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Dietary exposure to aflatoxin B₁ (AFB₁) is a risk factor for the development of hepatocellular carcinomas (HCCs). Following metabolic activation, AFB₁ reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer (COSMIC) database. Deficiencies in either base excision repair (BER) due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair (NER) due to the absence of xeroderma complementation group A protein (XPA) contribute to HCCs in murine models. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNAs of NEIL1-deficient, XPA-deficient, and DNA repair-proficient mice following neonatal injection of 1 mg/kg AFB₁. Analyses of AFB₁-induced mutations showed high cosine similarity to SBS24, regardless of repair proficiency status. The absence of NEIL1 resulted in an approximately 30% increase in the frequency of mutations, with distribution suggesting preferential NEIL1-dependent repair of AFB₁ lesions in open chromatin regions. A trend of increased mutagenesis was also observed in the absence of XPA. Consistent with the role of XPA in transcription-coupled repair, mutational profiles in XPA-deficient mice showed disruption of the transcriptional bias in mutations associated with SBS24. Implications: Our findings define the roles of DNA repair pathways in AFB₁-induced mutagenesis and carcinogenesis in murine models, with these findings having implications in human health for those with BER and NER deficiencies.

Abstract: Moeskops, S, Oliver, JL, Radnor, JM, Haff, GG, Myer, GD, Ramachandran, AK, Kember, LS, Pedley, JS, and Lloyd, RS. Effects of neuromuscular training on muscle architecture, isometric force production, and stretch-shortening cycle function in trained young female gymnasts. J Strength Cond Res 38(9): 1640-1650, 2024-This study evaluated the effects of a 10-month neuromuscular training (NMT) intervention on muscle architecture, isometric force production, and stretch-shortening cycle (SSC) function. Thirty-seven girls aged 6-12 years were placed into gymnastics + NMT (gNMT; n = 15), gymnastics only (GYM; n = 10), or maturity-matched control (CON; n = 12) groups. The gNMT group followed a 10-month NMT program in addition to gymnastics training, whereas the GYM group only participated in gymnastics training. Isometric midthigh pull (IMTP) and drop jump (DJ) kinetics were measured, in addition to muscle thickness, fascicle length, and pennation angle of the gastrocnemius medialis at baseline and at 4, 7, and 10 months. A 3 × 4 (group × time) repeated-measures ANCOVA (covariate, % predicted adult height) was used to evaluate within-group changes. Significance level was set at p < 0.05. Significant interaction effects were observed in muscle thickness, absolute (PF abs ) and relative peak force (PF rel ) in the IMTP and various DJ variables. The gNMT group demonstrated improvements in muscle thickness, IMTP PF abs and PF rel , and DJ kinetics, most commonly evidenced from 7 months onward. The GYM group's muscle thickness also significantly improved, accompanied by improvements in some DJ kinetics. The CON group did not experience any desirable changes. Overall, NMT elicited positive changes in muscle thickness, PF abs and PF rel , and SSC function to a greater extent than gymnastics training alone or growth and maturation. As most adaptations took 7 months, longer-term NMT programs should be implemented with youth female gymnasts., (Copyright © 2024 National Strength and Conditioning Association.)

