Regulation of Immunity by Butyrophilins.

Butyrophilin molecules (commonly contracted to BTN), collectively take their name from the eponymous protein in cow's milk. They are considered to be members of the B7 family of costimulatory receptors, which includes B7.1 (CD80), B7.2 (CD86), and related molecules, such as PD-L1 (B7-H1, CD274), ICOS-L (CD275), and B7-H3 (CD276). These coreceptors modulate T cell responses upon antigen presentation by major histocompatibility complex and cognate αß T cell receptor engagement. Molecules such as BTN3A1 (CD277), myelin oligodendrocyte glycoprotein, and mouse Skint1 and Btnl2, all members of the butyrophilin family, show greater structural and functional diversity than the canonical B7 receptors. Some butyrophilins mediate complex interactions between antigen-presenting cells and conventional αß T cells, and others regulate the immune responses of specific γδ T cell subsets by mechanisms that have characteristics of both innate and adaptive immunity.

Physical match demands across different playing positions during transitional play and high-pressure activities in elite soccer.

This study explored physical match demands across different playing positions during transitional play, to inform the need for position-specific training interventions. Data was collected using 10 Hz GPS units from 10 competitive matches including 23 elite soccer players of the 1st Polish Division (Ekstraklasa) in season 2020-21. A total of 4249 positional observations were made; center backs (n = 884), full backs (n = 972), central defensive midfielders (n = 236), central attacking midfielders (n = 270), central midfielders (n = 578), wingers (n = 778), and attackers (n = 531). Match data reflected distances covered per minute (m · min-1): total distance (TD), high-speed running distance (HSRD, > 19.8 km · h-1), sprint distance (SD, > 25.2 km · h-1), and the frequency of high-intensity accelerations and decelerations (A+D, > 3 m · s-2; n · min-1). Total absolute sprint distance (SD, > 25.2 km · h-1) and total relative sprint distance (Rel B5) were also quantified. A univariate analysis of variance revealed position-specific differences. Significant effects of position were found for all analysed metrics during transitional play (large ESs; p <.001). Central attacking midfielders displayed higher TD (m · min-1), fullbacks covered highest SD (m · min-1) and wingers achieved the highest A+D (n · min-1) (p ≤ 0.05). Centre backs displayed the lowest physical outputs when compared to all other positions, except in A+D (n · min-1) during defensive transitions (p ≤ 0.05). Attackers displayed the highest physical metrics during high pressure activities (p ≤ 0.05). Coaches should carefully consider positional transitional demands to better inform training design. With specific attention paid to drills that replicate game play.

Peak Running Speeds in Professional Male Football: Influence of Division and Playing Position.

ABSTRACT: Fahey, JT, Aldred, K, Greig, M, and Rhodes, D. Peak running speeds in professional male football: Influence of division and playing position. J Strength Cond Res 37(3): 636-640, 2023-Well-established physical demands of competitive professional football facilitate prescription and monitoring of training. However, many factors influence these physical demands with implications for efficacious practice. Match-play data were analyzed over 2 seasons using global positioning systems technology, differentiating English Championship (33 matches) and League One (27 matches) demands. Playing position categorized wide and central defenders and midfielders and forwards. Peak running speeds defined the outcome measure, assessing the influence of the competition level and playing position across 1, 5, and 10-minute rolling average durations using a linear mixed model. Significant effects were detected for the competition level (F1,324.5 = 5.44, p = 0.02) and playing position (F4,328.3 = 89.90, p < 0.001). League One matches demonstrated greater peak running speeds than Championship matches (mean difference = 2.72 m·min-1 [95% confidence intervals: 0.4, 5.0]). No difference was observed between central and wide midfielders (mean difference = 0.62 m·min-1 [95% confidence intervals: -3.1, 4.3]). Wide midfielders presented faster peak running speeds than forwards (mean difference = 18 m·min-1 [95% confidence intervals:14.1, 22.1], p < 0.05), central defenders (mean difference = 25 m·min-1 [95% confidence intervals: 21.7, 29.8], p < 0.05), and wide defenders (mean difference = 12 m·min-1 [95% confidence intervals: 8.2, 16.5], p < 0.05). Interaction effects were found for division*position (F4,328.3 = 2.57, p = 0.038) demonstrating greater running speeds in League One, except for central defenders. Wide midfielders presented greater peak 1-minute running speeds, whereas 5 and 10-minute peak running speeds were greatest in central midfielders. The sensitivity of peak running speeds to competition level and playing position has implications for training prescription, monitoring particularly when transitioning between competition levels, determining and monitoring positional training intensities, and objective targets for progressive overload during rehabilitation.

