Metabolomics reveals mouse plasma metabolite responses to acute exercise and effects of disrupting AMPK-glycogen interactions

Introduction: The AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that becomes activated by exercise and binds glycogen, an important energy store required to meet exercise-induced energy demands. Disruption of AMPK-glycogen interactions in mice reduces exercise capacity and impairs whole-body metabolism. However, the mechanisms underlying these phenotypic effects at rest and following exercise are unknown. Furthermore, the plasma metabolite responses to an acute exercise challenge in mice remain largely uncharacterized. Methods: Plasma samples were collected from wild type (WT) and AMPK double knock-in (DKI) mice with disrupted AMPK-glycogen binding at rest and following 30-min submaximal treadmill running. An untargeted metabolomics approach was utilized to determine the breadth of plasma metabolite changes occurring in response to acute exercise and the effects of disrupting AMPK-glycogen binding. Results: Relative to WT mice, DKI mice had reduced maximal running speed (p < 0.0001) concomitant with increased body mass (p < 0.01) and adiposity (p < 0.001). A total of 83 plasma metabolites were identified/annotated, with 17 metabolites significantly different (p < 0.05; FDR<0.1) in exercised (↑6; ↓11) versus rested mice, including amino acids, acylcarnitines and steroid hormones. Pantothenic acid was reduced in DKI mice versus WT. Distinct plasma metabolite profiles were observed between the rest and exercise conditions and between WT and DKI mice at rest, while metabolite profiles of both genotypes converged following exercise. These differences in metabolite profiles were primarily explained by exercise-associated increases in acylcarnitines and steroid hormones as well as decreases in amino acids and derivatives following exercise. DKI plasma showed greater decreases in amino acids following exercise versus WT. Conclusion: This is the first study to map mouse plasma metabolomic changes following a bout of acute exercise in WT mice and the effects of disrupting AMPK-glycogen interactions in DKI mice. Untargeted metabolomics revealed alterations in metabolite profiles between rested and exercised mice in both genotypes, and between genotypes at rest. This study has uncovered known and previously unreported plasma metabolite responses to acute exercise in WT mice, as well as greater decreases in amino acids following exercise in DKI plasma. Reduced pantothenic acid levels may contribute to differences in fuel utilization in DKI mice

Free-sugar, total-sugar, fibre and micronutrient intake within elite youth British soccer players: a nutritional transition from schoolboy to fulltime soccer player.

It is recommended that soccer players consume a high carbohydrate (CHO) diet to augment performance. However, growing evidence suggests that there is a link between high free-sugar (FS) intake (>5% total energy intake; TEI) and metabolic diseases. Furthermore, foods that are often high in sugar, such as processed foods, are typically lacking in nutrient quality. We therefore analysed total- and FS, dietary fibre and micronutrient intake of players from an English Premier League academy under(U) 18 (n=13); U15/16 (n=25); U13/14 (n=21) using a 7-day food diary. Data was compared to current UK dietary reference value (DRV) for free-sugar via a t-test. The U13/14s (1018 %) and U15/16s (1130 %) both consumed higher amounts of free-sugar in comparison to the UK DRV of 5% TEI 5% (P<0.01), conversely, the U18s did not exceed the DRV (513 %). Furthermore, FS intake of the U18s was significantly lower than the U13/14s and U15/16s (P<0.01). Dietary fibre was below the DRV (25g/d for U13/14 & U15/16s; 30g/d for U18s) for all squads (19.04.7; 19.68.3; 17.14.2 g/d, respectively), but not different between squads. Additionally, micronutrient reference intakes were generally met. In conclusion, we provide novel data on dietary sugar, fibre and micronutrient intake within elite youth soccer players. We report an apparent 'nutritional transition' from schoolboy to fulltime soccer player, with U18s showing a significantly lower intake of sugar in comparison to younger squads, and a similar intake of FS to the UK DRVs. Practitioners should target improving player education around sugar and fibre consumption

Three-dimensional general relativistic hydrodynamics II: long-term dynamics of single relativistic stars

This is the second in a series of papers on the construction and validation of a three-dimensional code for the solution of the coupled system of the Einstein equations and of the general relativistic hydrodynamic equations, and on the application of this code to problems in general relativistic astrophysics. In particular, we report on the accuracy of our code in the long-term dynamical evolution of relativistic stars and on some new physics results obtained in the process of code testing. The tests involve single non-rotating stars in stable equilibrium, non-rotating stars undergoing radial and quadrupolar oscillations, non-rotating stars on the unstable branch of the equilibrium configurations migrating to the stable branch, non-rotating stars undergoing gravitational collapse to a black hole, and rapidly rotating stars in stable equilibrium and undergoing quasi-radial oscillations. The numerical evolutions have been carried out in full general relativity using different types of polytropic equations of state using either the rest-mass density only, or the rest-mass density and the internal energy as independent variables. New variants of the spacetime evolution and new high resolution shock capturing (HRSC) treatments based on Riemann solvers and slope limiters have been implemented and the results compared with those obtained from previous methods. Finally, we have obtained the first eigenfrequencies of rotating stars in full general relativity and rapid rotation. A long standing problem, such frequencies have not been obtained by other methods. Overall, and to the best of our knowledge, the results presented in this paper represent the most accurate long-term three-dimensional evolutions of relativistic stars available to date.Comment: 19 pages, 17 figure

The effect of carbohydrate ingestion on the motor skill proficiency of soccer players

