Elevated activity of the sympathetic nervous system is related to diminished practice effects in memory:A pilot study

BACKGROUND: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load. OBJECTIVE: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects. METHODS: Thirty cognitively healthy individuals aged 40–70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance. RESULTS: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners. CONCLUSION: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline

Kepler Eclipsing Binary Stars. VI. Identification of Eclipsing Binaries in the K2 Campaign 0 Data-set

The original {\it Kepler} mission observed and characterized over 2400 eclipsing binaries in addition to its prolific exoplanet detections. Despite the mechanical malfunction and subsequent non-recovery of two reaction wheels used to stabilize the instrument, the {\it Kepler} satellite continues collecting data in its repurposed {\it K2} mission surveying a series of fields along the ecliptic plane. Here we present an analysis of the first full baseline {\it K2} data release: the Campaign 0 data-set. In the 7761 light curves, we have identified a total of 207 eclipsing binaries. Of these, 97 are new discoveries that were not previously identified. Our pixel-level analysis of these objects has also resulted in identification of several false positives (observed targets contaminated by neighboring eclipsing binaries), as well as the serendipitous discovery of two short period exoplanet candidates. We provide catalog cross-matched source identifications, orbital periods, morphologies and ephemerides for these eclipsing systems. We also describe the incorporation of the K2 sample into the Kepler Eclipsing Binary Catalog\footnote{\url{keplerebs.villanova.edu/k2}}, present spectroscopic follow-up observations for a limited selection of nine systems, and discuss prospects for upcoming {\it K2} campaigns.Comment: Accepted for publication in MNRAS. 51 pages [20 figures, 8 tables]. Results available online in the Kepler Eclipsing Binary Star Catalog http://keplerebs.villanova.edu/k

The C-Type Lectin Receptor CLECSF8/CLEC4D Is a Key Component of Anti-Mycobacterial Immunity

Open Access funded by Wellcome Trust: Under a Creative Commons license Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgments We would like to thank S. Hardison, P. Redelinghuys, J. Taylor, C. Wallace, A. Richmond, S. Hadebe, A. Plato, F. Abbass, L. Fick, N. Allie, R. Wilkinson, K. Wilkinson, S. Cooper, D. Lang, and V. Kumar for reagents and assistance, and the animal facility staff for the care of our animals. This work was supported by the MRC (UK) and Wellcome Trust (G.D.B.); MRC (South Africa) and Sydney Brenner Fellowship (M.J.M.); Vici (M.G.N.), Vidi (R.v.C.), and Veni grants (T.S.P.) from the Netherlands Organization for Scientific Research; the Royal Netherlands Academy of Arts and Sciences (T.H.M.O.); EC FP7 projects (NEWTBVAC, ADITEC; T.H.M.O.); Carnegie Corporation and CIDRI (J.C.H.); and the University of Aberdeen (B.K.).Peer reviewedPublisher PD

Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19) : autopsy reveals a ferroptosis signature

Aims Cardiovascular complications, including myocarditis, are observed in coronavirus disease 2019 (COVID-19). Major cardiac involvement is a potentially lethal feature in severe cases. We sought to describe the underlying pathophysiological mechanism in COVID-19 lethal cardiogenic shock. Methods and results We report on a 48-year-old male COVID-19 patient with cardiogenic shock; despite extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful. Severe acute respiratory syndrome coronavirus 2 RNA was detected at autopsy in the lungs and myocardium. Histopathological examination revealed diffuse alveolar damage, proliferation of type II pneumocytes, lymphocytes in the lung interstitium, and pulmonary microemboli. Moreover, patchy muscular, sometimes perivascular, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in the cardiac tissue. The lymphocytes 'interlocked' the myocytes, resulting in myocyte degeneration and necrosis. Predominantly, T-cell lymphocytes with a CD4:CD8 ratio of 1.7 infiltrated the interstitial myocardium, reflecting true myocarditis. The myocardial tissue was examined for markers of ferroptosis, an iron-catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids. Immunohistochemical staining with E06, a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes, near arteries, in the epicardium and myocardium. A similar ferroptosis signature was present in the myocardium of a COVID-19 subject without myocarditis. In a case of sudden death due to viral myocarditis of unknown aetiology, however, immunohistochemical staining with E06 was negative. The renal proximal tubuli stained positively for E06 and also hydroxynonenal (4-HNE), a reactive breakdown product of the lipid peroxides that execute ferroptosis. In the case of myocarditis of other aetiology, the renal tissue displayed no positivity for E06 or 4-HNE. Conclusions The findings in this case are unique as this is the first report on accumulated oxidized phospholipids (or their breakdown products) in myocardial and renal tissue in COVID-19. This highlights ferroptosis, proposed to detrimentally contribute to some forms of ischaemia-reperfusion injury, as a detrimental factor in COVID-19 cardiac damage and multiple organ failure

