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BACKGROUND: Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis. OBJECTIVE: To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. METHODS: Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined. RESULTS: Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. CONCLUSION: LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over- and under-diagnosis before LDL-C adjustments for Lp(a) can be recommended.

This article illuminates the dynamics of two of the most significant yet neglected youth subcultures of the late twentieth century: football’s casual culture and the acid house scene. Through the lens of two influential fanzines, Liverpool’s The End and London’s Boy’s Own I make a series of arguments about the relationship between ‘popular individualism’, emotion, and working-class communities. I argue that while conceptualizing the fanzines as ‘emotional communities’ can yield important insights about the role of feelings such as nostalgia in bonding people together, gendered sensibilities and satirical frameworks need to be taken into account in order to fully understand the subcultural affinities that the fanzines engendered. The framework of ‘popular individualism’ on the other hand can help to illuminate the tensions between individualism and collective belonging at a number of levels which the article discusses. The article concludes by noting that the analysis of these neglected subcultures offers fruitful ways of reconceptualizing community and belonging in a period when traditional forms of working-class organization were in decline.

Using an expert consensus-based approach, a netball video analysis consensus (NVAC) group of researchers and practitioners was formed to develop a video analysis framework of descriptors and definitions of physical, technical and contextual aspects for netball research. The framework aims to improve the consistency of language used within netball investigations. It also aims to guide injury mechanism reporting and identification of injury risk factors. The development of the framework involved a systematic review of the literature and a Delphi process. In conjunction with commercially used descriptors and definitions, 19 studies were used to create the initial framework of key descriptors and definitions in netball. In a two round Delphi method consensus, each expert rated their level of agreement with each of the descriptors and associated definition on a 5-point Likert scale (1—strongly disagree; 2—somewhat disagree; 3—neither agree nor disagree; 4—somewhat agree; 5—strongly agree). The median (IQR) rating of agreement was 5.0 (0.0), 5.0 (0.0) and 5.0 (0.0) for physical, technical and contextual aspects, respectively. The NVAC group recommends usage of the framework when conducting video analysis research in netball. The use of descriptors and definitions will be determined by the nature of the work and can be combined to incorporate further movements and actions used in netball. The framework can be linked with additional data, such as injury surveillance and microtechnology data.

Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

OBJECTIVES: Describe the highest frequency and variability for tackle events in rugby league. Investigate seasonal differences in total tackle events per match over a seven-year period. DESIGN: Retrospective observational. METHODS: Tackle events (i.e., ball carrier events [attacker] and tackler involvements [defender]) from 864 male professional rugby league players competing in 1176 Super League matches from 2014 to 2020 were included. A series of linear mixed effect models were used to determine the frequency and variability during peak 1-, 3-, 5-, 10-, 20-, 40-min and whole-match tackle events per player per match at a positional group level. Differences between seasons for the total number of tackle events per match were compared using a one-way analysis of variance and with Tukey's honestly significant difference test. RESULTS: Tackle events were greatest for Props (51.5 [47.7-55.4] per match). Within-players, between-matches, and between-seasons variability was

This article identifies an argument in Hobbes’s writings often overlooked but relevant to current philosophical debates. Political philosophers tend to categorize his thought as representing consent or rescue theories of political authority. Though these interpretations have textual support and are understandable, they leave out one of his most compelling arguments – what we call the lesser evil argument for political authority, expressed most explicitly in Chapter 20 of Leviathan. Hobbes frankly admits the state’s evils but appeals to the significant disparity between those evils and the greater evils outside the state as a basis for political authority. More than a passing observation, aspects of the lesser evil argument appear in each of his three major political works. In addition to outlining this argument, the article examines its significance both for Hobbes scholarship and recent philosophical debates on political authority.

Purpose: To examine the effect of fast- versus slow-speed eccentric-muscle-action resistance training on lower-body strength, vertical jump height, sprint speed, and change-of-direction performance in elite soccer players during a competitive season. Methods: Twenty-two elite soccer players, from a single team, were randomly assigned to groups that undertook either 1- (fast speed) or 4-second (slow speed) eccentric resistance training during the in-season period. A 5-week program was conducted during an elite top-division European League soccer season. Performance measures including predicted 1-repetition-maximum back squat, countermovement jump, 20-m sprint, and change of direction were tested before and after the intervention period. Total match and training running distance and muscle soreness were also recorded during each week of the intervention. Results: An analysis of covariance showed significant group effects (P = .01) for countermovement jump with a greater jump height in the 1-second fast-speed group postintervention (95% CI, 1.1–6.9 cm). Despite an overall increase in 1-repetition maximum pretraining to posttraining (95% CI, 10.0–15.3 kg, effect size 0.69), there were no significant differences (P > .05) between groups after the intervention. Similarly, there were no differences between groups for change of direction, 20-m sprint, or muscle soreness. Conclusion: Faster eccentric muscle actions may be superior for increasing movements in elite soccer players in-season.

Counselling and psychotherapy training often incorporates experiential learning to help students understand and explore different aspects of self. Lecturers and tutors, facilitating such courses, can also share aspects of their lived experience, as a form of experiential learning. This article describes a workshop on power and anti-oppressive practice that was delivered to counselling students in a Master of Arts (MA) in Counselling and Psychotherapy Practice. Two lecturers (Beverley and Peter) used their lived experiences of racism and homophobia to stimulate student discussion and debate—effectively, they were using self as a teaching tool. This article details their experiences and reflections whilst in discussion with two students (Ann-Marie and Ben), who attended the workshop.

This study aimed to 1) develop a consensus (≥70% agreement between experts) on injury risk factors specific to women playing rugby league, 2) establish the importance of the identified injury risk factors and the feasibility of mitigating these risk factors and 3) establish context specific barriers to injury risk management. Aim 1: A Delphi panel, consisting of 12 experts in rugby league and injury (e.g., physiotherapists, research scientists) were asked to identify injury risk factors specific to women playing rugby league. Aim 2: seven coaches of women's rugby league teams were asked to rate each risk factor that achieved consensus by their importance and feasibility to manage. Aim 3: Coaches reported barriers which restrict injury risk factor mitigation. Of the 53 injury risk factors which achieved consensus, the five injury risk factors with the highest combination of importance and feasibility ratings were: "poor tackle technique", "a lack of pre-season intensity", "training session are too short", "the current medical standards", and "limited access to physiotherapists". Following the identification of injury risk factors, their feasibility to manage and context specific barriers, this study proposes three constraint driven, integrated solutions which may reduce the barriers which limit injury risk factor management.

Purpose: Sleep is recognized as an important recovery strategy, yet little is known regarding its impact on postmatch fatigue. The aims of this study were to (1) describe sleep and postmatch fatigue, (2) understand how sleep is affected by contextual and match factors, and (3) assess how changes in sleep can affect postmatch fatigue. Methods: Twenty-three male rugby union players were monitored across 1 season (N = 71 player–match observations). Actigraphy was used during preseason to establish baseline sleep quality and quantity. Sleep was then measured 1 and 2 days after each match day (MD + 1 and MD + 2). Global positioning systems, notational analysis, and rating of perceived exertion represented external and internal load from matches. Subjective wellness and a standardized run were used to characterize postmatch fatigue 2 days prior (baseline) and at MD + 1 and MD + 2. Linear mixed models established the magnitude of change (effect size [ES]) between baseline, MD + 1, and MD + 2 for sleep and postmatch fatigue. Stepwise forward selection analysis ascertained the effect of match load on sleep and the effect of sleep on postmatch fatigue. Each analysis was combined with magnitude-based decisions. Results: Sleep characteristics and neuromuscular and perceptual postmatch fatigue were negatively affected at MD + 1 and MD + 2 (ES = small to very large). Kickoff and travel time had the greatest effect on sleep (ES = small). Wellness and soreness were influenced by sleep (fall-asleep time and fragmentation index) and collisions, respectively (ES = small). Conclusion: Sleep quality and quantity were affected independently of the match load (ie, running activity) sustained, and changes in sleep marginally affected postmatch fatigue.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell–specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5′-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R–targeting therapeutics.