Utilisation of performance markers to establish the effectiveness of cold-water immersion as a recovery modality in elite football.

Optimal strategies for recovery following training and competition in elite athletes presents ongoing debate. The effects of cold-water immersion (CWI) compared to passive recovery (PR) though a triad of performance measures after fatiguing exercise within a normal micro-cycle, during mid-competitive training cycle, in elite male footballers were investigated. Twenty-four elite footballers (age 20.58 ± 2.55 years; height 179.9 ± 5.6 cm; weight 75.7 ± 7.5 kg; body fat 6.2 ± 1.7%) were randomly assigned to CWI or PR following a fatiguing training session. Objective measures included eccentric hamstring strength, isometric adductor strength, hamstring flexibility and skin surface temperature (T sk ). Subjective measures included overall wellbeing. Data were collected at match day+3, immediately post-training, immediately post-intervention and 24 hrs post-intervention. Physiological, biomechanical and psychological measures displayed significant main effects for timepoint for eccentric hamstring strength, T sk , overall wellbeing, sleep, fatigue, stress and group for eccentric hamstring strength, T sk and sleep (groups combined). Group responses identified significant effects for timepoint for CWI and PR, for eccentric hamstring strength peak force, sleep, fatigue, and muscle soreness for CWI. Significant differences were displayed for eccentric hamstring strength (immediately post-intervention and immediately post-training) for peak force and between CWI and PR eccentric hamstring strength immediately post-intervention. Linear regression for individual analysis demonstrated greater recovery in peak torque and force for CWI. CWI may be useful to ameliorate potential deficits in eccentric hamstring strength that optimise readiness to train/play in elite football settings. Multiple measures and individual analysis of recovery responses provides sports medicine and performance practitioners with direction on the application of modified approaches to recovery strategies, within mid-competitive season training cycles.

Effects of contemporary cryo-compression on post-training performance in elite academy footballers.

Fatigue is a predisposing risk factor for injury commonly investigated in elite football populations. Little evidence advocates the most beneficial recovery strategies including contemporary cooling applications. The aim of the study was to examine immediate effects of the Game Ready® on physiological and biomechanical measures in a population of elite male academy footballers, following a fatiguing training session mid-competitive season. Twenty, elite male footballers took part (180.2 ± 8.7cm, 75.0 ± 11.4kg, 18 ± 0.5years). Following a normal fatiguing training session, players were randomly assigned to receive either cryotherapy (Game Ready®) (20-minutes at medium compression (5-55 mm Hg)) or passive recovery (PAS). Data was collected at match-day+1, immediately post-training and immediately post-intervention. Performance measures included countermovement jump (CMJ), isometric adductor strength (IAS), hamstring flexibility (HF), and skin surface temperature (Tsk). Significant main effects for group for CMJ data following exposure to cooling were displayed (p = < 0.05). Individual group analysis displayed a significant reduction in CMJ performance in the group exposed to cryotherapy (p = < 0.05) immediately post, but not for PAS. No main effects were identified for cryotherapy or PAS group for IAS or HF (p = > 0.05). Tsk reduced significantly (p = < 0.05) in the cryotherapy group, meeting therapeutic Tsk range. Reductions in performance immediately following exposure to pneumatic cryo-compressive devices may negate the justification of this recovery strategy if neuromuscular mechanisms are required in immediate short term. Application of such recovery strategies however are dependent on the type of recovery demand and should be adapted individually to suit the needs of the athlete to optimise readiness to train/play.

The mean and peak physical demands during transitional play and high pressure activities in elite football.

The aim of the present study was to establish the effect of transitional activities (TA) on physical metrics. Global Positioning System technology was utilized on 23 elite outfield footballers over 10 games to quantify absolute metrics per minute such as total distance (TD; m · min-1), sprint distance (SD; m · min-1), the number of high-intensity accelerations and decelerations (A+D; n · min-1), and high-speed running distance (HSRD; m · min-1). TD - total distance; HSRD - high-speed running distance; SD - sprint distance and high-intensity acceleration distance (Acc B3 Dist) were also quantified. Metrics were observed in relation to 4 TA's commonly observed in football matches. Positive Transitions (PT), Negative Transitions (NT), Fast Attacks (FA) and High Pressure Activities (HP). Main effects for transition and game were observed. Comparisons were also made between 90 minute averages and transitional mean scores. NT displayed the highest TD (m · min-1) when compared to other TA's (p ≤ 0.05). Observation of SD (m · min-1) for all transitions highlighted higher outputs when in PT (p ≤ 0.05). HP TA displayed the lowest output in all metrics (p ≤ 0.05), except high-intensity accelerations and decelerations A+D (n · min-1). The mean average and peak average outputs for TA and 90min average detailed elevated physical outputs across all metrics. Absolute physical metrics are increased when observing transitional play, representing the maximum physical exposure that athletes experience in games. This knowledge should be utilized when implementing high-velocity exposures within a weekly microcycle, to best prepare players for match play.

