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Context: General and local muscular fatigue is postulated to negatively alter lower limb biomechanics; however, few prospective studies have been done to examine the effect of fatigue on tuck-jump performance. The tuck-jump assessment (TJA) is a criteria-based visual screening tool designed to identify neuromuscular deficits associated with anterior cruciate ligament (ACL) injury. Use of kinetics during the TJA after an intense sport-specific fatigue protocol may identify fatigue-induced neuromuscular deficits associated with ACL injury risk., Objective: To examine the effects of a sport-specific fatigue protocol on visually evidenced (2-dimensional) technical performance of repeated tuck jumps and lower limb kinetic stabilization., Design: Cross-sectional study., Setting: Laboratory., Patients or Other Participants: Twelve female netball athletes (age = 20.8 ± 2.6 years, height = 170.0 ± 0.04 cm, mass = 67.5 ± 7.4 kg)., Main Outcome Measure(s): Participants performed 1 set of a TJA before and after a sport-specific fatigue protocol. Paired t tests and effect sizes were used to evaluate differences and the magnitude of differences in TJA scoring criterion, kinetics, and kinetic stabilization prefatigue to postfatigue., Results: A small increase was observed for vertical relative lower extremity stiffness postfatigue (P = .005; Hedges g = 0.45). Peak center-of-mass displacement, time of jump cycle, ground contact time, flight time, jump height, and vertical net impulse decreased with small to moderate effect sizes (P < .01; Hedges g range, 0.41-0.74). No differences were observed for TJA composite scores, peak vertical ground reaction force, and stabilization indices of kinetic variables after the fatigue protocol (P > .05)., Conclusions: Kinetic analysis of repeated tuck jumps after a fatigue protocol identified an altered jumping strategy, which was not identifiable via visual 2-dimensional assessment. However, based on kinetic measures, fatigue induces a stiffer jumping strategy, and practitioners should consider assessing load attenuation strategies that may not be visually evident when evaluating ACL-injury risk factors in athletes who are fatigued., (© by the National Athletic Trainers’ Association, Inc.)

Pixantrone and mitoxantrone are structurally related anticancer drugs which have been shown to generate covalent conjugates at apurinic/apyrimidinic (AP) sites in DNA. Mitoxantrone binding to AP sites induces DNA strand cleavage and inhibits the endonuclease activity of human AP endonuclease 1 (APE1). Here, pixantrone was demonstrated to have similar properties, but relative to mitoxantrone, it was significantly less potent in both DNA incision and APE1 inhibition. Consistent with these observations, pixantrone had ~ 15-fold lower affinity for DNA containing an AP site analogue, tetrahydrofuran, as measured by a Thiazole Orange (ThO) displacement assay., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Increased risk for the development of hepatocellular carcinoma (HCC) is driven by a number of etiological factors including hepatitis viral infection and dietary exposures to foods contaminated with aflatoxin-producing molds. Intracellular metabolic activation of aflatoxin B 1 (AFB 1 ) to a reactive epoxide generates highly mutagenic AFB 1 -Fapy-dG adducts. Previously, we demonstrated that repair of AFB 1 -Fapy-dG adducts can be initiated by the DNA glycosylase NEIL1 and that male Neil1 -/- mice were significantly more susceptible to AFB 1 -induced HCC relative to wild-type mice. To investigate the mechanisms underlying this enhanced carcinogenesis, WT and Neil1 -/- mice were challenged with a single, 4 mg/kg dose of AFB 1 and frequencies and spectra of mutations were analyzed in liver DNAs 2.5 months post-injection using duplex sequencing. The analyses of DNAs from AFB 1 -challenged mice revealed highly elevated mutation frequencies in the nuclear genomes of both males and females, but not the mitochondrial genomes. In both WT and Neil1 -/- mice, mutation spectra were highly similar to the AFB 1 -specific COSMIC signature SBS24. Relative to wild-type, the NEIL1 deficiency increased AFB 1 -induced mutagenesis with concomitant elevated HCCs in male Neil1 -/- mice. Our data establish a critical role of NEIL1 in limiting AFB 1 -induced mutagenesis and ultimately carcinogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Molecular Medicine.)

