Glycogen-fuelled metabolism supports rapid mucosal-associated invariant T cell responses.

Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells which recognize a limited repertoire of ligands presented by the MHC class-I like molecule MR1. In addition to their key role in host protection against bacterial and viral pathogens, MAIT cells are emerging as potent anti-cancer effectors. With their abundance in human, unrestricted properties, and rapid effector functions MAIT cells are emerging as attractive candidates for immunotherapy. In the current study, we demonstrate that MAIT cells are potent cytotoxic cells, rapidly degranulating and inducing target cell death. Previous work from our group and others has highlighted glucose metabolism as a critical process for MAIT cell cytokine responses at 18 h. However, the metabolic processes supporting rapid MAIT cell cytotoxic responses are currently unknown. Here, we show that glucose metabolism is dispensable for both MAIT cell cytotoxicity and early (<3 h) cytokine production, as is oxidative phosphorylation. We show that MAIT cells have the machinery required to make (GYS-1) and metabolize (PYGB) glycogen and further demonstrate that that MAIT cell cytotoxicity and rapid cytokine responses are dependent on glycogen metabolism. In summary, we show that glycogen-fueled metabolism supports rapid MAIT cell effector functions (cytotoxicity and cytokine production) which may have implications for their use as an immunotherapeutic agent.

Genetic Associations With Acceleration, Change of Direction, Jump Height, and Speed in English Academy Football Players.

ABSTRACT: McAuley, ABT, Hughes, DC, Tsaprouni, LG, Varley, I, Suraci, B, Bradley, B, Baker, J, Herbert, AJ, and Kelly, AL. Genetic associations with acceleration, change of direction, jump height, and speed in English academy football players. J Strength Cond Res 38(2): 350-359, 2024-High-intensity movements and explosive actions are commonly assessed during athlete development in football (soccer). Although many environmental factors underpin these power-orientated traits, research suggests that there is also a sizeable genetic component. Therefore, this study examined the association of 22 single-nucleotide polymorphisms (SNPs) with acceleration, change of direction, jump height, and speed in academy football players. One hundred and forty-nine, male, under-12 to under-23 football players from 4 English academies were examined. Subjects performed 5-, 10-, 20-, and 30-m sprints, countermovement jumps (CMJs), and the 5-0-5 agility test. Simple linear regression was used to analyze individual SNP associations, whereas both unweighted and weighted total genotype scores (TGS; TWGS) were computed to measure the combined influence of all SNPs. To control for multiple testing, a Benjamini-Hochberg false discovery rate of 0.05 was applied to all genotype model comparisons. In isolation, the GALNT13 (rs10196189) G allele and IL6 (rs1800795) G/G genotype were associated with faster (∼4%) 5-, 10-, and 20-m sprints and higher (∼16%) CMJs, respectively (p < 0.001). Furthermore, the TGS and TWGS significantly correlated with all performance assessments, explaining between 6 and 33% of the variance (p < 0.001). This study demonstrates that some genetic variants are associated with power-orientated phenotypes in youth football players and may add value toward a future polygenic profile of physical performance.

Can we reduce injury risk during the adolescent growth spurt? An iterative sequence of prevention in male academy footballers.

Background: The adolescent growth spurt is associated with an increased risk of injury in young athletes.Aim: This study aimed to use an interdisciplinary collaboration between technical coaches, sports scientists, and medical staff to mitigate this risk.Subjects and methods: 77 male academy footballers were followed across two seasons. At-risk players were identified using somatic maturity status and growth rate in stature and the lower limbs, using thresholds of 88% to 92.8% of predicted adult stature, ≥7.2 cm/year, and ≥3.6 cm/year, respectively. During the 2019-20 season, players with symptoms of a growth-related injury or two of three risk factors were included in an intervention strategy that included modified training load, football-specific skills, balance, coordination and landing drills, and an individualised strength program.Results: For players with the three risk factors, there was a significant reduction in the incidence (rate ratio [RR] = 0.14 (5.2 per 1000h → 0.8 per 1000h, p = 0.05) and burden (RR = 0.08 (216 per 1000h → 17 per 1000h, p = 0.02) between the seasons. For players with ≤2 risk factors, there were no significant differences in injury risk between the baseline and intervention seasons.Conclusion: Overall, it may be possible to mitigate injury incidence and burden during the adolescent growth spurt in high-risk athletes.

The influence of exposure, growth and maturation on injury risk in male academy football players.

Adolescence is a period of increased injury risk in youth footballers; however, no studies have considered the influence of growth-related factors and exposure time upon injury risk. Forty-nine elite male youth footballers were prospectively monitored for growth, lower-limb growth, maturation, training volume and injury for one season. Generalised linear mixed-effects models were used to model growth rate, lower-limb growth rate, maturation, and smoothed week-to-week changes in exposure on time-loss injury risk. The relationship between growth rate and injury incidence was linear (P = 0.031) and injury burden was non-linear (P = 0.019). The relationship between lower-limb growth rate and injury incidence was linear and positive (P = 0.098). A non-linear relationship was observed between lower-limb growth rate and injury burden (P = 0.001). A non-linear relationship between Percentage of Predicted Adult Stature and both injury incidence and injury burden were found, with peak risk occurring at 92% and 95% , respectively. There was a positive linear relationship between week-to-week changeand injury incidence (P = 0.001), and a non-linear relationship between week-to-week change and injury burden (P = 0.01). Practitioners should monitor the timing and rate of the growth spurt and exposure time to identify players at greater injury risk.

Natural selection according to Darwin: cause or effect?

In the 1940s, the 'modern synthesis' (MS) of Darwinism and genetics cast genetic mutation and recombination as the source of variability from which environmental events naturally select the fittest, such 'natural selection' constituting the cause of evolution. Recent biology increasingly challenges this view by casting genes as followers and awarding the leading role in the genesis of adaptations to the agency and plasticity of developing phenotypes-making natural selection a consequence of other causal processes. Both views of natural selection claim to capture the core of Darwin's arguments in On the Origin of Species. Today, historians largely concur with the MS's reading of Origin as a book aimed to prove natural selection the cause (vera causa) of adaptive change. This paper finds the evidence for that conclusion wanting. I undertake to examine the context and meaning of all Darwin's known uses of the phrase vera causa, documenting in particular Darwin's resistance to the pressure to prove natural selection a vera causa in letters written early in 1860. His resistance underlines the logical dependence of natural selection, an unobservable phenomenon, on the causal processes producing the observable events captured by the laws of inheritance, variation, and the struggle for existence, established in Chapters 1-3 of Origin.

Bio-banding in academy football: player's perceptions of a maturity matched tournament.

Background: Individual differences in biological maturation impact player selection and development in youth football.Aim: To evaluate players perceptions of competing in a football tournament where they were matched by maturity rather than chronological age.Subjects: Participants included male junior footballers from three professional academies (n = 115).Methods: The study employed multiple methods of analysis, including one sample mean t-tests, equivalence tests, ANOVAs, and thematic analysis of qualitative data derived from open-ended questions.Results and conclusions: Player's perceived the bio-banding format as providing two main benefits. Early maturing players perceived greater physical and technical challenge, and in turn new opportunities and challenges. Late maturing players perceived less physical and technical challenge, yet greater opportunity to demonstrate technical and tactical abilities. The players reported that they enjoyed and understood the purpose of the bio-banded format, and perceived less risk for injury. Players in all three maturity groups reported more opportunity to engage in leadership behaviours, influence game-play, and express themselves on the ball in the bio-banded format. Bio-banding may facilitate development for both early and late maturing academy players by presenting new learning environments and challenges.

A Genome-Wide Association Study of Sprint Performance in Elite Youth Football Players.

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leonska-Duniec, A, Pajak, B, Chycki, J, Moska, W, Lulinska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cieszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.

BABY EMPATHY: INFANT DISTRESS AND PEER PROSOCIAL RESPONSES.

Empathy is an important competence in our social world, a motivator of prosocial behavior, and thought to develop throughout the second year of life. The current study examined infants' responses to naturalistic peer distress to explore markers of empathy and prosocial behavior in young babies. Seventeen 8-month-old infants participated in a repeated measures design using the "babies-in-groups" paradigm, with maternal presence as the independent variable. Significant differences were found between response types: Gaze was the standard response to infant distress, followed by socially directed behaviors and affect, with self-distress rarely occurring. Maternal presence was not found to impact the nature or frequency of babies' responses to peer distress. During distress episodes, babies looked preferentially at the distressed peer, then other mothers, and least to their own mother. Data revealed that infant responses to peer distress resulted in a successful cessation of that distress episode over one third of the time. Case studies are provided to illustrate the quantitative data. The results provided evidence of empathic concern and prosocial behavior in the first year of life, and provoke a challenge to developmental theories of empathy.

The effect of obesity and increasing age on operative time and length of stay in primary hip and knee arthroplasty.

We retrospectively reviewed 589 patients undergoing lower-limb arthroplasty, recording age, body mass index (BMI) and co-morbidities. The effect of these on operative duration and length of stay (LOS) was analysed. For a 1 point increase in BMI we expect LOS to increase by a factor of 2.9% and mean theatre time to increase by 1.46minutes. For a 1-year increase in age, we expect LOS to increase by a factor of 1.2%. We have calculated the extra financial costs associated. The current reimbursement system underestimates the financial impact of BMI and age. The results have been used to produce a chart that allows prediction of LOS following lower limb arthroplasty based on BMI and age. These data are of use in planning operating lists.

Early intervention treatment in the first 2 weeks following concussion in adults: A systematic review of randomised controlled trials.

OBJECTIVE: International guidelines support a repertoire of therapeutic interventions that may assist recovery following concussion. We aimed to systematically review the efficacy of early pharmacological and non-pharmacological interventions initiated within two weeks of injury on symptoms and functional recovery of adults with concussion. METHODS: We conducted a Systematic Review (SR) of Randomised Controlled Trials (RCTs) without meta-analysis utilising the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed of four databases. Study inclusion criteria were adult participants diagnosed with concussion and commencing active intervention within 14 days of injury. RESULTS AND CONCLUSIONS: Of 7531 studies identified, 11 were included in the final review. Six studies were rated as high-risk of bias, three with some concerns and two as low-risk of bias. We found no evidence to support specific pharmacotherapeutic management to hasten the natural recovery time-course. Two studies reported significant improvement in selected concussion symptoms following manual therapy (at 48-72 hours post-treatment) or telephone counselling interventions (at 6 months post-injury). No high quality RCTs demonstrate superior effects of early therapeutic interventions on concussion recovery in the first 2 weeks. We advocate future research to examine impacts of health-clinician contact points aligned with symptom-specific interventions.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.

Mechanical, Physiological, and Perceptual Demands of Repeated Power Ability Lower-Body and Upper-Body Tests in Youth Athletes: Somatic Maturation as a Factor on the Performance.

This study aims (a) to assess and compare the acute mechanical, physiological, and perceptual demands induced by a lower and upper body repeated power ability (RPA) protocols, and (b) to examine how the somatic maturation could predict training response in RPA. Thirteen young male basketball players (chronological age = 15.2 ± 1.1 years; height = 173.8 ± 9.5 cm; body mass = 71.7 ± 18.3 kg) were selected to perform the parallel Back Squat (BS), and Bench Press (BP) RPA protocols (3 blocks of 5 sets of 5 repetitions with 30 s and 3 min of passive recovery between sets and blocks, respectively). Mean propulsive power (MPP), accelerometer-based data, cardio-respiratory data, blood lactate, rate of perceived exertion (RPE) and muscle soreness were recorded. Somatic maturation was estimated according to the Khamis and Roche method. On the BS protocol, the mean oxygen uptake (VO2), heart rate (HR), and RPE were 1006.33 ± 481.85 ml/min., 133.8 ± 12.5 bpm, and 6.14 ± 0.98 A.U., while on the BP protocol, were 684.6 ± 246.3 ml/min., 96.1 ± 10.4 bpm, and 5.08 ± 1.44 A.U., respectively. Significant between-blocks differences were found for MPP, RPE, and blood lactate for both exercises. The BS implies higher cardio-respiratory and perceptual demands, though lower power production fluctuation and movement variability than the BP. The somatic maturation was a strong predictor of RPA-derived variables in BS. The MPP during all protocol, and the MPP during the Best Set were significant predictable by somatic maturation in both exercises. Mechanical, physiological and perceptual training demands are exercise and maturation dependent.