This study examined the effects of ingesting a glucose-polymer (GP) solution on the motor skill proficiencies of association football (soccer) players from two teams playing during two matches in a cool environment. Fifteen minutes before each match and at halftime, players from both teams ingested 5 ml/kg of either placebo or a 6.9% GP solution. GP ingestion did not improve tackling, heading, dribbling, or shooting ability. On the contrary, the mean of successful tackles was lower with GP ingestion than with placebo. The success rate for heading, dribbling, and shooting also tended to be lower in the GP than in the placebo condition. In contrast, success in passing and ball control was similar in the two conditions. Improvements in passing and ball control may have been related to a decrease in the intensity of play in the second half of the game. These data indicate that there are no measurable benefits of GP ingestion for the motor skill proficiencies of soccer players during games played in a cool environment.IS

Current Status of Simulations

As the title suggests, the purpose of this chapter is to review the current status of numerical simulations of black hole accretion disks. This chapter focuses exclusively on global simulations of the accretion process within a few tens of gravitational radii of the black hole. Most of the simulations discussed are performed using general relativistic magnetohydrodynamic (MHD) schemes, although some mention is made of Newtonian radiation MHD simulations and smoothed particle hydrodynamics. The goal is to convey some of the exciting work that has been going on in the past few years and provide some speculation on future directions.Comment: 15 pages, 14 figures, to appear in the proceedings of the ISSI-Bern workshop on "The Physics of Accretion onto Black Holes" (8-12 October 2012

Accretion and ejection in black-hole X-ray transients

Aims: We summarize the current observational picture of the outbursts of black-hole X-ray transients (BHTs), based on the evolution traced in a hardness-luminosity diagram (HLD), and we offer a physical interpretation. Methods: The basic ingredient in our interpretation is the Poynting-Robertson Cosmic Battery (PRCB, Contopoulos & Kazanas 1998), which provides locally the poloidal magnetic field needed for the ejection of the jet. In addition, we make two assumptions, easily justifiable. The first is that the mass-accretion rate to the black hole in a BHT outburst has a generic bell-shaped form. This is guaranteed by the observational fact that all BHTs start their outburst and end it at the quiescent state. The second assumption is that at low accretion rates the accretion flow is geometrically thick, ADAF-like, while at high accretion rates it is geometrically thin. Results: Both, at the beginning and the end of an outburst, the PRCB establishes a strong poloidal magnetic field in the ADAF-like part of the accretion flow, and this explains naturally why a jet is always present in the right part of the HLD. In the left part of the HLD, the accretion flow is in the form of a thin disk, and such a disk cannot sustain a strong poloidal magnetic filed. Thus, no jet is expected in this part of the HLD. The counterclockwise traversal of the HLD is explained as follows: the poloidal magnetic field in the ADAF forces the flow to remain ADAF and the source to move upwards in the HLD rather than to turn left. Thus, the history of the system determines the counterclockwise traversal of the HLD. As a result, no BHT is expected to ever traverse the entire HLD curve in the clockwise direction. Conclusions: We offer a physical interpretation of accretion and ejection in BHTs with only one parameter, the mass transfer rate.Comment: Accepted for publication in A&

The Emergence of Hospital Federations: An Integration of Perspectives from Organizational Theory

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68464/2/10.1177_107755878704400206.pd

The burden of injury in China, 1990-2017: findings from the Global Burden of Disease Study 2017

Background A comprehensive evaluation of the burden of injury is an important foundation for selecting and formulating strategies of injury prevention. We present results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 of non-fatal and fatal outcomes of injury at the national and subnational level, and the changes in burden for key causes of injury over time in China. Methods Using the methods and results from GBD 2017, we describe the burden of total injury and the key causes of injury based on the rates of incidence, cause-specific mortality, and disability-adjusted life years (DALYs) in China estimated using DisMod-MR 2.1. We additionally evaluated these results at the provincial level for the 34 subnational locations of China in 2017, measured the change of injury burden from 1990 to 2017, and compared age-standardised DALYs due to injuries at the provincial level against the expected rates based on the Socio-demographic Index (SDI), a composite measure of development of income per capita, years of education, and total fertility rate. Findings In 2017, in China, there were 77·1 million (95% uncertainty interval [UI] 72·5–81·6) new cases of injury severe enough to warrant health care and 733517 deaths (681254–767006) due to injuries. Injuries accounted for 7·0% (95% UI 6·6–7·2) of total deaths and 10·0% (9·5–10·5) of all-cause DALYs in China. In 2017, there was a three-times variation in age-standardised injury DALY rates between provinces of China, with the lowest value in Macao and the highest in Yunnan. Between 1990 and 2017, the age-standardised incidence rate of all injuries increased by 50·6% (95% UI 46·6–54·6) in China, whereas the age-standardised mortality and DALY rates decreased by 44·3% (41·1–48·9) and 48·1% (44·6–51·8), respectively. Between 1990 and 2017, all provinces of China experienced a substantial decline in DALY rates from all injuries ranging from 16·3% (3·1–28·6) in Shanghai and 60·4% (53·7–66·1) in Jiangxi. Agestandardised DALY rates for drowning; injuries from fire, heat and hot substances; adverse effects of medical treatments; animal contact; environmental heat and cold exposure; self-harm; and executions and police conflict each declined by more than 60% between 1990 and 2017. Interpretation Between 1990 and 2017, China experienced a decrease in the age-standardised DALY and mortality rates due to injury, despite an increase in the age-standardised incidence rate. These trends occurred in all provinces. The divergent trends in terms of incidence and mortality indicate that with rapid sociodemographic improvements, the case fatality of injuries has declined, which could be attributed to an improving health-care system but also to a decreasing severity of injuries over this time period

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction