Galactic populations of radio and gamma-ray pulsars in the polar cap model

We simulate the characteristics of the Galactic population of radio and $\gamma$-ray pulsars using Monte Carlo techniques. At birth, neutron stars are spatially distributed in the Galactic disk, with supernova-kick velocities, and randomly dispersed in age back to $10^9$ years. They are evolved in the Galactic gravitational potential to the present time. From a radio luminosity model, the radio flux is filtered through a selected set of radio-survey parameters. $\gamma$-ray luminosities are assigned using the features of recent polar cap acceleration models invoking space-charge-limited flow, and a pulsar death valley further attenuates the population of radio-loud pulsars. Assuming a simple emission geometry with aligned radio and $\gamma$-ray beams of 1 steradian solid angle, our model predicts that EGRET should have seen 7 radio-loud and 1 radio-quiet, $\gamma$-ray pulsars. With much improved sensitivity, GLAST, on the other hand, is expected to observe 76 radio-loud and 74 radio-quiet, $\gamma$-ray pulsars of which 7 would be identified as pulsed sources. We also explore the effect of magnetic field decay on the characteristics of the radio and $\gamma$-ray pulsar populations. Including magnetic field decay on a timescale of 5 Myr improves agreement with the radio pulsar population and increases the predicted number of GLAST detected pulsars to 90 radio-loud and 101 radio-quiet (9 pulsed) $\gamma$-ray pulsars. The lower flux threshold allows GLAST to detect $\gamma$-ray pulsars at larger distances than those observed by the radio surveys used in this study.Comment: 38 pages, 11 figures, accepted for publication v565 n1 Ap

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

International Society of Sports Nutrition Position Stand: Probiotics.

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population

New insights on the regulation of the adenine nucleotide pool of erythrocytes in mouse models

<div><p>The observation that induced torpor in non-hibernating mammals could result from an increased AMP concentration in circulation led our investigation to reveal that the added AMP altered oxygen transport of erythrocytes. To further study the effect of AMP in regulation of erythrocyte function and systemic metabolism, we generated mouse models deficient in key erythrocyte enzymes in AMP metabolism. We have previously reported altered erythrocyte adenine nucleotide levels corresponding to altered oxygen saturation in mice deficient in both CD73 and AMPD3. Here we further investigate how these <i>Ampd3</i>^<i>-/-</i><i>/Cd73</i>^<i>-/-</i> mice respond to the administered dose of AMP in comparison with the control models of single enzyme deficiency and wild type. We found that <i>Ampd3</i>^<i>-/-</i><i>/Cd73</i>^<i>-/-</i> mice are more sensitive to AMP-induced hypometabolism than mice with a single enzyme deficiency, which are more sensitive than wild type. A dose-dependent rightward shift of erythrocyte p50 values in response to increasing amounts of extracellular AMP was observed. We provide further evidence for the direct uptake of AMP by erythrocytes that is insensitive to dipyridamole, a blocker for ENT1. The uptake of AMP by the erythrocytes remained linear at the highest concentration tested, 10mM. We also observed competitive inhibition of AMP uptake by ATP and ADP but not by the other nucleotides and metabolites tested. Importantly, our studies suggest that AMP uptake is associated with an erythrocyte ATP release that is partially sensitive to inhibition by TRO19622 and Ca⁺⁺ ion. Taken together, our study suggests a novel mechanism by which erythrocytes recycle and maintain their adenine nucleotide pool through AMP uptake and ATP release.</p></div

Effect of AMP on the p50 of intact erythrocytes.

<p>(A) Shift of WT erythrocytes’ p50 in response to extracellular AMP concentration; (B) Average AMPD3^-/-/CD73^-/- erythrocyte p50 values in PBS and 2 mM AMP (N = 3). (C) Shift of erythrocytes’ p50 after 2 mM AMP incubation in the four genotypes (N = 3).</p

Concentration dependent uptake of AMP by erythrocytes.

<p>(A) A typical assessment of AMP uptake by erythrocytes. [¹⁴C]-AMP signal as a percentage of total added radioactivity in the supernatant, cells, and wash fractions over a time course. Uptake of AMP by wild type (B) and <i>Cd73</i>^<i>-/-</i> (C) erythrocytes up to 10 mM extracellular AMP were measured. The difference in AMP uptake by the two genotypes at low extracellular AMP concentrations is exhibited by plots of uptake in the range of 0–1 mM extracellular AMP concentrations in wild type (D) and <i>Cd73</i>^<i>-/-</i> (E) erythrocytes.</p

Nucleotides’ induction of ATP release by erythrocytes.

<p>(A) ATP release time course after addition of various nucleotides and adenosine measured by luciferase assays. (B) Quantification of multiple samples for ATP release stimulated by various nucleotides (N = 3). (C) Quantification of multiple samples of AMP and adenosine stimulated ATP release (N = 3). (D) Effect of CBX on ATP release stimulated by AMP. (E) Effect of TRO19622 on ATP release stimulated by AMP. (F) Effect of Ca²⁺ on ATP release stimulated by AMP. P values = *** < .0001.</p

Evaluation of potential inhibitors of AMP uptake by erythrocytes.

<p>(A) CAT effect on erythrocyte AMP uptake. (B) Dipyridamole (Dip) effect on erythrocyte AMP uptake. (C) The inhibition of erythrocyte AMP uptake by Tannic Acid (TAN). (D) Titration of TAN concentration in percentages against erythrocyte AMP uptake. (E). AMP uptake inhibition assay to evaluate possible competitive nucleotide/metabolite inhibitors for AMP uptake. (F) Examining GMP inhibition of AMP uptake as a function of increasing concentrations of extracellular AMP.</p