Case Study: The Conservative Management of a Complex Mid Foot Injury in an Elite Professional Footballer.

Lisfranc injuries, often accompanied with tarsometatarsal joint (TMTJ) disruption, are not well documented in football despite becoming increasingly more prevalent within other athletic populations. Currently there is a paucity of evidence documenting prognosis, rehabilitation strategy and outcome. The presented case summarizes the conservative rehabilitation and return to play of a 26-year-old elite professional footballer who presented with a Lisfranc injury alongside a 3rd TMTJ coalition stress response. Injury was sustained when landing awkwardly from a jump causing the midfoot to be forced into a hyper-plantarflexed position. Palpation identified tenderness over the 2nd and 3rd MT, with a positive piano key test. Magnetic resonance imaging (MRI), computed tomography (CT), stork view x-ray and review from a leading foot and ankle specialist confirmed diagnosis, post-contradictory MRI results. Presented is a summary of the assessment process, conservative management of the injury and the resultant rehabilitation process followed, which led to the successful return to play of the athlete.

Impact of early versus late administration of bamlanivimab on readmissions in patients with high-risk COVID-19.

BACKGROUND: Recombinant monoclonal antibody therapies have been utilized under emergency use authorization (EUA) for the prevention of clinical decompensation in high-risk COVID-19 positive patients for up to 10 days from symptom onset. The purpose of this study was to determine the impact of the timing of the monoclonal antibody, bamlanivimab, on clinical outcomes in high-risk COVID-19 positive patients. METHODS: This was an IRB-approved, retrospective evaluation of adult patients who received bamlanivimab per EUA criteria in the emergency department (ED). Patients were dichotomized into two groups- 3 days of symptoms or less (early) versus 4 to 10 days (late). The primary outcome was hospitalization for COVID-related illness at 28 days (or treatment failure). Secondary outcomes were COVID-related ED visits at 28 days, hospital and intensive care unit (ICU) length of stay (LOS), and in-hospital mortality at 28 days. RESULTS: A total of 839 patients were included in the analysis. There was no difference observed in COVID-related hospitalization rates within 28 days between the early and late bamlanivimab administration groups (7.5% vs. 8.2%, p = 0.71). There was no difference in COVID-related ED visits within 28 days with 13% of patients returning to the ED. CONCLUSIONS: In conclusion, there were no differences in the rates of hospitalization at 28 days when bamlanivimab was administered in the first 3 days of illness versus days 4 to 10. Future prospective studies are warranted to expand upon the characteristics of patients that may or may not benefit from monoclonal antibody therapy.

The Temporal Pattern of Recovery in Directional Dynamic Stability Post Football-Specific Fatigue.

BACKGROUND: Rising injury rates within football require further understanding of the etiological risk factors associated with lower-limb injury. AIM: To examine the temporal pattern of recovery of directional dynamic stability measures post football-specific fatigue. METHODS: Eighteen male elite footballers completed baseline assessments of directional dynamic stability measures (Overall Stability Index, anterior-posterior stability [A-P], medial-lateral stability [M-L] on level 1 of the Biodex Stability System). Post Soccer-Specific Aerobic Field Test90 measures were repeated immediately, +24 hours, +48 hours, and +72 hours. The main effects for the recovery time and direction of stability were supplemented by regression modeling to describe the temporal pattern of recovery. RESULTS: Significant main effects for time were identified for all directions of stability (Overall Stability Index, A-P, and M-L) up to +48 hours postexercise (P ≤ .05). The quadratic pattern of temporal recovery highlights a minimum of 37.55 to 38.67 hours and maximum of 75.09 to 77.33 hours. Additionally, a main effect for direction of stability was observed, with significant differences identified between A-P and M-L stability at all time points (P ≤ .001). CONCLUSIONS: Reductions in directional dynamic stability +48 hours postfatigue highlight implications for training design, recovery strategies, and injury management for performance practitioners. Interestingly, A-P stability has been highlighted as being significantly reduced compared with M-L stability at all time points, regardless of the fatigue exposure. Practitioners should consider the reduction of stability in this plane in relation to common mechanisms of injury in the knee to inform injury-risk-reduction strategies.