Introduction: In Australia, only 22% of male and 8% of female adolescents meet the muscle-strengthening physical activity guidelines, and few school-based interventions support participation in resistance training (RT). After promising findings from our effectiveness trial, we conducted a state-wide dissemination of the ' Resistance Training for Teens ' (RT4T) intervention from 2015 to 2020. Despite high estimated reach, we found considerable variability in programme delivery and teachers reported numerous barriers to implementation. Supporting schools when they first adopt evidence-based programmes may strengthen programme fidelity, sustainability, and by extension, programme impact. However, the most effective implementation support model for RT4T is unclear., Objective: To compare the effects of three implementation support models on the reach (primary outcome), dose delivered, fidelity, sustainability, impact and cost of RT4T., Methods and Analysis: We will conduct a hybrid type III implementation-effectiveness trial involving grade 9 and 10 (aged 14-16 years) students from 90 secondary schools in New South Wales (NSW), Australia. Schools will be recruited across one cohort in 2023, stratified by school type, socioeconomic status and location, and randomised in a 1:1:1 ratio to receive one of the following levels of implementation support: (1) 'low' (training and resources), (2) 'moderate' (training and resources+external support) or 'high' (training and resources+external support+equipment). Training includes a teacher workshop related to RT4T programme content (theory and practical sessions) and the related resources. Additional support will be provided by trained project officers from five local health districts. Equipment will consist of a pack of semiportable RT equipment (ie, weighted bars, dumbbells, resistance bands and inverted pull up bar stands) valued at ~$A1000 per school. Study outcomes will be assessed at baseline (T0), 6 months (T1) and 18 months (T2). A range of quantitative (teacher logs, observations and teacher surveys) and qualitative (semistructured interviews with teachers) methods will be used to assess primary (reach) and secondary outcomes (dose delivered, fidelity, sustainability, impact and cost of RT4T). Quantitative analyses will use logistic mixed models for dichotomous outcomes, and ordinal or linear mixed effects regression models for continuous outcomes, with alpha levels set at p<0.025 for the outcomes and cost comparisons of the moderate and high support arms against the low support arm., Ethics and Dissemination: Ethics approval has been obtained from the University of Newcastle (H-2021-0418), the NSW Department of Education (SERAP:2022215), Hunter New England Human Research Ethics Committee (2023/ETH00052) and the Catholic Schools Office. The design, conduct and reporting will adhere to the Consolidated Standards of Reporting Trials statement, the Standards for Reporting Implementation Studies statement and the Template for Intervention Description and Replication checklist. Findings will be published in open access peer-reviewed journals, key stakeholders will be provided with a detailed report. We will support ongoing dissemination of RT4T in Australian schools via professional learning for teachers., Trial Registration Number: ACTRN12622000861752., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Neurovascular coupling (NVC) is mediated via nitric oxide signaling, which is independently influenced by sex hormones and exercise training. Whether exercise training differentially modifies NVC pre- versus postpuberty, where levels of circulating sex hormones will differ greatly within and between sexes, remains to be determined. Therefore, we investigated the influence of exercise training status on resting intracranial hemodynamics and NVC at different stages of maturation. Posterior and middle cerebral artery velocities (PCA v and MCA v ) and pulsatility index (PCA PI and MCA PI ) were assessed via transcranial Doppler ultrasound at rest and during visual NVC stimuli. N = 121 exercise-trained (males, n = 32; females, n = 32) and untrained (males, n = 28; females, n = 29) participants were characterized as pre (males, n = 33; females, n = 29)- or post (males, n = 27; females, n = 32)-peak height velocity (PHV). Exercise-trained youth demonstrated higher resting MCA v ( P = 0.010). Maturity and training status did not affect the ΔPCA v and ΔMCA v during NVC. However, pre-PHV untrained males (19.4 ± 13.5 vs. 6.8 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 6.4 ± 7.1%; P ≤ 0.001) had a higher ΔPCA PI during NVC than post-PHV untrained counterparts, whereas the ΔPCA PI was similar in pre- and post-PHV trained youth. Pre-PHV untrained males (19.4 ± 13.5 vs. 7.9 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 11.1 ± 7.3%; P = 0.016) also had a larger ΔPCA PI than their pre-PHV trained counterparts during NVC, but the ΔPCA PI was similar in trained and untrained post-PHV youth. Collectively, our data indicate that exercise training elevates regional cerebral blood velocities during youth, but training-mediated adaptations in NVC are only attainable during early stages of adolescence. Therefore, childhood provides a unique opportunity for exercise-mediated adaptations in NVC. NEW & NOTEWORTHY We report that the change in cerebral blood velocity during a neurovascular coupling task (NVC) is similar in pre- and postpubertal youth, regardless of exercise-training status. However, prepubertal untrained youth demonstrated a greater increase in cerebral blood pulsatility during the NVC task when compared with their trained counterparts. Our findings highlight that childhood represents a unique opportunity for exercise-mediated adaptations in cerebrovascular hemodynamics during NVC, which may confer long-term benefits in cerebrovascular function.

Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target-specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1g bw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1g bw/bw mice had no substantial retinal degeneration compared with Ush1g bw /+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and subsequent hydrolysis. It interconverts between α and β deoxyribose anomers. Synthetic oligodeoxynucleotides containing this adduct are efficiently incised by unedited (K242) and edited (R242) forms of the hNEIL1 glycosylase. The structure of a complex between the active site unedited mutant CΔ100 P2G hNEIL1 (K242) glycosylase and double-stranded (ds) DNA containing a urea lesion reveals a pre-cleavage intermediate, in which the Gly2 N-terminal amine forms a conjugate with the deoxyribose C1' of the lesion, with the urea moiety remaining intact. This structure supports a proposed catalytic mechanism in which Glu3-mediated protonation of O4' facilitates attack at deoxyribose C1'. The deoxyribose is in the ring-opened configuration with the O4' oxygen protonated. The electron density of Lys242 suggests the 'residue 242-in conformation' associated with catalysis. This complex likely arises because the proton transfer steps involving Glu6 and Lys242 are hindered due to Glu6-mediated H-bonding with the Gly2 and the urea lesion. Consistent with crystallographic data, biochemical analyses show that the CΔ100 P2G hNEIL1 (K242) glycosylase exhibits a residual activity against urea-containing dsDNA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Aflatoxin B 1 (AFB 1 ) exposure through contaminated food is a primary contributor to hepatocellular carcinogenesis worldwide. Hepatitis B viral infections in livers dramatically increase the carcinogenic potency of AFB 1 exposures. Liver cytochrome P450 oxidizes AFB 1 to the epoxide, which in turn reacts with N7-guanine in DNA, producing the cationic trans -8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B 1 adduct (AFB 1 -N7-Gua). The opening of the imidazole ring of AFB 1 -N7-Gua under physiological conditions causes the formation of the cis - and trans -diastereomers of 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua). These adducts primarily lead to G → T mutations, with AFB 1 -FapyGua being significantly more mutagenic than AFB 1 -N7-Gua. The unequivocal identification and accurate quantification of these AFB 1 -Gua adducts as biomarkers are essential for a fundamental understanding and prevention of AFB 1 -induced hepatocellular carcinogenesis. Among a variety of analytical techniques used for this purpose, liquid chromatography-tandem mass spectrometry, with the use of the stable isotope-labeled analogues of AFB 1 -FapyGua and AFB 1 -N7-Gua as internal standards, provides the greatest accuracy and sensitivity. cis -AFB 1 -FapyGua- 15 N 5 , trans -AFB 1 -FapyGua- 15 N 5 , and AFB 1 -N7-Gua- 15 N 5 have been synthesized and used successfully as internal standards. However, the availability of these standards from either academic institutions or commercial sources ceased to exist. Thus, quantitative genomic data regarding AFB 1 -induced DNA damage in animal models and humans remain challenging to obtain. Previously, AFB 1 -N7-Gua- 15 N 5 was prepared by reacting AFB 1 - exo -8,9-epoxide with the uniformly 15 N 5 -labeled DNA isolated from algae grown in a pure 15 N-environment, followed by alkali treatment, resulting in the conversion of AFB 1 -N7-Gua- 15 N 5 to AFB 1 -FapyGua- 15 N 5 . In the present work, we used a different and simpler approach to synthesize cis -AFB 1 -FapyGua- 15 N 5 , trans -AFB 1 -FapyGua- 15 N 5 , and AFB 1 -N7-Gua- 15 N 5 from a partial double-stranded 11-mer Gua- 15 N 5 -labeled oligodeoxynucleotide, followed by isolation and purification. We also show the validation of these 15 N 5 -labeled standards for the measurement of cis -AFB 1 -FapyGua, trans -AFB 1 -FapyGua, and AFB 1 -N7-Gua in DNA of livers of AFB 1 -treated mice., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Physical education (PE) teachers and strength and conditioning (S&C) coaches are well placed to develop motor competence within youth populations. However, both groups' perceptions of important motor competencies are relatively unknown, especially when considering stage of maturity. Therefore, this study aimed to 1) present PE teachers and S&C coaches' perceptions of motor competence importance according to stage of maturity; 2) compare perceptions of motor competence between stages of maturity, and between PE teachers and S&C coaches; and 3) explore factors that influence PE teachers and S&C coaches' perceptions of motor competence importance. Via a mixed-method questionnaire, 47 PE teachers (professional experience = 10.3±6.6 years) and 48 S&C coaches (professional experience = 8.6±4.8 years) rated the importance of developing 21 motor competencies across four stages of maturity (childhood, pre-peak height velocity [PHV], circa-PHV, and post-PHV) using a Likert-scale (1 = not important, 5 = very important). Participants also provided open-ended explanations for their perceptions. Frequency analysis indicated that participants rated a broad range of competencies important, with S&C coaches rating more competencies important than PE teachers across all stages of maturity. Mixed-model analysis highlighted several differences in motor competence importance when comparing perceptions between participant groups, and between stages of maturity for PE teachers and S&C coaches. For example, S&C coaches rated strength-based motor competencies less important during childhood (d = -1.83 to -0.43), while PE teachers rated them less important during childhood (d = -2.22 to -0.42) and pre-PHV (d = -1.70 to -0.51) compared to other stages of maturity. Codebook thematic analysis showed several factors that influenced participant's perceptions of motor competence importance (e.g., participants understanding of themselves). The findings suggest that multiple environments may be required to adequately facilitate motor competence development amongst youth. Coach education should target misunderstandings around the risks of strength-based activity during early stages of maturity and the benefits of developing strength-based motor competencies across youth populations., Competing Interests: The authors have declared that no competing interests exist.