Aim To determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations. Materials and Methods This study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4–based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling. Conclusion The results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-type 2 diabetes therapies with optimized downstream kinomic profiles.

Background With the increasing professionalisation of youth sports, training load monitoring is increasingly common in adolescent athletes. However, the research examining the relationship between training load and changes in physical qualities, injury, or illness in adolescent athletes is yet to be synthesised in a systematic review. Objective The aim of this review was to systematically examine the research assessing internal and external methods of monitoring training load and physical qualities, injury, or illness in adolescent athletes. Methods Systematic searches of SPORTDiscus, Web of Science, CINAHL and SCOPUS were undertaken from the earliest possible records to March 2022. Search terms included synonyms relevant to adolescents, athletes, physical qualities, injury, or illness. To be eligible for inclusion, articles were required to (1) be original research articles; (2) be published in a peer-reviewed journal; (3) include participants aged between 10 and 19 years and participating in competitive sport; (4) report a statistical relationship between a measure of internal and/or external load and physical qualities, injury or illness. Articles were screened and assessed for methodological quality. A best-evidence synthesis was conducted to identify trends in the relationships reported. Results The electronic search yielded 4125 articles. Following screening and a review of references, 59 articles were included. The most commonly reported load monitoring tools were session ratings of perceived exertion (n = 29) and training duration (n = 22). Results of the best-evidence synthesis identified moderate evidence of positive relationships between resistance training volume load and improvement in strength, and between throw count and injury. However, evidence for other relationships between training load and change in physical qualities, injury, or illness were limited or inconsistent. Conclusions Practitioners should consider monitoring resistance training volume load for strength training. Additionally, where appropriate, monitoring throw counts may be useful in identifying injury risk. However, given the lack of clear relationships between singular measures of training load with physical qualities, injury, or illness, researchers should consider multivariate methods of analysing training load, as well as factors that may mediate the load–response relationship, such as maturation.

In this paper we report the progress of our SiC trench etch development using enhanced ICP-based etch technology. Computer modelling of the electric field strength in the gate oxide as a function of corner geometry was used to illustrate trench corner rounding as an effective method to avoid to high gate oxide field strengths. This is an effort to examine a major ongoing issue in device reliability, and to govern future device design.

Objective: This study aimed to investigate the prevalence of self-reported shoulder dysfunction using the Rugby Shoulder Score (RSS) reported in arbitrary units (AU) of rugby players available for match selection (uninjured). Design: Cross-sectional survey. Methods: Paper survey at the mid-point of the season of uninjured players (n = 86 males (mean age (±SD): 26 ± 6.9y) from 8 squads (professional n = 34; amateur; n = 52)), using the RSS, subjective impact on rugby performance and previous shoulder injury, analysed using a Mann-Whitney U test. Results: 55% of players reported a level of RSS dysfunction despite being uninjured. Players who also reported their shoulder was impacting on performance had significantly higher median RSS (61, IQR 28AU, p = 0.02) than those who reported no impact on performance (40, IQR 22AU). Conclusions: Findings from this study show that over half of players were playing with a level of self-reported shoulder dysfunction. This figure is higher in the professional game, for those with a history of previous injury and for forwards.

Deuteration enhances photophysical and chemical properties of fluorescent rhodamine dyes for higher brightness in sensitive microscopy.

AimTo determine the kinase activity profiles of human pancreatic beta cells downstream of GLP-1R balancedversusbiased agonist stimulations.Materials and methodsThis study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and glucagon-like peptide-1 receptor (GLP-1R) stimulation with the pharmacological agonist exendin-4, as well as exendin-4-based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute)versussustained (120-minute) responses, using PamChip® protein tyrosine kinase (PTK) and serine/threonine kinase (STK) assays. The raw data were filtered and normalised using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.ResultsThe present analysis reveals that kinomic responses are distinct for acuteversussustained GLP-1R agonist (GLP-1RA) exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling.ConclusionResults from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-T2D therapies with optimised downstream kinomic profiles.