Dendritic cells interact with CD4 T cells in intestinal mucosa.

Absence of lymph nodes in nonmammalian species, expression of MHCII by APCs in the periphery, and the recent findings that T cells can change their polarization status after presentation in the lymph nodes imply a role for MHCII-mediated presentation outside the organized lymphoid tissue. This study shows that MHCII(+) ECs and DCs from the intestinal mucosa of the pig can present antigen to T cells in vitro. In vivo, APCs colocalize with T cells in pig and mouse intestinal mucosa. In the pig, endothelium is involved in these interactions in neonates but not in adults, indicating different roles for stromal and professional APCs in the neonate compared with the adult. The ratio of expression of DQ and DR MHCII locus products was lower on ECs than on other mucosal APCs, indicating that the two types of cells present different peptide sets. Adult nonendothelial APCs expressed a higher ratio of DQ/DR than in neonates. These results suggest that mucosal DCs can present antigen locally to primed T cells and that stromal APCs are recruited to these interactions in some cases. This raises the possibility that local presentation may influence T cell responses at the effector stage after initial presentation in the lymph node.

Cytokine expansion culture of cord blood CD34+ cells induces marked and sustained changes in adhesion receptor and CXCR4 expressions.

Recent studies have demonstrated defective bone marrow homing of hematopoietic stem cells after cytokine expansion culture. Adhesion receptors (ARs) are essential to the homing process, and it is possible that cytokine culture modulates AR expression. We studied changes in expression of very late antigen-4 (VLA-4), VLA-5, L-selectin, leukocyte function-associated antigen-1 (LFA-1), CD44, and the stromal cell-derived factor-1 (SDF-1) receptor, CXCR4, during cytokine culture of cord blood (CB) CD34(+) cells. Expression of ARs was studied by flow cytometry on CB CD34(+) cells in whole blood, after purification and during culture for up to 10 days. Cells were cultured with stem cell factor (SCF), thrombopoietin (TPO), Flt3-ligand (Flt3), and G-CSF. Results showed that 80% or more of uncultured CD34(+) cells were positive for VLA-4, L-selectin, LFA-1, CD44, and CXCR4 while 50% were positive for VLA-5. Purification of CD34(+) cells did not affect AR expression, but cytokines increased expression three- to nine-fold throughout the 10-day culture period. In contrast, expression of CXCR4 decreased. Expression changes of ARs and CXCR4 on CD34(+)/CD38(-) cells mirrored those of the total CD34(+) population. The results indicate that cytokine culture significantly increases AR expression on CB CD34(+) cells, which may be related to the decrease in homing of cytokine-cultured hematopoietic stem cells.

Cobblestone area-forming cells in human cord blood are heterogeneous and differ from long-term culture-initiating cells.