Abstract: Morris, SJ, Oliver, JL, Pedley, JS, Radnor, JM, Haff, GG, Cooper, S-M, and Lloyd, RS. Kinetic predictors of weightlifting performance in young weightlifters. J Strength Cond Res 38(9): 1551-1560, 2024-Relationships between force-generating capabilities and weightlifting performance ( e.g ., snatch, clean and jerk [C&J], and combined total) have previously been explored in adult weightlifters; however, associations in young athletes are unknown. The purpose of this study was twofold: (a) to examine the relationships between countermovement jump (CMJ) and isometric midthigh pull (IMTP) kinetics and weightlifting performance in young weightlifters and (b) to determine the proportion of weightlifting performance that could be accounted for by CMJ and IMTP kinetics using principal component analysis (PCA). Thirty-seven young weightlifters (12-18 years of age) completed 3 trials of CMJ and 2 trials of the IMTP assessments on dual force plates. Recent competition maximum loads, obtained within 2 weeks of the data collection, for the C&J and snatch were also recorded. Pearson's zero-order correlation coefficients demonstrated moderate to very high correlations ( r = 0.359-0.801; all p ≤ Benjamini-Hochberg critical values [ B-Hα ]) between CMJ kinetic variables, including jump height, average braking force, average braking velocity, absolute and relative braking net impulse, absolute and relative force at minimum displacement, absolute and relative propulsive force, absolute and relative propulsive net impulse and average propulsive velocity, and weightlifting performance. High to very high correlations were evident between IMTP peak force and relative peak force and all weightlifting performance metrics (snatch, C&J, combined total, combined total [kg]/body mass [kg -0.67 ], and Sinclair's total; r = 0.538-0.796; p ≤ B-Hα ). Components from the PCA were used to conduct stepwise, multiple, linear regression analyses. Moderate (45.8-52.9%) and large percentages (79.1-81.3%) of variance in absolute measures of weightlifting performance were explained by IMTP peak force variables and CMJ propulsive variables, respectively. These novel findings indicate that IMTP peak force variables and CMJ propulsive variables could provide valuable insight for talent identification and long-term athletic development in junior weightlifting pathways., (Copyright © 2024 National Strength and Conditioning Association.)

Chronic exercise training is associated with an "athlete's artery" phenotype in young adults and an attenuated age-related decline in endothelium-dependent arterial function. Adolescence is associated with an influx of sex-specific hormones that may exert divergent effects on endothelial function, but whether training adaptations interact with biological maturation to produce a "youth athlete's artery" has not been explored. We investigated the influence of exercise-training status on endothelium-dependent arterial function during childhood and adolescence. Brachial artery flow-mediated dilation (FMD) was assessed in n = 102 exercise-trained (males, n = 25; females, n = 29) and untrained (males, n = 23; females, n = 25) youths, characterized as pre (males, n = 25; females, n = 26)- or post (males, n = 23; females, n = 28)-predicted age at peak height velocity (PHV). Baseline brachial artery diameter was larger in post- compared with pre-PHV youths ( P ≤ 0.001), males compared with females ( P ≤ 0.001), and trained compared with untrained youths (3.26 ± 0.51 vs. 3.11 ± 0.42 mm; P = 0.041). Brachial FMD was similar in pre- and post-PHV youths ( P = 0.298), and males and females ( P = 0.946). However, exercise-trained youths demonstrated higher FMD when compared with untrained counterparts (5.3 ± 3.3 vs. 3.0 ± 2.6%; P ≤ 0.001). Furthermore, brachial artery diameter ( r 2 = 0.142; P = 0.007 vs. r 2 = 0.004; P = 0.652) and FMD ( r 2 = 0.138; P = 0.008 vs. r 2 = 0.003; P = 0.706) were positively associated with cardiorespiratory fitness in post-, but not pre-PHV youths, respectively. Collectively, our data indicate that exercise training is associated with brachial artery remodeling and enhanced endothelial function during youth. However, arterial remodeling and endothelium-dependent function are only associated with elevated cardiorespiratory fitness during later stages of adolescence. NEW & NOTEWORTHY We report preliminary evidence of the "youth athlete's artery," characterized by training-related arterial remodeling and elevated endothelium-dependent arterial function in children and adolescents. However, training-related adaptations in brachial artery diameter and flow-mediated dilation (FMD) were associated with cardiorespiratory fitness in adolescents, but not in children. Our findings indicate that endothelium-dependent arterial function is modifiable with chronic exercise training during childhood, but the association between FMD and elevated cardiorespiratory fitness is only apparent during later stages of adolescence.

Background: Female athletes are four to six times more likely to sustain an anterior cruciate ligament (ACL) injury than male athletes. Jump-landing biomechanics are influenced by maturation, with post-pubertal female athletes at a heightened risk of ACL injuries., Objective: The aim of our systematic review was to identify and summarise the current evidence regarding the changes in kinematic and kinetic risk factors associated with ACL injuries during jump-landing tasks in female athletes at various stages of maturity., Methods: A systematic search was conducted in PubMed, CINAHL, Web of Science, SPORTDiscus, EMBASE and Scopus. Articles were included if they: (1) conducted the research on uninjured female athletes with no restriction on playing level/experience; (2) provided information regarding the stage of the maturity and the scale used for estimating the maturity status of the participants; and (3) reported a biomechanical risk factor associated with ACL injuries during jump-landing tasks across at least two different maturity groups (e.g. pre-pubertal vs post-pubertal)., Results: Sixteen articles involving 2323 female athletes were included in our review. A total of 12 kinematic and 8 kinetic variables were identified across these studies. Of the 12 kinematic variables reported in our review, we found strong evidence for higher peak knee abduction angle in post-pubertal female individuals compared with pre-pubertal girls (p < 0.05). With regard to the 8 kinetic variables, we found strong evidence for lower relative peak vertical ground reaction force, higher external knee abduction moment and internal rotation moment in post-pubertal compared with pre-pubertal athletes. The strength of evidence for the remaining kinematic and kinetic variables ranged from conflicting to moderate and, in some instances, could not be determined., Conclusions: Our study provides an overview of the changes in biomechanical risk factors in female athletes during jump-landing tasks at various stages of maturity. We found moderate-to-limited evidence for most kinematic and kinetic variables, highlighting the need for further research., (© 2024. The Author(s).)

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.)

The base excision repair (BER) pathway is a precise and versatile mechanism of DNA repair that is initiated by DNA glycosylases. Endonuclease VIII-like 1 (NEIL1) is a bifunctional glycosylase/abasic site (AP) lyase that excises a damaged base and subsequently cleaves the phosphodiester backbone. NEIL1 is able to recognize and hydrolyze a broad range of oxidatively-induced base lesions and substituted ring-fragmented guanines, including aflatoxin-induced 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua). Due to NEIL1's protective role against these and other pro-mutagenic lesions, it was hypothesized that naturally occurring single nucleotide polymorphic (SNP) variants of NEIL1 could increase human risk for aflatoxin-induced hepatocellular carcinoma (HCC). Given that populations in South Asia experience high levels of dietary aflatoxin exposures and hepatitis B viral infections that induce oxidative stress, investigations on SNP variants of NEIL1 that occur in this region may have clinical implications. In this study, the most common South Asian variants of NEIL1 were expressed, purified, and functionally characterized. All tested variants exhibited activities and substrate specificities similar to wild type (wt)-NEIL1 on high-molecular weight DNA containing an array of oxidatively-induced base lesions. On short oligodeoxynucleotides (17-mers) containing either a site-specific apurinic/apyrimidinic (AP) site, thymine glycol (ThyGly), or AFB 1 -FapyGua, P206L-NEIL1 was catalytically comparable to wt-NEIL1, while the activities of NEIL1 variants Q67K and T278I on these substrates were ≈2-fold reduced. Variant T103A had a greatly diminished ability to bind to 17-mer DNAs, limiting the subsequent glycosylase and lyase reactions. Consistent with this observation, the rate of excision by T103A on 17-mer oligodeoxynucleotides containing ThyGly or AFB 1 -FapyGua could not be measured. However, the ability of T103A to excise ThyGly was improved on longer oligodeoxynucleotides (51-mers), with ≈7-fold reduced activity compared to wt-NEIL1. Our studies suggest that NEIL1 variant T103A may present a pathogenic phenotype that is limited in damage recognition, potentially increasing human risk for HCC., Competing Interests: Declaration of Competing Interest 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. Certain equipment, instruments, software, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement of any product or service by NIST, nor is it intended to imply that the materials or equipment identified are necessarily the best available for the purpose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.)