The aim of this study was to investigate the prevalence of oral contraceptive use in domestic rugby union, to compare symptomology by contraceptive use, and to determine symptom management strategies. Additionally, to characterise the perceived influence of oral contraceptive use and non-use on wellness and performance. A total of 238 Premiership and Championship women's rugby union players completed an online questionnaire. The survey was comprised of questions relating to player characteristics, hormonal or non-hormonal contraceptive characteristics, perceived symptomology, symptom management strategies, and performance and wellness characteristics. The prevalence of oral contraceptive users was 26%. Non-hormonal contraceptive users reported greater perceived negative symptomology (i.e., back pain, nausea, sore breasts) and performance and wellness effects (i.e., fatigue, stress, mood, concentration, power, match-play) than oral contraceptive users. The most common symptom management strategies were medication (33%), nutritional interventions (20%), and training modulation (20%). Twelve percent of players had previously spoken to staff about their menstrual cycle (i.e., regular and irregular) or contraceptive use. The most common barriers to speaking to staff were 'male staff' (29%) and 'club culture' (24%). The importance of assisting non-hormonal contraceptive users in managing symptoms is evident. Emphasis on overcoming barriers to staff-player dialogue regarding menstrual/contraceptive cycle is required.

This study quantified the position-, duration-, and phase-of-play specific peak locomotor characteristics of senior professional rugby league match-play at a multi-club level. Match-play data were ...

Determining key performance indicators and classifying players accurately between competitive levels is one of the classification challenges in sports analytics. A recent study applied Random Forest algorithm to identify important variables to classify rugby league players into academy and senior levels and achieved 82.0% and 67.5% accuracy for backs and forwards. However, the classification accuracy could be improved due to limitations in the existing method. Therefore, this study aimed to introduce and implement feature selection technique to identify key performance indicators in rugby league positional groups and assess the performances of six classification algorithms. Fifteen and fourteen of 157 performance indicators for backs and forwards were identified respectively as key performance indicators by the correlation-based feature selection method, with seven common indicators between the positional groups. Classification results show that models developed using the key performance indicators had improved performance for both positional groups than models developed using all performance indicators. 5-Nearest Neighbour produced the best classification accuracy for backs and forwards (accuracy = 85% and 77%) which is higher than the previous method's accuracies. When analysing classification questions in sport science, researchers are encouraged to evaluate multiple classification algorithms and a feature selection method should be considered for identifying key variables.

ObjectiveThe reduction in circulating low-density lipoprotein cholesterol (LDL-c) is the primary aim of lipid-lowering therapies as a method of atherosclerotic cardiovascular disease risk reduction. Inclisiran is a new and potent lipid-lowering drug that is shown to be effective in reducing LDL-c in randomised controlled trials, however, real-world data of its use are not yet known. We sought to analyse the early effects of this drug in a tertiary centre lipid and cardiovascular risk clinic.MethodsWe performed a retrospective analysis of the first 80 patients who received a single dose of inclisiran at our lipid clinic between 1 December 2021 and 1 September 2022. Data were collected using electronic healthcare records. Baseline blood tests were taken prior to start of treatment and were repeated at 2 months follow-up. Data on adverse events were also recorded.ResultsAt 2 months after treatment initiation, mean baseline LDL-c fell from 3.5±1.1 mmol/L by 48.6% to 1.8±1.0 mmol/L and total cholesterol from 5.7±1.3 mmol/L by 33.3% to 3.8±1.1 mmol/L (both pConclusionInclisiran use in line with National Institute for Health and Care Excellence guidelines led to significant lowering of LDL-c at 2 months, with efficacy similar to that reported in trials with good tolerability.