This cross-sectional study investigated how stretch-shortening cycle (SSC) function and kinetic variables differed between young female gymnasts of varying competitive levels. Drop jump (DJ) force−time profiles were examined in 118 female gymnasts, sub-divided by competitive level (n = 21 recreational, n = 41 regional and n = 50 elite). DJ force−time data were analyzed to calculate performance and kinetic variables. Participants’ SSC function was categorized as poor, moderate, or good, depending on the presence of an impact peak and spring-like behavior. A high proportion of gymnasts across each group were categorized as having “good” or “moderate” SSC function (i.e., >94.8%), with a trend of increasingly better SSC function observed with competitive level. Significant differences in reactive strength index, contact time, time of landing peak force, relative propulsive peak force, impulse, and ratio of braking: propulsive impulse were found between the elite and recreational group (p < 0.05). While SSC function was generally good to moderate, elite gymnasts had a more desirable kinetic jump-landing strategy than recreational level gymnasts. Drop jump kinetic variables appear to distinguish between elite and recreational gymnasts but not between regional standard gymnasts. Practitioners should consider the kinetic profile of gymnasts when benchmarking and setting training objectives.

The aim of this review was to describe and summarize the scientific literature on programming parameters related to jump or plyometric training in male and female soccer players of different ages and fitness levels. A literature search was conducted in the electronic databases PubMed, Web of Science and Scopus using keywords related to the main topic of this study (e.g., “ballistic” and “plyometric”). According to the PICOS framework, the population for the review was restricted to soccer players, involved in jump or plyometric training. Among 7556 identified studies, 90 were eligible for inclusion. Only 12 studies were found for females. Most studies (n = 52) were conducted with youth male players. Moreover, only 35 studies determined the effectiveness of a given jump training programming factor. Based on the limited available research, it seems that a dose of 7 weeks (1−2 sessions per week), with ~80 jumps (specific of combined types) per session, using near-maximal or maximal intensity, with adequate recovery between repetitions (<15 s), sets (≥30 s) and sessions (≥24−48 h), using progressive overload and taper strategies, using appropriate surfaces (e.g., grass), and applied in a well-rested state, when combined with other training methods, would increase the outcome of effective and safe plyometric-jump training interventions aimed at improving soccer players physical fitness. In conclusion, jump training is an effective and easy-to-administer training approach for youth, adult, male and female soccer players. However, optimal programming for plyometric-jump training in soccer is yet to be determined in future research.

Purpose: This study aimed to evaluate a 10-month neuromuscular training (NMT) intervention on isometric and dynamic kinetics, standing long jump (SLJ) distance, speed, and sport-specific performance., Methods: Forty-three prepubertal female gymnasts were allocated into either a gymnastics + NMT (gNMT; n = 16), gymnastics only (GYM, n = 15), or maturity-matched control (CON; n = 12) group. The gNMT followed a 10-month, twice-weekly NMT program that targeted movement competency, strength, power, and speed. Vaulting vertical take-off velocity, speed, SLJ distance, and kinetics during an isometric mid-thigh pull (IMTP), countermovement jump (CMJ), and drop jump (DJ) were measured at baseline and thereafter at 4, 7, and 10 months. Within-group differences were calculated using 3 × 4 repeated-measures ANCOVA., Results: Interaction effects were observed for SLJ distance and various IMTP, DJ, and vaulting variables. The gNMT showed significant improvements in IMTP absolute force and SLJ distance after 4 months and each subsequent testing session. IMTP relative force and various CMJ and DJ kinetics significantly improved in the gNMT from 7 months. Significant gains in speed and vaulting take-off velocity occurred after 10 months. The GYM group achieved some significant improvements in CMJ impulse, absolute isometric strength, and DJ spring-like behavior, whereas the CON group did not experience any changes., Conclusions: The addition of NMT to gymnastics training improved various isometric and dynamic kinetics, SLJ distance, speed, and vaulting take-off velocity in the gNMT, changes that were not equally evidenced for GYM or CON. The threshold for most of the training-induced adaptations observed in IMTP relative force, CMJ and DJ kinetics, sprint speed, and vaulting were achieved after 7 months, emphasizing the efficacy of long-term NMT programs for young gymnasts., (Copyright © 2022 by the American College of Sports Medicine.)

The purpose of this study was to examine the relationships between athletic motor skill competencies (AMSC), maturation, sex, body mass index, physical performance, and psychological constructs (motivation to exercise, physical self-efficacy, and global self-esteem). Two-hundred and twenty-four children aged 11-13 years old were included in the study and sub-divided by sex. The athlete introductory movement screen (AIMS) and tuck jump assessment (TJA) were used to assess AMSC, while standing long jump distance assessed physical performance. Online surveys examined participants' motivation to exercise, physical self-efficacy, and self-esteem. Trivial to moderate strength relationships were evident between AMSC and BMI (boys: r s = -0.183; girls: r s = -0.176), physical performance (boys: r s = 0.425; girls: r s = 0.397), and psychological constructs (boys: r s = 0.130-0.336; girls r s = 0.030-0.260), with the strength of relationships different between the sexes. Higher levels of AMSC were related to significantly higher levels of physical performance ( d = 0.25), motivation to exercise ( d = 0.17), and physical self-efficacy ( d = 0.15-0.19) in both boys and girls. Enhancing AMSC may have mediating effects on levels of physical performance and psychological constructs in school-aged children, which may hold important implications for physical activity levels and the development of physical literacy.

