Passing on the exercise baton: What can endocrine patients learn from elite athletes?

As elite athletes demonstrate through the Olympic motto ‘citius, altius, fortius’, new performance records are driven forward by favourable skeletal muscle bioenergetics, cardiorespiratory, and endocrine system adaptations. At a recreational level, regular physical activity is an effective non-pharmacological therapy in the treatment of many endocrine conditions. However, the impact of physical exercise on endocrine function and how best to incorporate exercise therapy into clinical care are not well understood. Beyond the pursuit of an Olympic medal, elite athletes may therefore serve as role models for showcasing how exercise can help in the management of endocrine disorders and improve metabolic dysfunction.This review summarises research evidence for clinicians who wish to understand endocrine changes in athletes who already perform high levels of activity as well as to encourage patients to exercise more safely. Herein, we detail the upper limits of athleticism to showcase the adaptability of human endocrine-metabolic-physiological systems. Then, we describe the growing research base that advocates the importance of understanding maladaptation to physical training and nutrition in males and females; especially the young. Finally, we explore the impact of physical activity in improving some endocrine disorders with guidance on how lessons can be taken from athletes training and incorporated into strategies to move more people more often

Response to Qian and Colvin : zinc-mediated regulation of the cardiac ryanodine receptor occurs via multiple binding sites

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The 8q24 Gene Desert: An Oasis of Non-Coding Transcriptional Activity

Understanding the functional effects of the wide-range of aberrant genetic characteristics associated with the human chromosome 8q24 region in cancer remains daunting due to the complexity of the locus. The most logical target for study remains the MYC proto-oncogene, a prominent resident of 8q24 that was first identified more than a quarter of a century ago. However, many of the amplifications, translocation breakpoints, and viral integration sites associated with 8q24 are often found throughout regions surrounding large expanses of the MYC locus that include other transcripts. In addition, chr.8q24 is host to a number of single nucleotide polymorphisms associated with cancer risk. Yet, the lack of a direct correlation between cancer risk alleles and MYC expression has also raised the possibility that MYC is not always the target of these genetic associations. The 8q24 region has been described as a “gene desert” because of the paucity of functionally annotated genes located within this region. Here we review the evidence for the role of other loci within the 8q24 region, most of which are non-coding transcripts, either in concert with MYC or independent of MYC, as possible candidate gene targets in malignancy

Improved Nocturnal Glycaemia and Reduced Insulin Use Following Clinical Exercise Trial Participation in Individuals With Type 1 Diabetes

Aim: To explore the influence of clinical exercise trial participation on glycaemia and insulin therapy use in adults with type 1 diabetes (T1D). Research Design and Methods: This study involved a secondary analysis of data collected from 16 individuals with T1D who completed a randomized clinical trial consisting of 23-h in-patient phases with a 45-min evening bout of moderate intensity continuous exercise. Participants were switched from their usual basal-bolus therapy to ultra-long acting insulin degludec and rapid-acting insulin aspart as well as provided with unblinded interstitial flash-glucose monitoring systems. To assess the impact of clinical trial participation, weekly data obtained at the screening visit (pre-study involvement) were compared against those collated on the last experimental visit (post-study involvement). Interstitial glucose [iG] data were split into distinct glycaemic ranges and stratified into day (06:00–23:59) and night (00:00–05:59) time periods. A p-value of ≤ 0.05 was accepted for significance. Results: Following study completion, there were significant decreases in both the mean nocturnal iG concentration (Δ-0.9 ± 4.5 mmol.L−1, p < 0.001) and the time spent in severe hyperglycaemia (Δ-7.2 ± 9.8%, p = 0.028) during the night-time period. The total daily (Δ-7.3 ± 8.4 IU, p = 0.003) and basal only (Δ-2.3 ± 3.8 IU, p = 0.033) insulin dose requirements were reduced over the course of study involvement. Conclusions: Participation in clinical research may foster improved nocturnal glycaemia and reduced insulin therapy use in people with T1D. Recognition of these outcomes may help encourage volunteers to partake in clinical research opportunities for improved diabetes-related health outcomes. Clinical Trial Registration: DRKS.de; DRKS00013509

Experimental Measurements of the Shapes Adopted by Textiles when Subject to Wind Loading

An investigation of the behaviour of Nylon and Polyester textiles subjected to wind loading was undertaken in an experimental study. Variable parameters of wind speed, incidence and excess length of the textiles were studied. As expected, increasing wind speeds and amount of slackness led to higher deflections above 4 degrees incidence. Below this angle large instabilities are found. Polyester with a higher air permeability, experienced greater levels of eflection at low slackness when compared to the Nylon. Only small differences in deflection were found between the textiles when using higher slackness ratios

Human-Robot Team Performance Compared to Full Robot Autonomy in 16 Real-World Search and Rescue Missions: Adaptation of the DARPA Subterranean Challenge