Pinnatoxin G is a cyclic imine neurotoxin produced by dinoflagellates that has been reported in shellfish. Like other members of the pinnatoxin family, it has been shown to have its effects via antagonism of the nicotinic acetylcholine receptors, with preferential binding to the α7 subunit often upregulated in cancer. Because increased activity of α7 nicotinic acetylcholine receptors contributes to increased growth and resistance to apoptosis, the effect of pinnatoxin G on cancer cell viability was tested. In a panel of six cancer cell lines, all cell types lost viability, but HT29 colon cancer and LN18 and U373 glioma cell lines were more sensitive than MDA-MB-231 breast cancer cells, PC3 prostate cancer cells, and U87 glioma cells, correlating with expression levels of α7, α4, and α9 nicotinic acetylcholine receptors. Some loss of cell viability could be attributed to cell cycle arrest, but significant levels of classical apoptosis were found, characterized by caspase activity, phosphatidylserine exposure, mitochondrial membrane permeability, and fragmented DNA. Intracellular Ca2+ levels also dropped immediately upon pinnatoxin G treatment, which may relate to antagonism of nicotinic acetylcholine receptor-mediated Ca2+ inflow. In conclusion, pinnatoxin G can decrease cancer cell viability, with both cytostatic and cytotoxic effects.

Despite the importance and complexity of developing sprint performance in football code athletes, there are limited studies exploring practitioners’ practices to improves Sprinting. Therefore, this study aimed to describe and evaluate the practices used with elite football code athletes to develop sprint performance. Ninety subjects completed a survey comprised of four sections (coaching demographic, evaluation of training, organisation of training, and training protocols). Survey responses showed that 98% of practitioners monitor sprint performance, and 92% integrated monitoring strategies into sprint development programmes to inform training. All practitioners used combined training methods including specific (e.g., sprints with or without overload) and non-specific (e.g., strength training or plyometrics) methods targeting the underpinning determinants of sprint performance. Most practitioners reported prescribing 1–3 or 2–4 days · wk−1 for sprint development, both in-season and pre-season. Sprint development programmes were uncommon in the off-season. Most specific sprint training sessions were reportedly shorter in duration (5–15 and 15–30min) than non-specific sprint training methods (30–45 and >45min) irrespective of the season phases. Sprint development was integrated before and after sport-specific training, regularly using warm-ups and gym sessions. Specific training methods were also implemented in separate sessions. The specific content (e.g., exercise selection, training load prescription) was highly variable between practitioners. This study represents the first detailed survey (practices and justification) of sprint development practices (evaluation and organisation of training protocols) in football code cohorts. These findings present multiple methods of structuring, integrating and manipulating sprint training based on the training aims and the individual context.

The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), are class B GPCRs and prime therapeutic targets for the treatment of type 2 diabetes (T2D) and obesity. They are expressed in pancreatic beta cells where they potentiate insulin release in response to food intake. Despite GIP being the main incretin in healthy individuals, GLP-1R has been favoured versus GIPR as a therapeutic target due to GIPR responses being blunted in T2D patients and the conflicting effects of GIPR agonists and antagonists in improving glucose tolerance and preventing weight gain. There is, however, a recently renewed interest in GIPR biology following the realisation that GIPR responses can be restored after an initial period of blood glucose normalization and the recent development of dual GLP-1R-GIPR agonists with superior capacity for the control of blood glucose levels and weight. The importance of GLP-1R trafficking and subcellular signaling in the control of receptor outputs is well established, but little is known about the pattern of spatiotemporal signaling from the GIPR in beta cells. Here we have directly compared the main trafficking and signaling characteristics of both receptors in pancreatic beta cells, finding striking differences in their propensities for internalization, recycling, and degradation, as well as plasma membrane versus endosomal activity, with potential implications for receptor-specific control of beta cell function.