Long-term athletic development practices have been recommended for the past two decades. However, limited research exists exploring the knowledge and skills required by practitioners to optimise long-term athletic development. Therefore, this study aimed to evaluate the knowledge, adherence, practices, and challenges of practitioners responsible for delivering long-term athletic development. A mixed methods survey was completed by 236 practitioners (e.g., sport coaches, physical education teachers) consisting of four parts; 1) demographics, 2) knowledge, 3) adherence, and 4) practices and challenges. Quantitative and qualitative data were analysed by Friedman's analysis of variance and thematic analyses, respectively. Quantitative findings showed practitioners 1) recognised their responsibility for delivering long-term athletic development, 2) have a familiarity with existing developmental models, and 3) had high adherence, focused upon health and wellbeing, to delivering long-term athletic development. However, practices associated with growth and maturity, monitoring and assessment, and the systematic progression and individualisation of training had lower adherence. Qualitative analysis indicated that practitioner's perceived definitions of athleticism and long-term athletic development were inconsistent, especially according to the psychological components (i.e., confidence). Practitioners' descriptions of their long-term athletic development practices identified two higher order themes; 1) goals, in which long-term athletic development "is for life" and the importance of "an individual centered journey" highlighted as sub-themes; and 2) realities of delivering long-term athletic development, whereby variety in programme delivery, monitoring development and practical challenges were noted as key priorities. Eight practical challenges were identified including governance and priorities, resources, education, early specialization, high training volumes, staff communication, parents and youth motivation. This mixed method survey highlighted a multitude of knowledge, adherence, practices and challenges towards long-term athletic development. These novel findings can help inform policy to optimise long-term athletic development and to support the complex problem of developing a healthier, fitter and more physically active youth population., Competing Interests: The authors have declared that no competing interests exist.

Background: Youth populations benefit from neuromuscular training; however, the extent to which training frequency, baseline fitness, and maturity status moderate the response to long-term neuromuscular training in male youth remains unclear., Hypothesis: Twice-weekly training (G2x) would induce larger improvements in movement competency and strength and power kinetics compared with once-weekly training (G1x). Maturity status and baseline fitness would also moderate the training response in strength and power kinetics., Study Design: Nonrandomized, repeated-measures design., Level of Evidence: Level 3., Methods: Ninety-five male athletes of varying maturity status (pre- or post-peak height velocity) were divided into G2x, G1x, or control (CON) groups. Training groups received G2x or G1x for 28 weeks. Back squat assessment (BSA) movement competency and isometric mid-thigh pull (IMTP), squat jump (SJ), and countermovement jump (CMJ) kinetics were measured pre- and postintervention., Results: The G2x achieved significantly greater adaptations in BSA total score, IMTP allometrically scaled peak force (PF allo ), IMTP peak rate-of-force development (PRFD), SJ PF allo and PRFD compared with G1x and CON ( P < 0.05; d = 0.3-0.9). Baseline fitness, training frequency and maturity status were significant predictors of IMTP PF allo ( R 2 = 27.5%) and PRFD ( R 2 = 42.9%), while a combination of training frequency and baseline fitness explained a small amount of variance in SJ PF allo ( R 2 = 12.2%) and SJ PRFD ( R 2 = 6.5%). There were no significant predictors of CMJ kinetics., Conclusion: G2x achieved significantly larger improvements in movement competency, isometric strength and concentric jump variables compared with G1x, with the training response greater in those youth with lower baseline fitness and more advanced maturity status., Clinical Relevance: Exposure to neuromuscular training twice-weekly elicits a greater response than G1x in young male athletes. Practitioners should take maturity status, training frequency, and baseline fitness levels of young male athletes into account when interpreting testing data, as these variables appear to moderate training responsiveness.

This prospective longitudinal trial aimed to (1) determine the role of head impact exposure on behavioral/cognitive outcomes, and (2) assess the protective effect(s) of a jugular vein compression (JVC) collar on behavioral/cognitive outcomes after one season of high-school football. Participants included 284 male high-school football players aged 13-18 years enrolled from seven Midwestern high-schools. Schools were allocated to the JVC collar intervention (four teams, 140 players) or no collar/no intervention control (three teams, 144 players) condition. Head impact exposure was measured throughout the season using CSx accelerometers. Outcome measures included post-season parent and adolescent report on Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale ( SWAN) and Post-Concussion Symptom Inventory (PCSI), as well as adolescent performance on Attention Network Task (ANT), digital Trail Making Task (dTMT), and Cued Switching task. No significant effect of head impact exposure or JVC collar use on post-season SWAN or PCSI scores or performance on dTMT and Cued Switching task were noted. There was no effect of head impact exposure on ANT performance; however, the JVC collar group had greater post-season Alerting network scores than the no collar group ( p  = 0.026, d  = 0.22). Findings provide preliminary evidence that the JVC collar may provide some protection to the alerting attention system. These findings should be interpreted cautiously as a greater understanding of the long-term sequelae of head impact exposure and the role of cumulative head impact exposure behavioral/cognitive outcomes is required.

This study aimed to: (1) examine differences in physical performance across birth-quartiles and maturity-status, and (2) determine the relationships among relative age, maturation and physical performance in young male soccer players. The sample included 199 males aged between 8.1 and 18.9 years, from two professional soccer academies in the English Football League. Data were collected for height, weight, self-reported biological parent heights, 30 m sprint time and countermovement jump (CMJ) height. Relative age was conveyed as a decimal, while maturity status was determined as the percentage of predicted adult height (PAH). There were no significant differences in any measure between birth quartiles, however early maturers outperformed on-time and later maturers in most performance measures. Pearson-product-moment correlations revealed that maturation was inversely associated with 30 m sprint time in U12 to U16 ( r = -0.370-0.738; p < 0.05), but only positively associated with CMJ performance in U12 ( r = 0.497; p < 0.05). In contrast, relative age was unrelated to sprint performance and only significantly associated with superior CMJ performance in U16. This study indicates that maturity has a greater association with sprint performance than relative age in English male academy soccer players. Practitioners should monitor and assess biological maturation in young soccer players to attempt to control for the influence on physical performance, and avoid biasing selection on absolute performance rather than identifying the most talented player.