TRIM21 and the Function of Antibodies inside Cells.

Therapeutic antibodies targeting disease-associated antigens are key tools in the treatment of cancer and autoimmunity. So far, therapeutic antibodies have targeted antigens that are, or are presumed to be, extracellular. A largely overlooked property of antibodies is their functional activity inside cells. The diverse literature dealing with intracellular antibodies emerged historically from studies of the properties of some autoantibodies. The identification of tripartite motif (TRIM) 21 as an intracellular Fc receptor linking cytosolic antibody recognition to the ubiquitin proteasome system brings this research into sharper focus. We review critically the research related to intracellular antibodies, link this to the TRIM21 effector mechanism, and highlight how this work is exposing the previously restricted intracellular space to the potential of therapeutic antibodies.

Temporal Patterns of Knee-Extensor Isokinetic Torque Strength in Male and Female Athletes Following Comparison of Anterior Thigh and Knee Cooling Over a Rewarming Period.

CONTEXT: The effect of local cooling on muscle strength presents conflicting debates, with literature undecided as to the potential implications for injury, when returning to play following cryotherapy application. OBJECTIVE: To investigate concentric muscle strength following local cooling over the anterior thigh compared with the knee joint in males and females and the temporal pattern over a 30-minute rewarming period. DESIGN: Repeated-measures crossover design. METHOD: Twelve healthy participants randomly assigned to receive cooling intervention on one location, directly over either the anterior thigh or the knee, returning 1 week later to receive the cooling intervention on opposite location. Muscle strength measured via an isokinetic dynamometer at multiple time points (immediately post, 10-, 20-, and 30-min post) coincided with measurement of skin surface temperature (Tsk) using a noninvasive infrared camera. RESULTS: Significant main effects for time (P ≤ .001, η2 = .126) with preice application higher than all other time points (P ≤ .05) were demonstrated for both peak torque and average torque. There were also significant main effects for isokinetic testing speed, sex of the participant, and position of the ice application for both peak torque and average torque (P ≤ .05). Statistically significant decreases in Tsk were reported in both gender groups across all time points compared with preintervention Tsk for the anterior thigh and knee (P < .05). CONCLUSIONS: Reductions reported for concentric peak torque and average torque knee-extensor strength in males and females did not fully recover to baseline measures at 30-minute postcryotherapy interventions. Sports medicine practitioners should consider strength deficits of the quadriceps after wetted ice applications, regardless of cooling location (joint/muscle) or gender.

The Effect of Proprioceptive Training on Directional Dynamic Stabilization.

OBJECTIVES: Significant loss of playing time and the impact of treatment costs due to lower limb injury in football demonstrates a need for improved protocols for injury risk reduction. The aim of the present study is to assess the effect of a proprioceptive training program on the lower limb dynamic stability of elite footballers. METHODS: A total of 16 elite premier league footballers were randomly allocated by matched pair design to a 8-week proprioception training group (group A, n = 8) or nontraining group (group B, n = 8), to determine the effect of this training over a 16-week period. Group A completed 8 weeks of bilateral proprioceptive training, 5 times per week for 10 minutes. The Biodex Stability System measures of overall stability index, anterior-posterior (A-P), and medial-lateral stability (M-L) at levels 8-6-4-1 were taken for both groups at baseline, 4, 8, and 16 weeks. Main effects of time, level of stability, and direction of stability were determined, with comparisons of effect made between the 2 groups. RESULTS: The training group displayed significant differences for multidirectional stability at week 8 (P ≤ .05). The A-P stability within the training group displayed significant differences between baseline measures and 16 weeks (P > .05), with significant increases in scores displayed for M-L and A-P stability between weeks 8 and 16 (P ≤ .05), representing a detraining effect. No significant differences were detected at any time point for the nontraining group (P > .05). CONCLUSIONS: Proprioceptive training over 8 weeks has a positive effect on all directions of stability. Greater declines in A-P stability were evident at 16 weeks when compared with M-L and overall stability index. Consideration must be given to the increased stability scores presented pretesting for A-P when compared with M-L. Findings of this work present implications for training design.