Abstract: Shaw, J, Gould, ZI, Oliver, JL, and Lloyd, RS. Twelve weeks of progressive resistance training positively improves physical fitness and golf swing performance in talented youth golfers. J Strength Cond Res 38(6): 1103-1110, 2024-This aim of this study was to investigate the effects of a 12-week resistance training program in talented junior golfers. Eighteen talented youth golfers were pair matched by maturity status and handicap, and subsequently allocated to an experimental (EXP) or control group. During the 12-week intervention, both groups continued with their normal golf practice while the EXP group also completed a progressive twice-weekly resistance training program. At baseline, subjects performed multiple trials of an isometric midthigh pull (IMTP), countermovement jump (CMJ), standing long jump, golf movement screen (GMS), and isometric plank hold. Club head speed (CHS) and carry distance for a 6-iron and driver were also measured using a commercial launch monitor. When controlled for maturity offset, there were significant ( p < 0.05) interaction effects in favor of the EXP group for absolute ( g = 1.29) and relative ( g = 2.06) peak force for the IMTP, CMJ absolute ( g = 0.73) and relative ( g = 0.66) peak power, jump height ( g = 1.05), modified reactive strength index ( g = 1.30), lateral ( g = 0.48-0.88) and horizontal jump distance ( g = 1.20), and GMS total score ( g = 1.07). Significant interaction effects were also reported in 6-iron and driver CHS and carry distance in favor of the EXP group ( p < 0.05; g = 0.41-1.64). These findings indicate that twice-weekly resistance training in combination with regular golf practice can stimulate increases in measures of strength, power, and movement competency in youth golfers, which should contribute to enhanced golf swing performance., (Copyright © 2024 National Strength and Conditioning Association.)

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.)

Objective: To analyse interlimb kinetics and asymmetries during the tuck jump assessment (TJA), before and after kinetic stabilization, to identify injury risk in healthy female athletes., Design: Cross-sectional study., Setting: Laboratory., Participants: Twenty-five healthy females (age 21.0 ± 1.83 yrs; height 1.68 ± 0.06 m; body mass 69.4 ± 10.7 kg)., Main Outcome Measures: Kinetics were measured during 10-s trials of the TJA and absolute asymmetries compared, before and after kinetic stabilization using paired sample t-tests. Statistical parametric mapping (SPM) compared vertical ground reaction force (VGRF) data for each limb during the jumping cycles before and after stabilization., Results: Small to moderate increases in interlimb asymmetries were observed after stabilization for VGRF, relative vertical leg stiffness, average loading rate, total and propulsive impulse, peak braking and propulsive force (p < 0.05). SPM revealed significant interlimb differences between 77-98% and 83-99% of ground contact for the jumping cycles pre- and post-stabilization respectively., Conclusions: Larger asymmetries were evident after kinetic stabilization, with increased VGRF in the non-dominant limb. We speculate that participants sacrificed interlimb landing symmetry to achieve kinetic stability, which may reflect a primal landing strategy that forgoes movement quality. Assessing lower limb biomechanics using the TJA should involve examining kinetic stability and interlimb kinetic asymmetries., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The extent of structural cardiac remodeling in response to endurance training is maturity dependent. In adults, this structural adaptation is often associated with the adaptation of left ventricular (LV) twist mechanics. For example, an increase in LV twist often follows an expansion in end-diastolic volume, whereas a reduction in twist may follow a thickening of the