Obesity and related metabolic disorders are pressing public health concerns, raising the risk for a multitude of chronic diseases. Obesity is multi-factorial disease, with both diet and lifestyle, as well as genetic and developmental factors leading to alterations in energy balance. In this regard, a novel role for DNA repair glycosylases in modulating risk for obesity has been previously established. Global deletion of either of two different glycosylases with varying substrate specificities, Nei-like endonuclease 1 (NEIL1) or 8-oxoguanine DNA glycosylase-1 (OGG1), both predispose mice to diet-induced obesity (DIO). Conversely, enhanced expression of the human OGG1 gene renders mice resistant to obesity and adiposity. This resistance to DIO is mediated through increases in whole body energy expenditure and increased respiration in adipose tissue. Here, we report that hOGG1 expression also confers resistance to genetically-induced obesity. While Agouti obese ( A y /a ) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in A y /a mice ( A y /a Tg ) prevents increased body weight, without reducing food intake. Instead, obesity resistance in A y /a Tg mice is accompanied by increased whole body energy expenditure and tissue mitochondrial content. We also report for the first time that OGG1-mediated obesity resistance in both the A y /a model and DIO model requires maternal transmission of the hOGG1 transgene. Maternal, but not paternal, transmission of the hOGG1 transgene is associated with obesity resistance and increased mitochondrial content in adipose tissue. These data demonstrate a critical role for OGG1 in modulating energy balance through changes in adipose tissue function. They also demonstrate the importance of OGG1 in modulating developmental programming of mitochondrial content and quality, thereby determining metabolic outcomes in offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burchat, Sharma, Ye, Komakula, Dobrzyn, Vartanian, Lloyd and Sampath.)

The purpose of this article is to provide an overview of the growth, maturation and resistance training-related changes in muscle-tendon and neuromuscular mechanisms in youth, and the subsequent effect on performance. Sprinting, jumping, kicking, and throwing are common movements in sport that have been shown to develop naturally with age, with improvements in performance being attributed to growth and maturity-related changes in neuromuscular mechanisms. These changes include moderate to very large increases in muscle physiological cross-sectional area (CSA), muscle volume and thickness, tendon CSA and stiffness, fascicle length, muscle activation, pre-activation, stretch reflex control accompanied by large reductions in electro-mechanical delay and co-contraction. Furthermore, a limited number of training studies examining neuromuscular changes following four to 20 weeks of resistance training have reported trivial to moderate differences in tendon stiffness, muscle CSA, muscle thickness, and motor unit activation accompanied by reductions in electromechanical delay (EMD) in pre-pubertal children. However, the interaction of maturity- and training-related neuromuscular adaptions remains unclear. An understanding of how different neuromuscular mechanisms adapt in response to growth, maturation and training is important in order to optimise training responsiveness in youth populations. Additionally, the impact that these muscle-tendon and neuromuscular changes have on force producing capabilities underpinning performance is unclear.

Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. There is also evidence suggesting that inhibition of the BER enzyme 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-dG), could be useful in treating certain cancers. Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of OGG1 expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients. Here we present data demonstrating that AML cell lines deficient in OGG1 have enhanced sensitivity to cytarabine (cytosine arabinoside [Ara-C]) relative to OGG1-proficient cells. This enhanced cytotoxicity correlated with endogenous oxidatively-induced DNA damage and Ara-C-induced DNA strand breaks, with a large proportion of these breaks occurring at common fragile sites. This lethality was highly specific for Ara-C treatment of AML cells deficient in OGG1, with no other replication stress-inducing agents showing a correlation between cell killing and low OGG1 levels. The mechanism for this preferential toxicity was addressed using in vitro replication assays in which DNA polymerase δ was shown to insert Ara-C opposite 8-oxo-dG, resulting in termination of DNA synthesis. Overall, these data suggest that incorporation of Ara-C opposite unrepaired 8-oxo-dG may be the fundamental mechanism conferring selective toxicity and therapeutic effectiveness in OGG1-deficient AML cells., Competing Interests: The authors declare no competing interest.

Leading global physical activity guidelines advocate that young children need to engage in activities that strengthen musculoskeletal tissues and improve movement skill competency. The purpose of this study was to examine the effects of delivering strength and conditioning as part of the physical education curriculum on athletic motor skill competencies (AMSC), physical performance, and psychosocial factors. Forty-six school children aged 11-14 were included in the study, and sub-divided firstly by sex and then into intervention and control groups. Intervention groups received nine lessons of strength and conditioning based activities over a six-week period, while the control groups continued with traditional physical education curricula. The resistance training skills battery (RTSB) and tuck jump assessment (TJA) assessed AMSC. Standing long jump distance assessed lower limb strength, and online surveys examined motivation, physical self-efficacy and self-esteem. Male and female intervention groups significantly improved RTSB ( p > 0.05) whereas no changes were observed in the control groups. No changes were observed in the intervention groups TJA and only trivial and small non-significant changes in standing long jump performance. Significant increases in motivation of the male intervention group occurred. Strength and conditioning integrated in physical education can improve AMSC in short-term interventions.

Examining association between serial participation in youth organized sports (OS) and concurrent cardiometabolic risk factors, with long-term health status, will aid understanding the role of OS participation. Combining data from a prospective study and a follow-up survey, we aimed to determine association between youth OS participation and cardiometabolic risk factors with health and physical activity (PA) in young adulthood. Cardiometabolic risk factors were monitored yearly, and OS involvement through middle school, high school, and college, together with current status was recorded 12 years after the initial study began; 462 participants completed follow-up. Cardiometabolic risk factors included: body mass index (BMI), waist circumference, blood pressure, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol and triglycerides, fasting glucose and insulin. Participants continuing OS participation from middle to high school and/or college had significantly lower BMI/BMI z-scores [24.7 vs 27.4 (p < 0.05) and 0.51 vs 0.82 (p < 0.05), respectively] and significantly higher HDL [48.7 vs 45.4 (p ≤ 0.05)] than those without OS participation after middle school. Waist circumference of females was significantly smaller in those who participated in OS from middle to high school and/or college (84.9 cm) compared to those who had no OS (92.1 cm), (p < 0.05). Participants continuing OS from middle to high school and/or college reported significantly higher follow-up PA levels than those who had no OS after middle school (p < 0.001). This study provides novel data showing serial participation in OS from middle to high school and/or college was associated with a superior cardiometabolic health profile in school and increased PA levels at 12-year follow-up., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Published by Elsevier Inc.)