A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes

Lectin-like bacteriocins from pseudomonas spp. utilise D-rhamnose containing lipopolysaccharide as a cellular receptor

Lectin-like bacteriocins consist of tandem monocot mannose-binding domains and display a genus-specific killing activity. Here we show that pyocin L1, a novel member of this family from Pseudomonas aeruginosa, targets susceptible strains of this species through recognition of the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide that is predominantly a homopolymer of d-rhamnose. Structural and biophysical analyses show that recognition of CPA occurs through the C-terminal carbohydrate-binding domain of pyocin L1 and that this interaction is a prerequisite for bactericidal activity. Further to this, we show that the previously described lectin-like bacteriocin putidacin L1 shows a similar carbohydrate-binding specificity, indicating that oligosaccharides containing d-rhamnose and not d-mannose, as was previously thought, are the physiologically relevant ligands for this group of bacteriocins. The widespread inclusion of d-rhamnose in the lipopolysaccharide of members of the genus Pseudomonas explains the unusual genus-specific activity of the lectin-like bacteriocins

Kepler eclipsing binary stars. VII. the catalogue of eclipsing binaries found in the entire Kepler data set

The primary Kepler Mission provided nearly continuous monitoring of ~200,000 objects with unprecedented photometric precision. We present the final catalog of eclipsing binary systems within the 105 deg2 Kepler field of view. This release incorporates the full extent of the data from the primary mission (Q0-Q17 Data Release). As a result, new systems have been added, additional false positives have been removed, ephemerides and principal parameters have been recomputed, classifications have been revised to rely on analytical models, and eclipse timing variations have been computed for each system. We identify several classes of systems including those that exhibit tertiary eclipse events, systems that show clear evidence of additional bodies, heartbeat systems, systems with changing eclipse depths, and systems exhibiting only one eclipse event over the duration of the mission. We have updated the period and galactic latitude distribution diagrams and included a catalog completeness evaluation. The total number of identified eclipsing and ellipsoidal binary systems in the Kepler field of view has increased to 2878, 1.3% of all observed Kepler targets

Pre-hospital assessment of the role of adrenaline : measuring the effectiveness of drug administration in cardiac arrest (PARAMEDIC-2) : trial protocol

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest. This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant. 8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes). Trial registration (ISRCTN73485024)

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

The relationship of primary health care use with persistence of insomnia: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Prevalence of insomnia symptoms in the general population is high. Insomnia is linked with high health care use and within primary care there are a number of treatment options available. The objective of this study was to determine the association of persistence and remission of insomnia with primary health care using a longitudinal study.</p> <p>Methods</p> <p>A postal survey of registered adult (over 18 years) populations of five UK general practices, repeated after 1 year, linked to primary care records. Baseline survey responders were assessed for persistence of insomnia symptoms at 12 months. The association of primary care consultation or prescription for any mood disorder (defined as anxiety, depression, stress, neurosis, or insomnia) in the 12 months between baseline and follow-up surveys with persistence of insomnia was determined.</p> <p>Results</p> <p>474 participants reporting insomnia symptoms at baseline were followed up at 12 months. 131(28%) consulted for mood problem(s) or received a relevant prescription. Of these 100 (76%) still had insomnia symptoms at one year, compared with 227 (66%) of those with no contact with primary care for this condition (OR 1.37; 95% CI 0.83, 2.27). Prescription of hypnotics showed some evidence of association with persistence of insomnia at follow-up (OR 3.18; 95% CI 0.93, 10.92).</p> <p>Conclusion</p> <p>Insomniacs continue to have problems regardless of whether or not they have consulted their primary care clinician or received a prescription for medication over the year. Hypnotics may be associated with persistence of insomnia. Further research is needed to determine more effective methods of identifying and managing insomnia in primary care. There may however be a group who have unmet need such as depression who would benefit from seeking primary health care.</p