The temporal pattern of recovery in eccentric hamstring strength post-soccer specific fatigue.

Eccentric hamstring strength is an aetiological risk factor for soccer injury. The temporal pattern of recovery post-exercise is critical in injury management. 18 male professional soccer players completed baseline assessments of eccentric hamstring strength at isokinetic speeds of 60, 150 and 300°· s-1. Post SAFT90 measures were repeated immediately, + 24 hrs, + 48 hrs and + 72 hrs. Main effects for recovery time and testing speed in average torque (AvT), peak torque (PT) and the corresponding angle (Ɵ) were supplemented by regression modelling to describe the temporal pattern of recovery. A main effect for isokinetic testing speed was observed in PT and AvT. A main effect for recovery time highlighted greater strength pre-exercise, with a quadratic pattern to temporal recovery highlighting minima achieved at between 40-48 hrs. Strength parameters are not fully recovered until 96 hrs post soccer specific fatigue, with implications for training design and injury management, particularly within fixture-congested periods.

Multifaceted plant responses to circumvent Phe hyperaccumulation by downregulation of flux through the shikimate pathway and by vacuolar Phe sequestration.

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase (PAL) isoforms that catalyze the non-oxidative deamination of Phe to trans-cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81-94% led to an 18-fold expansion of the internal Phe pool. Phe accumulation had multifaceted intercompartmental effects on aromatic amino acid metabolism. It resulted in a decrease in the overall flux through the shikimate pathway, and a redirection of carbon flux toward the shikimate-derived aromatic amino acids tyrosine and tryptophan. Accumulation of Phe did not lead to an increase in flux toward phenylacetaldehyde, for which Phe is a direct precursor. Metabolic flux analysis revealed this to be due to the presence of a distinct metabolically inactive pool of Phe, likely localized in the vacuole. We have identified a vacuolar cationic amino acid transporter (PhCAT2) that contributes to sequestering excess of Phe in the vacuole. In vitro assays confirmed PhCAT2 can transport Phe, and decreased PhCAT2 expression in PAL-RNAi transgenic plants resulted in 1.6-fold increase in phenylacetaldehyde emission. These results demonstrate mechanisms by which plants maintain intercompartmental aromatic amino acid homeostasis, and provide critical insight for future phenylpropanoid metabolic engineering strategies.

Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin.

The three butyrophilin BTN3A molecules, BTN3A1, BTN3A2, and BTN3A3, are members of the B7/butyrophilin-like group of Ig superfamily receptors, which modulate the function of T cells. BTN3A1 controls activation of human Vγ9/Vδ2 T cells by direct or indirect presentation of self and nonself phosphoantigens (pAg). We show that the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate binds to the intracellular B30.2 domain of BTN3A1 with an affinity of 1.1 µM, whereas the endogenous pAg isopentenyl pyrophosphate binds with an affinity of 627 µM. Coculture experiments using knockdown cell lines showed that in addition to BTN3A1, BTN3A2 and BTN3A3 transmit activation signals to human γδ T cells in response to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and the aminobisphosphonate drug zoledronate that causes intracellular accumulation of isopentenyl pyrophosphate. The plakin family member periplakin, identified in yeast two-hybrid assays, interacted with a membrane-proximal di-leucine motif, located proximal to the B30.2 domain in the BTN3A1 cytoplasmic tail. Periplakin did not interact with BTN3A2 or BTN3A3, which do not contain the di-leucine motif. Re-expression into a BTN3A1 knockdown line of wild-type BTN3A1, but not of a variant lacking the periplakin binding motif, BTN3A1Δexon5, restored γδ T cell responses, demonstrating a functional role for periplakin interaction. These data, together with the widespread expression in epithelial cells, tumor tissues, and macrophages detected using BTN3A antiserum, are consistent with complex functions for BTN3A molecules in tissue immune surveillance and infection, linking the cell cytoskeleton to γδ T cell activation by indirectly presenting pAg to the Vγ9/Vδ2 TCR.

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction.

From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 µM in a combination 3'-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 µM.

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway.

Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled with ß2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. ß2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR:MHC class I complex trafficks through the Golgi apparatus, demonstrating a function of TAPBPR beyond the endoplasmic reticulum/cis-Golgi. The identification of TAPBPR as an additional component of the MHC class I antigen-presentation pathway demonstrates that mechanisms controlling MHC class I expression remain incompletely understood.