Darrall-Jones, J, Roe, G, Cremen, E, and Jones, B. Can team-sport athletes accurately run at submaximal sprinting speeds? Implications for rehabilitation and warm-up protocols. J Strength Cond Res 36(8): 2218-2222, 2022-The aim of this study is to examine the ability of team-sport athletes to accurately run at a range of submaximal sprint velocities (60-90% maximal velocity; Vmax) under verbal instruction without any objective feedback. Twelve professional male rugby union players (age 19.7 ± 0.9 years, body mass 98.3 ± 13.9 kg, height 184.0 ± 7.5 cm) were verbally instructed to complete three 40-m sprints at each of 60, 70, 80, and 90% of Vmax in a randomized order. Percentage Vmax achieved during each sprint was compared with criterion velocities calculated from Vmax testing undertaken a week prior. Players underestimated (ran faster) their sprint velocity when asked to run at 60% (very large to extremely large mean bias, 23%; range, 57-88% Vmax), 70% (large to very large, 11%; 67-93% Vmax), and 80% (small, 2%; 71-91% Vmax) of their Vmax, whereas overestimated (ran slower) their sprint velocity when asked to run at 90% Vmax (moderate, -4%; 77-95% Vmax). Team sport players may require objective feedback when performing submaximal sprinting to ensure that velocities achieved are similar to those prescribed. This may be particularly important where graded exposure to maximum velocities is required, for example during rehabilitation or warm-ups.

Control of tropical theileriosis, caused by the apicomplexan Theileria annulata, depends on the use of a single drug, buparvaquone, the efficacy of which is compromised by the emergence of resistance. The present study was undertaken to improve understanding of the role of mutations conferring buparvaquone resistance in T. annulata, and the effects of selection pressures on their emergence and spread. First, we investigated genetic characteristics of the cytochrome b locus associated with buparvaquone resistance in 10 susceptible and 7 resistant T. annulata isolates. The 129G (GGC) mutation was found in the Q01 binding pocket and 253S (TCT) and 262S (TCA) mutations were identified within the Q02 binding pocket. Next, we examined field isolates and identified cytochrome b mutations 129G (GGC), 253S (TCT) and 262S (TCA) in 21/75 buffalo-derived and 19/119 cattle-derived T. annulata isolates, providing evidence of positive selection pressure. Both hard and soft selective sweeps were identified, with striking differences between isolates. For example, 19 buffalo-derived and 7 cattle-derived isolates contained 129G (GGC) and 253S (TCT) resistance haplotypes at a high frequency, implying the emergence of resistance by a single mutation. Two buffalo-derived and 12 cattle-derived isolates contained equally high frequencies of 129G (GGC), 253S (TCT), 129G (GGC)/253S (TCT) and 262S (TCA) resistance haplotypes, implying the emergence of resistance by pre-existing or recurrent mutations. Phylogenetic analysis further revealed that 9 and 21 unique haplotypes in buffalo and cattle-derived isolates were present in a single lineage, suggesting a single origin. We propose that animal migration between farms is an important factor in the spread of buparvaquone resistance in endemic regions of Pakistan. The overall outcomes will be useful in understanding how drug resistance emerges and spreads, and this information will help design strategies to optimise the use and lifespan of the single most drug use to control tropical theileriosis.

Glucagon-like peptide-1 receptor (GLP-1R) is a well-studied incretin hormone receptor and target of several therapeutic drugs for type 2 diabetes (T2D), obesity and, more recently, cardiovascular disease. Some signalling pathways downstream of GLP-1R may be responsible for drug adverse effects such as nausea, while others mediate therapeutic outcomes of incretin-based T2D therapeutics. Understanding the interplay between different factors that alter signalling, trafficking, and receptor activity, including biased agonism, single nucleotide polymorphisms and structural modifications is key to develop the next-generation of personalised GLP-1R agonists. However, these interactions remain poorly described, especially for novel therapeutics such as dual and tri-agonists that target more than one incretin receptor. Comparison of GLP-1R structures in complex with G proteins and different peptide and non-peptide agonists has revealed novel insights into important agonist-residue interactions and networks crucial for receptor activation, recruitment of G proteins and engagement of specific signalling pathways. Here, we review the latest knowledge on GLP-1R structure and activation, providing structural evidence for biased agonism and delineating important networks associated with this phenomenon. We survey current biased agonists and multi-agonists at different stages of development, highlighting possible challenges in their translational potential. Lastly, we discuss findings related to non-synonymous genomic variants of GLP1R and the functional importance of specific residues involved in GLP-1R function. We propose that studies of GLP-1R polymorphisms, and specifically their effect on receptor dynamics and pharmacology in response to biased agonists, could have a significant impact in delineating precision medicine approaches and development of novel therapeutics.