Human operators in human-robot teams are commonly perceived to be critical for mission success. To explore the direct and perceived impact of operator input on task success and team performance, 16 real-world missions (10 hrs) were conducted based on the DARPA Subterranean Challenge. These missions were to deploy a heterogeneous team of robots for a search task to locate and identify artifacts such as climbing rope, drills and mannequins representing human survivors. Two conditions were evaluated: human operators that could control the robot team with state-of-the-art autonomy (Human-Robot Team) compared to autonomous missions without human operator input (Robot-Autonomy). Human-Robot Teams were often in directed autonomy mode (70% of mission time), found more items, traversed more distance, covered more unique ground, and had a higher time between safety-related events. Human-Robot Teams were faster at finding the first artifact, but slower to respond to information from the robot team. In routine conditions, scores were comparable for artifacts, distance, and coverage. Reasons for intervention included creating waypoints to prioritise high-yield areas, and to navigate through error-prone spaces. After observing robot autonomy, operators reported increases in robot competency and trust, but that robot behaviour was not always transparent and understandable, even after high mission performance.Comment: Submitted to Transactions on Human-Robot Interactio

Personalised Drug Identifier for Cancer Treatment with Transformers using Auxiliary Information

Cancer remains a global challenge due to its growing clinical and economic burden. Its uniquely personal manifestation, which makes treatment difficult, has fuelled the quest for personalized treatment strategies. Thus, genomic profiling is increasingly becoming part of clinical diagnostic panels. Effective use of such panels requires accurate drug response prediction (DRP) models, which are challenging to build due to limited labelled patient data. Previous methods to address this problem have used various forms of transfer learning. However, they do not explicitly model the variable length sequential structure of the list of mutations in such diagnostic panels. Further, they do not utilize auxiliary information (like patient survival) for model training. We address these limitations through a novel transformer based method, which surpasses the performance of state-of-the-art DRP models on benchmark data. We also present the design of a treatment recommendation system (TRS), which is currently deployed at the National University Hospital, Singapore and is being evaluated in a clinical trial

Metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes

Introduction This study sought to compare the metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes (T1D).Research design and methods Thirteen individuals with T1D (hemoglobin; 7.0%±1.3% (52.6±13.9 mmol/mol), age; 36±15 years, duration diabetes; 15±12 years) performed a maximum of 45 min submaximal exercise (60%±6% V̇O2max). Retrospectively identified exercise sessions that ended in hypoglycemia ((HypoEx) blood glucose (BG)≤3.9 mmol/L) were compared against a participant-matched euglycemic condition ((EuEx) BG≥4.0, BG≤10.0 mmol/L). Samples were compared for detailed physiological and hormonal parameters as well as metabolically profiled via large scale targeted ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. Data were assessed using univariate and multivariate analysis techniques with false discovery rate adjustment. Significant results were considered at p≤0.05.Results Cardiorespiratory and counterregulatory hormone responses, whole-body fuel use and perception of fatigue during exercise were similar under conditions of hypoglycemia and euglycemia (BG 3.5±0.3 vs 5.8±1.1 mmol/L, respectively p<0.001). HypoEx was associated with greater adenosine salvage pathway activity (5’-methylthioadenosine, p=0.023 and higher cysteine and methionine metabolism), increased utilization of glucogenic amino acids (glutamine, p=0.021, alanine, aspartate and glutamate metabolism and homoserine/threonine, p=0.045) and evidence of enhanced β-oxidation (lower carnitine p<0.001, higher long-chain acylcarnitines).Conclusions Exposure to acute hypoglycemia during exercise potentiates alterations in subclinical indices of metabolic stress at the level of the metabolome. However, the physiological responses induced by dynamic physical exercise may mask the symptomatic recognition of mild hypoglycemia during exercise in people with T1D, a potential clinical safety concern that reinforces the need for diligent glucose management

Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells

<p>Abstract</p> <p>Background</p> <p>Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival.</p> <p>Results</p> <p>A small-scale RNAi screen of ~400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently <it>CASP8AP2</it>/<it>FLASH</it>. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of <it>CASP8AP2</it>/<it>FLASH </it>resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of <it>CASP8AP2</it>/<it>FLASH </it>also mediated enrichment of changes in the expression of targets of the NFκB and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of <it>CASP8AP2</it>/<it>FLASH </it>silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/ß-catenin pathway.</p> <p>Conclusions</p> <p>We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene <it>NEFH</it>.</p

Resistance isn't futile: the physiological basis of the health effects of resistance exercise in individuals with type 1 diabetes

The importance of regular exercise for glucose management in individuals with type 1 diabetes is magnified by its acknowledgment as a key adjunct to insulin therapy by several governmental, charitable, and healthcare organisations. However, although actively encouraged, exercise participation rates remain low, with glycaemic disturbances and poor cardiorespiratory fitness cited as barriers to long-term involvement. These fears are perhaps exacerbated by uncertainty in how different forms of exercise can considerably alter several acute and chronic physiological outcomes in those with type 1 diabetes. Thus, understanding the bodily responses to specific forms of exercise is important for the provision of practical guidelines that aim to overcome these exercise barriers. Currently, the majority of existing exercise research in type 1 diabetes has focused on moderate intensity continuous protocols with less work exploring predominately non-oxidative exercise modalities like resistance exercise. This is surprising, considering the known neuro-muscular, osteopathic, metabolic, and vascular benefits associated with resistance exercise in the wider population. Considering that individuals with type 1 diabetes have an elevated susceptibility for complications within these physiological systems, the wider health benefits associated with resistance exercise may help alleviate the prevalence and/or magnitude of pathological manifestation in this population group. This review outlines the health benefits of resistance exercise with reference to evidence in aiding some of the common complications associated with individuals with type 1 diabetes