The long-term culture-initiating cell (LTC-IC) assay is a physiological approach to the quantitation of primitive human hematopoietic cells. The readout using identification of cobblestone area-forming cells (CAFC) has gained popularity over the LTC-IC readout where cells are subcultured in a colony-forming cell assay. However, comparing the two assays, cord blood (CB) mononuclear cell (MNC) samples were found to contain a higher frequency of CAFC than LTC-IC (126 +/- 83 versus 40 +/- 31 per 10(5) cells, p = 0.0001). Overall, 60% of week-5 cobblestones produced by CB MNC were not functional LTC-IC and were classified as "false." Separation of CB MNC using immunomagnetic columns showed that false cobblestones were CD34(-)/lineage(+). Purified CD34(+) cells, as expected, gave very similar readouts in the two assays, with 4,084 and 3,468/10(5) cells being CAFC and LTC-IC, respectively. CD34(-)/lineage(-) cells did not form cobblestones or become CD34(+) on stroma or in cytokine culture. Human CB MNC contain a population of mature lineage(+) cells, possibly mature T or B cells, which, although producing cobblestone areas (CA), are not functional LTC-IC. The CAFC readout by this method, therefore, is unreliable for estimation of primitive hematopoietic cells by limiting dilution analysis in whole human CB or MNC and also may not detect CD34(-) CA stem cells.

Estimation of individual sensitivity to cyclosporin in children awaiting renal transplantation.

BACKGROUND: Optimal immunosuppressive drug therapy requires that efficacy be balanced against toxicity. We have performed in vitro assays of cyclosporin (CsA) efficacy in children awaiting renal transplantation. METHODS: Peripheral blood mononuclear cells (PBMC) from 13 children awaiting renal transplantation and 10 healthy paediatric controls ("responders") were incubated in the presence of CsA (0-250 ng/ml). Irradiated PBMC from a parent (prospective live donor) were cultured with those of the child in the presence of interleukin 2. Europium-labelled, non-irradiated phytohaemagluttinin-stimulated target cells from the parent were added to the culture after 7 days incubation. Target cell lysis was quantified by time resolved fluorometry. CsA-mediated inhibition of target cell lysis was calculated and used to compare individual responses to the drug. Two-colour flow cytometry was performed to identify activated subsets of lymphocytes at varying concentrations of CsA. RESULTS: Wide inter-individual variations in per cent lysis and per cent inhibition were observed in patients and controls. Immunophenotyping indicated expansion of CD8(+) and CD25(+) lymphocyte subsets following allo-stimulation that was inhibited by increasing concentrations of CsA. Eight out of 13 patients and four out of 10 controls were "sensitive" to CsA in vitro in that they achieved 50% inhibition of cell lysis (IC(50)) at low concentrations of the drug (<50 ng/ml). Eleven patients have subsequently received a renal transplant. Five out of seven of these patients with IC(50) <50 ng/ml have suffered problems with infection, nephrotoxicity and graft vasculopathy raising the possibility of "over-immunosuppression". CONCLUSION: The data imply a useful role for this model in the prediction of individual response to immunosuppression following allo-stimulation in the pre-transplant setting.

Adult bone marrow is a rich source of human mesenchymal 'stem' cells but umbilical cord and mobilized adult blood are not.

In postnatal life, mesenchymal stem cells (MSC) self-replicate, proliferate and differentiate into mesenchymal tissues, including bone, fat, tendon, muscle and bone marrow (BM) stroma. Possible clinical applications for MSC in stem cell transplantation have been proposed. We have evaluated the frequency, phenotype and differentiation potential of MSC in adult BM, cord blood (CB) and peripheral blood stem cell collections (PBSC). During culture, BM MSC proliferated to confluence in 10-14 d, maintaining a stable non-haemopoietic phenotype, HLA class-1+, CD29+, CD44+, CD90+, CD45-, CD34- and CD14 through subsequent passages. Using the colony forming unit fibroblasts assay, the estimated frequency of MSC in the BM nucleated cell population was 1 in 3.4 x 10(4) cells. Both adipogenic and osteogenic differentiation of BM MSC was demonstrated. In contrast, CB and PBSC mononuclear cells cultured in MSC conditions for two passages produced a population of adherent, non-confluent fibroblast-like cells with a haemopoietic phenotype, CD45+, CD14+, CD34-, CD44-, CD90- and CD29-. In paired experiments, cultured BM MSC and mature BM stroma were seeded with CB cells enriched for CD34+. Similar numbers of colony-forming units of granulocytes-macrophages were produced by MSC-based and standard stroma cultures over 10 weeks. We conclude that adult BM is a reliable source of functional cultured MSC, but CB and PBSC are not.