The gene encoding the tumor suppressor, phosphatase and tensin homolog (PTEN), located on chromosome 10, is frequently expressed at low levels in various tumors, resulting in the stimulation of cell proliferation and migration. However, the role of exosomal PTEN in cell-cell communication during the progress of benzene-induced carcinogenesis remains unclear. The goal of this study was to explore whether exosomes derived from normal human bronchial epithelial cells (16HBE) could transmit PTEN to hydroquinone-transformed malignant recipient cells (16HBE-t) and its possible effects on cell proliferation and migration. Consistent with PTEN expression being down-regulated in transformed cells, we found that its expression was significantly decreased in 16HBE-t relative to 16HBE cells and that purified exosomes secreted by 16HBE, up-regulated PTEN levels in recipient 16HBE-t cells. Thus, down-regulating their proliferation and migration. Further, when exosomes derived from 16HBE cells that had been treated with the PTEN inhibitor SF1670, were incubated with recipient 16HBE-t cells, they exhibited decreased PTEN levels, with a corresponding increase in their proliferation and migration. In conclusion, our study demonstrates that exosomes derived from 16HBE cells can down-regulate proliferation and migration of recipient 16HBE-t cells via transferring PTEN., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

OGG1-deficient (Ogg1-/-) animals display increased propensity to age-induced and diet-induced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1-/- mice subjected to different nutritional challenges. Interestingly, Ogg1-/- mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. Consistent with this observation, Ogg1-/- mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1-/- mice., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to examine the extent to which maturity offset, strength, and movement competency influences motor skill performance in adolescent boys. One hundred and eight secondary school boys completed anthropometric and physical testing on two non-consecutive days for the following variables: Maturity offset, isometric mid-thigh pull absolute (IMTP ABS ) and relative (IMTP REL ) peak force, resistance training skills quotient, 10-, 20-, and 30-m sprint time, countermovement jump height, horizontal jump distance, anaerobic endurance performance, and seated medicine ball throw (SMBT). The IMTP REL displayed significant small to large correlations with all performance variables ( r = 0.27-0.61), whereas maturity offset was significantly correlated with IMTP ABS ( r = 0.69), sprint ( r = 0.29-0.33), jump ( r = 0.23-0.34), and SMBT ( r = 0.32). Absolute and relative strength were the strongest predictors of all performance variables and combined with maturity to explain 21%-76% of the variance. Low and average relative strength boys were nearly eight times (odds ratio: 7.80, confidence interval: 1.48-41.12, p < 0.05) and nearly four times (odds ratio: 3.86, confidence interval: 0.95-15.59, p < 0.05) more likely to be classified as lower competency compared to high relative strength boys. Relative strength has more influence on motor skill performance than maturity when compared with movement competency.

The purpose of this study was to examine the usefulness of individual load-velocity profiles and the between-athlete variation using the decrement in maximal velocity (Vdec) approach to prescribe training loads in resisted sled pulling in young athletes. Seventy high school, team sport, male athletes (age 16.7 ± 0.8 years) were recruited for the study. All participants performed one un-resisted and four resisted sled-pull sprints with incremental resistance of 20% BM. Maximal velocity was measured with a radar gun during each sprint and the load-velocity relationship established for each participant. A subset of 15 participants was used to examine the reliability of sled pulling on three separate occasions. For all individual participants, the load-velocity relationship was highly linear ( r > 0.95). The slope of the load-velocity relationship was found to be reliable (coefficient of variation (CV) = 3.1%), with the loads that caused a decrement in velocity of 10, 25, 50, and 75% also found to be reliable (CVs = <5%). However, there was a large between-participant variation (95% confidence intervals (CIs)) in the load that caused a given Vdec, with loads of 14-21% body mass (% BM) causing a Vdec of 10%, 36-53% BM causing a Vdec of 25%, 71-107% BM causing a Vdec of 50%, and 107-160% BM causing a Vdec of 75%. The Vdec method can be reliably used to prescribe sled-pulling loads in young athletes, but practitioners should be aware that the load required to cause a given Vdec is highly individualized.

This study examined individual responses in leg stiffness, reactive strength index (RSI), movement proficiency (deep overhead squat and in-line lunge), and trunk muscular endurance (flexor and extensor tests) in young female gymnasts following an 8-week neuromuscular training intervention. Thirty-four pre-peak height velocity (PHV) female gymnasts were divided into either an experimental group (EXP n = 17) or control group (CON n = 17). The EXP replaced their normal gymnastics physical preparation with a neuromuscular training program, while the CON continued with their habitual gymnastics program. Chi square analysis showed that the EXP resulted in significantly more positive responders compared to CON for measures of leg stiffness (41% versus 12% responded positively), extensor muscular endurance, (76% versus 29%), and competency in the deep overhead squat, (76% versus 29%) and in-line lunge (left lead leg) (65% versus 18%). Conversely, the number of positive responders for RSI (53% versus 61%), the flexor endurance test (88% versus 53%), and the right in-line lunge (47% versus 35%) were not significantly different between groups. These findings suggest that most young gymnasts responded positively to neuromuscular training from the perspective of improving movement proficiency and trunk endurance; however, changes in leg stiffness and RSI were more variable and may require higher intensities to realise further adaptations.

Obesity and related metabolic pathologies represent a significant public health concern. Obesity is associated with increased oxidative stress that damages genomic and mitochondrial DNA. Oxidatively-induced lesions in both DNA pools are repaired via the base-excision repair pathway, initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). Global deletion of OGG1 and common OGG1 polymorphisms render mice and humans susceptible to metabolic disease. However, the relative contribution of mitochondrial OGG1 to this metabolic phenotype is unknown. Here, we demonstrate that transgenic targeting of OGG1 to mitochondria confers significant protection from diet-induced obesity, insulin resistance, and adipose tissue inflammation. These favorable metabolic phenotypes are mediated by an increase in whole body energy expenditure driven by specific metabolic adaptations, including increased mitochondrial respiration in white adipose tissue of OGG1 transgenic (Ogg1 Tg ) animals. These data demonstrate a critical role for a DNA repair protein in modulating mitochondrial energetics and whole-body energy balance.