LV walls. While structural cardiac remodeling has been shown to be more prominent post-peak height velocity (PHV), it remains to be determined how this maturation-dependent structural remodeling influences LV twist. Therefore, we aimed to (1) compare LV twist mechanics between trained and untrained children pre- and post-PHV and (2) investigate how LV structural variables relate to LV twist mechanics pre- and post-PHV., Methods: Left ventricular function and morphology were assessed (echocardiography) in endurance-trained and untrained boys (n = 38 and n = 28, respectively) and girls (n = 39 and n = 34, respectively). Participants were categorized as either pre- or post-PHV using maturity offset to estimate somatic maturation., Results: Pre-PHV, there were no differences in LV twist or torsion between trained and untrained boys (twist: P = .630; torsion: P = .382) or girls (twist: P = .502; torsion: P = .316), and LV twist mechanics were not related with any LV structural variables (P > .05). Post-PHV, LV twist was lower in trained versus untrained boys (P = .004), with torsion lower in trained groups, irrespective of sex (boys: P < .001; girls: P = .017). Moreover, LV torsion was inversely related to LV mass (boys: r = -0.55, P = .001; girls: r = -0.46, P = .003) and end-diastolic volume (boys: r = -0.64, P < .001; girls: r = -0.36, P = .025) in both sexes., Conclusions: A difference in LV twist mechanics between endurance-trained and untrained cohorts is only apparent post-PHV, where structural and functional remodeling were related., Competing Interests: Conflicts of Interest None., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Aflatoxin B 1 (AFB 1 ) is a potent human liver carcinogen produced by certain molds, particularly Aspergillus flavus and Aspergillus parasiticus , which contaminate peanuts, corn, rice, cottonseed, and ground and tree nuts, principally in warm and humid climates. AFB 1 undergoes bioactivation in the liver to produce AFB 1 - exo -8,9-epoxide, which forms the covalently bound cationic AFB 1 - N 7-guanine (AFB 1 -N 7-Gua) DNA adduct. This adduct is unstable and undergoes base-catalyzed opening of the guanine imidazolium ring to form two ring-opened diastereomeric 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy-aflatoxin B 1 (AFB 1 -FapyGua) adducts. The AFB 1 formamidopyrimidine (Fapy) adducts induce G → T transversion mutations and are likely responsible for the carcinogenic effects of AFB 1 . Quantitative liquid chromatography-mass spectrometry (LC-MS) methods have shown that AFB 1 - N 7-Gua is eliminated in rodent and human urine, whereas ring-opened AFB 1 -FapyGua adducts persist in rodent liver. However, fresh frozen biopsy tissues are seldom available for biomonitoring AFB 1 DNA adducts in humans, impeding research advances in this potent liver carcinogen. In contrast, formalin-fixed paraffin-embedded (FFPE) specimens used for histopathological analysis are often accessible for molecular studies. However, ensuring nucleic acid quality presents a challenge due to incomplete reversal of formalin-mediated DNA cross-links, which can preclude accurate quantitative measurements of DNA adducts. In this study, employing ion trap or high-resolution accurate Orbitrap mass spectrometry, we demonstrate that ring-opened AFB 1 -FapyGua adducts formed in AFB 1 -exposed newborn mice are stable to the formalin fixation and DNA de-cross-linking retrieval processes. The AFB 1 -FapyGua adducts can be detected at levels comparable to those in a match of fresh frozen liver. Orbitrap MS 2 measurements can detect AFB 1 -FapyGua at a quantification limit of 4.0 adducts per 10 8 bases when only 0.8 μg of DNA is assayed on the column. Thus, our breakthrough DNA retrieval technology can be adapted to screen for AFB 1 DNA adducts in FFPE human liver specimens from cohorts at risk of this potent liver carcinogen.

