Carbohydrate, protein and fat metabolism during exercise after oral carnitine supplementation in humans

Twenty non-vegetarian active males were pair-matched and randomly assigned to receive 2 g L-Carnitine L-tartrate (LC).d-1 or placebo for 2 weeks. Subjects exercised for 90 min at 70% O2max following 2 days of a prescribed diet (mean ± SD: 13.6 ± 1.6 MJ, 57% carbohydrate, 15% protein, 26% fat, 2% alcohol) before and after supplementation. Results indicated no change in carbohydrate oxidation, nitrogen excretion, branched-chain amino acid oxidation, or plasma urea during exercise between the beginning and end of supplementation in either group. Following 2 weeks LC supplementation the plasma ammonia response to exercise tended to be suppressed (0 vs. 2wk at 60 min exercise: 97 ± 26 vs. 80 ± 9; and 90 min exercise: 116 ± 47 vs. 87 ± 25 µmol.L-1), with no change in the placebo group. The data indicate that 2 weeks of LC supplementation does not affect fat, carbohydrate and protein contribution to metabolism during prolonged moderate intensity cycling exercise. However, the tendency towards suppressed ammonia accumulation indicates that oral LC supplementation may have the potential to reduce the metabolic stress of exercise or alter ammonia production/removal which warrants further investigation

Effects of exercise intensity and altered substrate availability on cardiovascular and metabolic responses to exercise after oral carnitine supplementation in athletes

The effects of 15 d of supplementation with L-carnitine L-tartrate (LC) on metabolic responses to graded-intensity exercise under conditions of altered substrate availability were examined. Fifteen endurance-trained male athletes undertook exercise trials after a 2-d high-carbohydrate diet (60% CHO, 25% fat) at baseline (D0), on Day 14 (D14), and after a single day of high fat intake (15% CHO, 70% fat) on Day 15 (D15) in a double-blind, placebo-controlled, pair-matched design. Treatment consisted of 3 g LC (2 g L-carnitine/d; n = 8) or placebo (P, n = 7) for 15 d. Exercise trials consisted of 80 min of continuous cycling comprising 20-min periods at each of 20%, 40%, 60%, and 80% VO2peak. There was no significant difference between whole-body rates of CHO and fat oxidation at any workload between D0 and D14 trials for either the P or LC group. Both groups displayed increased fat and reduced carbohydrate oxidation between the D14 and D15 trials (p less than .05). During the D15 trial, heart rate (p less than .05 for 20%, 40%, and 60% workloads) and blood glucose concentration (p less than .05 for 40% and 60% workloads) were lower during exercise in the LC group than in P. These responses suggest that LC may induce subtle changes in substrate handling in metabolically active tissues when fatty-acid availability is increased, but it does not affect whole-body substrate utilization during short-duration exercise at the intensities studied

Differences in visceral adipose tissue and biochemical cardiometabolic risk markers in elite rugby union athletes of Caucasian and Polynesian descent

Polynesian individuals are leaner with greater musculature than Caucasians of an equivalent size, and this genetically different morphology provides a physique that is often compatible with success in a number of sports, including rugby union. Evidence indicates that Polynesians have greater stores of absolute and relative abdominal fat mass and this is known to confer cardiometabolic risk. The aims of this study were to (1) explore the relationship between ethnicity, visceral adipose tissue (VAT), and cardiometabolic disease risk markers in elite Caucasian and Polynesian rugby union athletes, and (2) assess the impact of a pre-season training programme on these markers. Twenty-two professional rugby union athletes of Caucasian (n = 11) and Polynesian (n = 11) descent underwent physique assessment via surface anthropometry, dual-energy X-ray absorptiometry, and magnetic resonance imaging before and after an 11-week pre-season. A fasted blood test was undertaken at both time points. Compared to Caucasians, at baseline Polynesians displayed significantly higher VAT (771 ± 609 cm3 vs 424 ± 235 cm3; p = 0.043), triglycerides (1.0 ± 0.9 mmol/L vs 0.6 ± 0.2 mmol/L; p = 0.050), and low-density lipoprotein cholesterol (3.1 ± 0.9 mmol/L vs 2.3 ± 0.7 mmol/L; p = 0.019). Similar changes were observed in both groups over the pre-season period in VAT and blood biochemical markers. Polynesian rugby union athletes were more likely than Caucasians to exhibit risk factors associated with cardiometabolic disease, such as elevated VAT and unfavourable lipid profiles. Further longitudinal research is required to identify and explain the short- and long-term risk of cardiometabolic disease in athletes of Polynesian descent

Longitudinal changes in body composition assessed using DXA and surface anthropometry show good agreement in elite Rugby Union athletes

Rugby union athletes have divergent body composition based on the demands of their on-field playing position and ethnicity. With an established association between physique traits and positional requirements, body composition assessment is routinely undertaken. Surface anthropometry and dual-energy X-ray absorptiometry (DXA) are the most common assessment techniques utilised, often undertaken synchronously. This study aims to investigate the association between DXA and surface anthropometry when assessing longitudinal changes in fat free mass (FFM) and fat mass (FM) in rugby union athletes. Thirty-nine elite male rugby union athletes (age 25.7 ± 3.1 years; stature 187.6 ± 7.7 cm; mass 104.1 ± 12.2 kg) underwent assessment via DXA and surface anthropometry multiple times over three consecutive international seasons. Changes in the lean mass index (LMI), an empirical measure to assess proportional variation in FFM, showed large agreement with changes in DXA FFM (r=0.54, SEE=1.5%,

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature.

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks

Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD

Science- and Engineering-Related Ethics and Values Studies: Characteristics of an Emerging Field of Research

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68834/2/10.1177_016224399001500109.pd

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License