Context:   Despite the high frequency of knee injuries in athletes, few researchers have studied the effects of chronologic age and stage of maturation on knee-joint kinematics in male youth soccer players., Objective:   To use a coach-friendly screening tool to examine knee-valgus scores for players of different ages and at different stages of maturation., Design:   Cross-sectional study., Setting:   Academy soccer clubs., Patients or Other Participants:   A total of 400 elite male youth soccer players aged 10 to 18 years categorized by chronologic age and stage of maturation based on their years from peak height velocity (PHV)., Main Outcome Measure(s):   Knee valgus was evaluated during the tuck-jump assessment via 2-dimensional analysis. Frontal-plane projection angles were subjectively classified as minor (<10°), moderate (10°-20°), or severe (>20°), and using these classifications, we scored knee valgus in the tuck jump as 0 ( no valgus), 1 ( minor), 2 ( moderate), or 3 ( severe)., Results:   A trend toward higher valgus scores was observed in the younger age groups and the pre-PHV group. The lowest frequency of no valgus occurred in the U18 and post-PHV groups. The highest percentages of severe scores were in the U13 and pre-PHV groups for the right limb. Knee-valgus scores were lower for both lower extremities in the U18 group than in all other age groups ( P < .001) except the U16 group. Scores were lower for the post-PHV than the pre-PHV group for the right limb ( P < .001) and both pre-PHV and circa-PHV groups for the left limb ( P < .001). Noteworthy interlimb asymmetries were evident in the U14, U15, and circa-PHV groups., Conclusions:   Reductions in knee valgus with incremental age and during the later stages of maturation indicated that this risk factor was more prevalent in younger players. Interlimb asymmetry may also emerge around the time of the peak growth spurt and early adolescence, potentially increasing the risk of traumatic injury.

The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT. Further, a NLS was engineered onto a pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (cv-pdg-NLS). Purified enzymes were encapsulated into liposomes and topically delivered to the dorsal surface of SKH1 hairless mice in a UVB-induced carcinogenesis study. Total tumor burden was significantly reduced in mice receiving either UVDE-TAT or UVDE-NLS-TAT versus control empty liposomes and time to death was significantly reduced with the UVDE-NLS-TAT. These data suggest that efficient delivery of exogenous enzymes for the initiation of repair of UVB-induced DNA damage may protect from UVB induction of squamous and basal cell carcinomas.

Nitrogen mustards (NMs) are DNA-alkylating compounds that represent the earliest anticancer drugs. However, clinical use of NMs is limited because of their own mutagenic properties. The mechanisms of NM-induced mutagenesis remain unclear. The major product of DNA alkylation by NMs is a cationic NM-N7-dG adduct that can yield the imidazole ring-fragmented lesion, N 5 -NM-substituted formamidopyrimidine (NM-Fapy-dG). Characterization of this adduct is complicated because it adopts different conformations, including both a canonical β- and an unnatural α-anomeric configuration. Although formation of NM-Fapy-dG in cellular DNA has been demonstrated, its potential role in NM-induced mutagenesis is unknown. Here, we created site-specifically modified single-stranded vectors for replication in primate (COS7) or Escherichia coli cells. In COS7 cells, NM-Fapy-dG caused targeted mutations, predominantly G → T transversions, with overall frequencies of ∼11-12%. These frequencies were ∼2-fold higher than that induced by 8-oxo-dG adduct. Replication in E. coli was essentially error-free. To elucidate the mechanisms of bypass of NM-Fapy-dG, we performed replication assays in vitro with a high-fidelity DNA polymerase, Saccharomyces cerevisiae polymerase (pol) δ. It was found that pol δ could catalyze high-fidelity synthesis past NM-Fapy-dG, but only on a template subpopulation, presumably containing the β-anomeric adduct. Consistent with the low mutagenic potential of the β-anomer in vitro , the mutation frequency was significantly reduced when conditions for vector preparation were modified to favor this configuration. Collectively, these data implicate the α-anomer as a major contributor to NM-Fapy-dG-induced mutagenesis in primate cells., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

The purpose of this study was to examine the effects of a neuromuscular training (NMT) program on lower-extremity biomechanics in youth female netball athletes. The hypothesis was that significant improvements would be found in landing biomechanics of the lower-extremities, commonly associated with anterior cruciate ligament (ACL) injury, following NMT. Twenty-three athletes (age = 12.2 ± 0.9 years; height = 1.63 ± 0.08 m; mass = 51.8 ± 8.5 kg) completed two testing sessions separated by 7-weeks and were randomly assigned to either a experimental or control group. Thirteen athletes underwent 6-weeks of NMT, while the remaining 10 served as controls and continued their regular netball training. Three-dimensional lower-extremity kinematics and vertical ground reaction force (VGRF) were measured during two landing tasks, a drop vertical jump and a double leg broad jump with a single leg landing. The experimental group significantly increased bilateral knee marker distance during the bilateral landing task at maximum knee-flexion range of motion. Knee internal rotation angle during the unilateral landing task at maximum knee flexion-extension range of motion was significantly reduced ( p ≤ 0.05, g > 1.00). The experimental group showed large, significant decreases in peak vertical ground reaction force in both landing tasks ( p ≤ 0.05, g > -1.30). Control participants did not demonstrate any significant pre-to-post-test changes in response to the 6-week study period. Results of the study affirm the hypothesis that a 6-week NMT program can enhance landing biomechanics associated with ACL injury in 11-13 year old female netball athletes.

Oxidative stress resulting from endogenous and exogenous sources causes damage to cellular components, including genomic and mitochondrial DNA. Oxidative DNA damage is primarily repaired via the base excision repair pathway that is initiated by DNA glycosylases. 8-oxoguanine DNA glycosylase (OGG1) recognizes and cleaves oxidized and ring-fragmented purines, including 8-oxoguanine, the most commonly formed oxidative DNA lesion. Mice lacking the OGG1 gene product are prone to multiple features of the metabolic syndrome, including high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Here, we report that OGG1-deficient mice also display skeletal muscle pathologies, including increased muscle lipid deposition and alterations in genes regulating lipid uptake and mitochondrial fission in skeletal muscle. In addition, expression of genes of the TCA cycle and of carbohydrate and lipid metabolism are also significantly altered in muscle of OGG1-deficient mice. These tissue changes are accompanied by marked reductions in markers of muscle function in OGG1-deficient animals, including decreased grip strength and treadmill endurance. Collectively, these data indicate a role for skeletal muscle OGG1 in the maintenance of optimal tissue function.

Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB 1 ) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB 1 -induced HCCs are poorly understood. Herein, it is shown that the DNA base excision repair (BER) enzyme, DNA glycosylase NEIL1, efficiently recognizes and excises the highly mutagenic imidazole ring-opened AFB 1 -deoxyguanosine adduct (AFB 1 -Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB 1 show significant increases in the levels of AFB 1 -Fapy-dG in Neil1 -/- vs. wild-type liver DNA. Further, Neil1 -/- mice are highly susceptible to AFB 1 -induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1 -/- The magnitude of this effect in Neil1 -/- mice is greater than that previously measured in Xeroderma pigmentosum complementation group A (XPA) mice that are deficient in nucleotide excision repair (NER). Given that several human polymorphic variants of NEIL1 are catalytically inactive for their DNA glycosylase activity, these deficiencies may increase susceptibility to AFB 1 -associated HCCs., Competing Interests: The authors declare no conflict of interest.