Dietary exposure to aflatoxin B 1 (AFB 1 ) is a recognized risk factor for developing hepatocellular carcinoma. The mutational signature of AFB 1 is characterized by high-frequency base substitutions, predominantly G>T transversions, in a limited subset of trinucleotide sequences. The 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua) has been implicated as the primary DNA lesion responsible for AFB 1 -induced mutations. This study evaluated the mutagenic potential of AFB 1 -FapyGua in four sequence contexts, including hot- and cold-spot sequences as apparent in the mutational signature. Vectors containing site-specific AFB 1 -FapyGua lesions were replicated in primate cells and the products of replication were isolated and sequenced. Consistent with the role of AFB 1 -FapyGua in AFB 1 -induced mutagenesis, AFB 1 -FapyGua was highly mutagenic in all four sequence contexts, causing G>T transversions and other base substitutions at frequencies of ~80%-90%. These data suggest that the unique mutational signature of AFB 1 is not explained by sequence-dependent fidelity of replication past AFB 1 -FapyGua lesions., (© 2023 Environmental Mutagenesis and Genomics Society.)

Background: Male youth soccer players competing at a high level will typically engage in large volumes of soccer training from a young age. However, it is not known whether the high levels of habitual training that these high-performing players are exposed to limit their ability to respond to strength, plyometric or combined training interventions., Objective: The primary aim of our systematic review and meta-analysis was to compare the specific effects of strength, plyometric and combined training with active controls (standard soccer training) on the strength, power and speed characteristics of high-level, highly trained young male soccer players., Methods: We performed a literature search across PubMed, Scopus, CINAHL, Web of Science and SPORTDiscus to identify controlled studies that implemented strength, plyometric or combined training in high-level male youth soccer players. Participants were defined as high level or highly trained based on established guidelines related to either competition level or age-related weekly hours spent in soccer training. Studies needed to report at least one outcome of lower body strength, squat jump, countermovement jump, horizontal power, acceleration (0-10 m), speed (15-40 m) or change of direction speed. A meta-analysis was then performed using a random-effects model to determine the magnitude (Hedge's g) of training responses and whether effects differed across modes of training., Results: From an initial return of 5464 papers, n = 34 studies met the inclusion criteria and provided a total sample of n = 1396 high-level male youth soccer players. Strength, plyometric and combined training resulted in improvements in strength, squat and countermovement jump, horizontal power, acceleration, change of direction speed (all p < 0.05; g = 0.73-1.08, moderate) and speed (p < 0.05; g = 0.40-0.59, small). Lower body strength was the only outcome where training mode had a significant effect (p < 0.05), with plyometric training producing small effects (g = 0.27, p < 0.05) compared with moderate effects for strength (g = 1.07, p < 0.05) and combined (g = 0.75, p < 0.05) training. Prediction intervals for overall effects (all training modes combined) showed that the greatest confidence that future training will lead to positive effects was in the squat and countermovement jump, horizontal power and acceleration (prediction intervals = 0.03-1.81)., Conclusions: High-level, highly trained male youth soccer players can experience positive gains in indices of strength, power and speed from strength, plyometric and combined training, and the magnitude of gains are mostly similar across modes of training. Based on prediction intervals, there is a good level of certainty that future strength, plyometric and combined training in this population would lead to positive improvements in vertical and horizontal power and sprint acceleration., (© 2023. The Author(s).)

Cerebral blood velocity (CBv) increases in response to moderate exercise in humans, but the magnitude of change is smaller in children compared with postpubertal adolescents and adults. Whether sex differences exist in the anterior or posterior CBv response to exercise across pubertal development remains to be determined. We assessed middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) blood velocity via transcranial Doppler in 38 prepubertal (18 males) and 48 postpubertal (23 males) with cerebrovascular and cardiorespiratory measures compared at baseline and ventilatory threshold. At baseline, MCAv was higher in both sexes pre- versus postpuberty. Females demonstrated a greater MCAv ( P < 0.001) than their male counterparts (prepubertal females; 78 ± 11 cm·s -1 vs. prepubertal males; 72 ± 8 cm·s -1 , and postpubertal females; 68 ± 10 cm·s -1 vs. postpubertal males; 62 ± 7 cm·s -1 ). During exercise, MCAv remained higher in postpubertal females versus males (81 ± 15 cm·s -1 vs. 73 ± 11 cm·s -1 ), but there were no differences in prepuberty. The relative increase in PCAv was greater in post- versus prepubertal females (51 ± 9 cm·s -1 vs. 45 ± 11 cm·s -1 ; P = 0.032) but was similar in males and females. Our findings suggest that biological sex alters anterior cerebral blood velocities at rest in both pre- and postpubertal youth, but the response to submaximal exercise is only influenced by sex postpuberty. NEW & NOTEWORTHY Cerebral blood velocity (CBv) in the anterior circulation was higher in females compared with males irrespective of maturational stage, but not in the posterior circulation. In response to exercise, females demonstrated a greater CBv compared with males, especially post-peak height velocity (post-PHV) where the CBv response to exercise was more pronounced. Our findings suggest that both CBv at rest and in response to acute submaximal exercise are altered by biological sex in a maturity-dependent manner.

Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. In this study, mitoxantrone-mediated inhibition of APE1 at THF sites was shown to be consistent with preferential binding to, and thermal stabilization of DNA containing a THF site as compared to non-damaged DNA. Investigations into the properties of mitoxantrone at AP and 3' α,β-unsaturated aldehyde sites demonstrated that in addition to being a potent inhibitor of APE1 at these biologically-relevant substrates (∼ 0.5 μM IC 50 on AP site-containing DNA), mitoxantrone also incised AP site-containing DNA by catalyzing β- and β/δ-elimination reactions. The efficiency of these reactions to generate the 3' α,β-unsaturated aldehyde and 3' phosphate products was modulated by DNA structure. Although these cell-free reactions revealed that mitoxantrone can generate 3' phosphates, cells lacking polynucleotide kinase phosphatase did not show increased sensitivity to mitoxantrone treatment. Consistent with its ability to inhibit APE1 activity on DNAs containing either an AP site or a 3' α,β-unsaturated aldehyde, combined exposures to clinically-relevant concentrations of mitoxantrone and a small molecule APE1 inhibitor revealed additive cytotoxicity. These data suggest that in a cellular context, mitoxantrone may interfere with APE1 DNA repair functions., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Abstract: Kumar, NTA, Radnor, JM, Oliver, JL, Lloyd, RS, CSCSD, Pedley, JS, Wong, MA, and Dobbs, IJ. The influence of maturity status on drop jump kinetics in male youth. J Strength Cond Res 38(1): 38-46, 2024-The aim of this study was to examine the effects of maturity status on drop jump (DJ) kinetics in young male athletes (categorized as early-pre-peak height velocity [PHV] [<-2.51 years], late-pre-PHV [-1.99 to -1.00 years], circa-PHV [-0.50 to 0.50 years], and post-PHV [>1.00 years]). All athletes performed a DJ from a 30-cm box onto force plates with performance variables (jump height, ground contact time, and reactive strength index) and absolute and relative kinetic variables during the braking and propulsive phases assessed. Subjects were categorized into GOOD (no impact-peak and spring-like), MODERATE (impact-peak and spring-like), or POOR (impact-peak and not spring-like) stretch-shortening cycle (SSC) function. The post-PHV group exhibited significantly greater values for most absolute kinetic variables compared with early-pre-PHV, late-pre-PHV, and circa-PHV (p < 0.05). The differences observed between consecutive maturity groups were similar in magnitude for most absolute variables (Cohen's d = 0.53-1.70). Post-PHV male athletes outperform their less mature counterparts during a DJ, and this may be attributed to the growth and maturity-related structural and motor control strategy changes that occur in children. Stretch-shortening cycle function in boys seems to improve with maturity status reflected by a greater number of post-PHV participants displaying GOOD SSC function (65.8%) and a greater number of early-pre-PHV participants displaying POOR SSC function (54.4%). However, a number of mature boys displayed POOR SSC function (17.8%), suggesting that the development of SSC function is not exclusively related to maturation., (Copyright © 2023 National Strength and Conditioning Association.)

Abstract: Shaw, J, Gould, ZI, Oliver, JL, and Lloyd, RS. Within- and between-session reliability of golf swing variables using the TrackMan launch monitor in talented golfers. J Strength Cond Res 37(12): 2431-2437, 2023-The purpose of the current study was to establish the within- and between-session reliability of the TrackMan launch monitor to measure golf swing variables. Twenty-one golfers attended 2 test sessions, with data captured from 3 golf shots using a 6-iron and 3 using a driver. Club head speed (CHS), ball speed, smash factor, attack angle, club path, launch angle, spin rate, spin axis, carry distance, and total distance were determined from data collected using a TrackMan launch monitor. Within- and between-session reliability for each variable was calculated using repeated-measures analysis of variance, intraclass correlation coefficients (ICCs), and coefficients of variation (CVs) with 95% confidence intervals. Within-session measures of CHS, ball speed, carry distance, and total distance were found to be reliable for both 6-iron and driver (CV ≤ 5.8, ICC ≥ 0.87) and launch angle for the 6-iron (CV = 6.7-9.3%, ICC = 0.87-0.92). Between-session measures of CHS, ball speed, smash factor, launch angle, carry distance, and total distance for both 6-iron and driver (CV% = 0.7-9.1%, ICC = 0.5-0.99) and spin rate for 6-iron (CV% = 9.4%, ICC = 0.89) were also shown to be reliable. These findings indicate that the TrackMan launch monitor is a reliable method for measuring CHS, ball speed, carry distance, and total distance in talented golfers, both within and between sessions. Practitioners can confidently use these variables to assess golf swing performance in golfers and evaluate meaningful changes in response to training interventions., (Copyright © 2023 National Strength and Conditioning Association.)

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.)

