 2.5. The charged-particle multiplicity, its dependence on transverse momentum and pseudorapidity and the dependence of the mean transverse momentum on multiplicity are measured in events containing at least two charged particles satisfying the above kinematic criteria. The results are corrected for detector effects and compared to the predictions from several Monte Carlo event generators

Measurement of the inelastic proton-proton cross section at √s=13 TeV with the ATLAS detector at the LHC

This Letter presents a measurement of the inelastic proton-proton cross section using 60  μb −1 of pp collisions at a center-of-mass energy √s of 13 TeV with the ATLAS detector at the LHC. Inelastic interactions are selected using rings of plastic scintillators in the forward region (2.0710 −6 , where M X is the larger invariant mass of the two hadronic systems separated by the largest rapidity gap in the event. In this ξ range the scintillators are highly efficient. For diffractive events this corresponds to cases where at least one proton dissociates to a system with M X >13  GeV . The measured cross section is compared with a range of theoretical predictions. When extrapolated to the full phase space, a cross section of 78.1±2.9  mb is measured, consistent with the inelastic cross section increasing with center-of-mass energy

Search for supersymmetry at √s = 13 TeV in final states with jets and two same-sign leptons or three leptons with the ATLAS detector

A search for strongly produced supersymmetric particles is conducted using signatures involving multiple energetic jets and either two isolated leptons (e or μμ ) with the same electric charge or at least three isolated leptons. The search also utilises b-tagged jets, missing transverse momentum and other observables to extend its sensitivity. The analysis uses a data sample of proton–proton collisions at s√=13s=13 TeV recorded with the ATLAS detector at the Large Hadron Collider in 2015 corresponding to a total integrated luminosity of 3.2 fb −1−1. No significant excess over the Standard Model expectation is observed. The results are interpreted in several simplified supersymmetric models and extend the exclusion limits from previous searches. In the context of exclusive production and simplified decay modes, gluino masses are excluded at 95%95% confidence level up to 1.1–1.3 TeV for light neutralinos (depending on the decay channel), and bottom squark masses are also excluded up to 540 GeV. In the former scenarios, neutralino masses are also excluded up to 550–850 GeV for gluino masses around 1 TeV