The Tuck Jump Assessment (TJA) is a clinician-friendly screening tool that was designed to support practitioners with identification of neuromuscular deficits associated with anterior cruciate ligament injury. This study aimed to evaluate the inter- and intra-rater reliability of the modified scoring (0 to 2) TJA to add an additional range of objectivity for each criterion. A total of 24 elite youth volleyball athletes (12 males and 12 females) were included in this study. Each participant's recorded performance of the TJA was scored independently by two raters across ten criteria using the modified scale. The two raters then scored the same videos one week later. Another investigator who was blind to the identity of the raters analyzed the scores from both raters for each participant. Kappa coefficient ( k ) and percentage of exact agreement (PEA) for both intra- and inter-rater reliability were analyzed for each item. Intraclass correlation coefficients (ICC) were calculated to determine intra- and inter-rater reliability of the modified TJA total score. Intra- and inter-rater k was good to excellent for most items (0.65-0.91). Average PEA between the two raters and two sessions ranged from 83.3 to 100% in all scored items. The ICC for the total score was excellent in both inter- and inter-rater correlations (0.94-0.96). This research demonstrated that the modified version of the TJA predominantly shows good to excellent intra- and inter-rater reliability in all analyzed criteria.

Purpose: This study examined how the characteristics of maximal overground sprint performance are affected by the period of peak height velocity (PHV) in boys., Methods: One hundred eighty-nine school-age boys completed two assessments of maximal sprint performance, separated by a 21-month period. Kinematic characteristics of sprint performance were collected during a 30-m sprint using a floor-level optical measurement system, with modeled force and stiffness characteristics also calculated. Participants were grouped according to maturation using a noninvasive predictive equation. Individuals whose maturity offset was <-0.5 yr in both assessments were classed as "pre-PHV" (n = 67), whereas those whose maturity offset developed from <-0.5 to >0.5 yr in test two were classed as "pre-to-post PHV" (n = 39). Participants with a maturity offset between >-0.5 and <0.5 yr at test 2 were removed from analysis (n = 67) to ensure that the entire pre-to-post-PHV group had experienced the PHV spurt., Results: The pre-to-post-PHV group experienced significantly greater increases in speed (10.4% vs 5.6%) and relative vertical stiffness (12.1% vs 5.6%) compared with the pre-PHV group. Step frequency declined (-2.4%) and contact time increased (2.3%) in the pre-PHV group, whereas step frequency increased (2.7%) and contact time decreased (-3.6%) in the pre-PHV to post-PHV group. Changes in relative measures of vertical stiffness, maximal force, and leg stiffness accounted for 79% and 83% of the changes in speed between assessments for pre-PHV and pre-to-post-PHV groups, respectively., Conclusions: As boys experience PHV, there are greater increases in maximal sprint speed compared with those who remain pre-PHV. Furthermore, measures of relative stiffness and relative maximal force appear to exert an important influence on the development of maximal sprint speed in boys, regardless of maturity.

Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B 1 (AFB 1 ) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB 1 -N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB 1 (AFB 1 -Fapy-dG). Because this latter adduct is known to persist in human tissues and contributes to the high frequency G-to-T mutation signature associated with many hepatocellular carcinomas, we sought to establish the identity of the polymerase(s) involved in processing this lesion. Although our previous biochemical analyses demonstrated the ability of polymerase ζ (pol ζ) to incorporate an A opposite AFB 1 -Fapy-dG and extend from this mismatch, biological evidence supporting a unique role for this polymerase in cellular tolerance following aflatoxin exposure has not been established. Following challenge with AFB 1 , survival of mouse cells deficient in pol ζ (Rev3L -/- ) was significantly reduced relative to Rev3L +/- cells or Rev3L -/- cells complemented through expression of the wild-type human REV3L. Furthermore, cell-cycle progression of Rev3L -/- mouse embryo fibroblasts was arrested in late S/G2 following AFB 1 exposure. These Rev3L -/- cells showed an increase in replication-dependent formation of γ-H2AX foci, micronuclei, and chromosomal aberrations (chromatid breaks and radials) relative to Rev3L +/- cells. These data suggest that pol ζ is essential for processing AFB 1 -induced DNA adducts and that, in its absence, cells do not have an efficient backup polymerase or a repair/tolerance mechanism facilitating survival., Competing Interests: The authors declare no conflict of interest.

Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring.

Aflatoxin B1 (AFB1) is a known carcinogen associated with early-onset hepatocellular carcinoma (HCC) and is thought to contribute to over half a million new HCCs per year. Although some of the fundamental risk factors are established, the molecular basis of AFB1-induced mutagenesis in primate cells has not been rigorously investigated. To gain insights into genome instability that is produced as a result of replicating DNAs containing AFB1 adducts, site-specific mutagenesis assays were used to establish the mutagenic potential of the persistent ring-opened AFB1 adduct, AFB1-formamidopyrimidine (AFB1-FAPY). This lesion was highly mutagenic, yielding replication error frequencies of 97%, with the predominant base substitution being a G to T transversion. This transversion is consistent with previous mutational data derived from aflatoxin-associated HCCs. In vitro translesion synthesis assays demonstrated that polymerase (pol) ζ was the most likely candidate polymerase that is responsible for the G to T mutations induced by this adduct., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hepatocellular carcinomas (HCCs) are the third leading cause of cancer deaths worldwide. The highest rates of early onset HCCs occur in geographical regions with high aflatoxin B1 (AFB1) exposure, concomitant with hepatitis B infection. Although the carcinogenic basis of AFB1 has been ascribed to its mutagenic effects, the mutagenic property of the primary AFB1-DNA adduct, AFB1-N7-Gua, in mammalian cells has not been studied extensively. Taking advantage of the ability to create vectors containing a site-specific DNA adduct, the mutagenic potential was determined in primate cells. This adduct was highly mutagenic following replication in COS-7 cells, with a mutation frequency of 45%. The spectrum of mutations was predominantly G to T base substitutions, a result that is consistent with previous mutation data derived from aflatoxin-associated HCCs. To assess which DNA polymerases (pol) might contribute to the mutational outcome, in vitro replication studies were performed. Unexpectedly, replicative pol δ and the error-prone translesion synthesis pol ζ were able to accurately bypass AFB1-N7-Gua. In contrast, replication bypass using pol κ was shown to occur with low fidelity and could account for the commonly detected G to T transversions., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)