This study investigated measures of physical fitness and golf swing performance in competitive youth golfers. Sixty-four golfers, subdivided into three handicap groups (CAT0, <1 handicap, n  = 21; CAT1, 1-5 handicap, n  = 20; CAT2, >5 handicap, n  = 23), were assessed for isometric strength, power, movement competency and core endurance. Clubhead speed (CHS) and carry distance for 6-iron and driver were also measured. When controlled for maturity offset, CAT0 golfers produced significantly greater peak power, isometric absolute and relative peak force, movement competency, and jump distance than higher handicap golfers (all p  < 0.05). Maturity status was strongly associated with CHS and carry distance for both clubs ( R 2  = 0.552-0.784). Linear regressions showed maturity offset explained a larger amount of variance in CHS (driver = 78.4%, 6-iron = 71.3%) and carry distance (driver = 55.2%, 6-iron = 57.4%) than handicap. Multiple linear regression analyses showed that peak power explained 79.4% and 82.4% of variation in 6-iron and driver CHS, respectively, while isometric absolute peak force explained 69.6% and 74.3% of the variation in 6-iron and driver carry distance, respectively. Subsequently, interventions targeting the development of peak force and power could aid golf swing performance in young golfers.

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.

Nei-like glycosylase 1 (NEIL1) is a DNA repair enzyme that initiates the base excision repair (BER) pathway to cleanse the human genome of damage. The substrate specificity of NEIL1 includes several common base modifications formed under oxidative stress conditions, as well as the imidazole ring open adducts that are induced by alkylating agents following initial modification at N7 guanine. An example of the latter is the persistent and mutagenic 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua) adduct, resulting from the alkylating agent aflatoxin B 1 (AFB 1 ) exo-8-9-epoxide. Naturally occurring single nucleotide polymorphic (SNP) variants of NEIL1 are hypothesized to be associated with an increased risk for development of early-onset hepatocellular carcinoma (HCC), especially in environments with high exposures to aflatoxins and chronic inflammation from viral infections and alcohol consumption. Given that AFB 1 exposures and hepatitis B viral (HBV) infections represent a major problem in the developing countries of sub-Saharan Africa, it is pertinent to study SNP NEIL1 variants that are present in this geographic region. In this investigation, we characterized the three most common NEIL1 variants found in this region: P321A, R323G, and I182M. Biochemical analyses were conducted to determine the proficiencies of these variants in initiating the repair of DNA lesions. Our data show that damage recognition and excision activities of P321A and R323G were near that of wild-type (WT) NEIL1 for both thymine glycol (ThyGly) and AFB 1 -FapyGua. The substrate specificities of these variants with respect to various oxidatively-induced base lesions were also similar to that of WT. In contrast, the I182M variant was unstable, such that it precipitated under a variety of conditions and underwent rapid inactivation at a biologically relevant temperature, with partial stabilization being observed in the presence of undamaged DNA. This study provides insight regarding the potential increased risk for early-onset HCC in human populations carrying the NEIL1 I182M variant., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Kyles, A, Oliver, JL, Cahill, MJ, Lloyd, RS, and Pedley, J. Linear and change of direction repeated sprint ability tests: a systematic review. J Strength Cond Res 37(8): 1703-1717, 2023-The ability to repeatedly sprint is important in many sports, but there is no established protocol for measuring repeated sprint ability (RSA). The purpose of this review was to identify overground RSA protocols previously reported in the literature and to recommend standardized protocols. A systematic review of the literature was used to identify studies that have used an RSA test, with data describing protocol design extracted. One hundred eight studies were included in the review, across which 47 unique protocols were identified. Eighteen protocols included at least one change of direction (COD), and this increased mean sprint time compared with linear RSA tests (7.26 ± 1.84 vs. 4.48 ± 1.02 seconds). There was considerable variability across protocols regarding sprint distance (20-40 m), sprint repetitions (3-15), recovery duration (10-60 seconds), recovery type (active vs. passive), and work-to-rest ratio (≤1:1.4-19.2). Separate protocols are needed for linear and COD tests, and these should reflect the brief nature of intense periods of competition and stress the ability to recover. Based on data across studies for protocol design and to ensure a demanding work-to-rest ratio, it is suggested that a linear RSA should comprise 6 × 30 m sprints separated by 15 seconds of active recovery. To provide some parity to linear tests, to keep work duration brief and to maintain a demanding work-to-rest ratio, a COD RSA should comprise 6 × 30 m shuttle sprints (15 + 15 m), providing one change of direction (180° COD), and maintaining a 15-second active recovery., (Copyright © 2023 National Strength and Conditioning Association.)

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.)