VCP regulates early tau seed amplification via specific cofactors.

Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. In vitro seeding reactions typically take days, yet seeding into the complex cytoplasmic milieu happens within hours, implicating a machinery with unknown players that controls this process in the acute phase. Methods: We used proximity labeling to identify factors that control seed amplification within 5h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and chemical manipulations of VCP. Results: VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on aggregation in HEK293T tau biosensor cells and human neurons alike: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors were effective only when administered within 8h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding. Conclusions: Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a dedicated cytoplasmic processing complex based on VCP that directs seeds acutely towards degradation vs. amplification.

Testicular Cancer Incidence and Mortality Within Rural and Urban Regions.

Purpose: Testicular cancer (TCa) is among the most common cancers within adolescent and young adult (AYA) male populations. However, information is limited to variations in incidence and mortality outside of racial/ethnic subgroups. Rural regions historically have a greater overall cancer incidence than urban regions, although some key differences exist regarding site. TCa-specific incidence and mortality disparities are not commonly reported in this context. This study aims to help fill that gap by providing discovery evidence if there is an association between US rural/urban regions and TCa incidence and mortality. Methods: Secondary analysis of Surveillance, Epidemiology, and End Results incidence and mortality data were employed to determine if rural/urban TCa incidence and mortality disparities exist among U.S. males. Results: There was a 2.6% increased rate of TCa in U.S. urban as compared with rural geographic regions from 2011 to 2015. When geographic region is disaggregated, rural regions see higher rates than urban. When factoring in race/ethnicity, White/Caucasians and Hispanics had statistically higher urban rates whereas American Indian/Alaskan Natives and Asian/Pacific Islander groups had statistically higher rural rates. Conclusion: Geographic regional TCa variation research is virtually nonexistent for U.S. males, specifically AYAs of color. Determining preliminary trends in rural and urban regions can assist in the creation of more targeted services, particularly among underserved and vulnerable populations that have tenuous access to health care, to reduce disparate health outcomes. Exploring geographic differences in TCa incidence and mortality can have implications within service industry, health care accessibility, and public health justice areas of research and outreach.

Front squat data reproducibility collected with a triple-axis accelerometer.

The purpose of our study was to assess data reproducibility from 2 consecutive front squat workouts, spaced 1 week apart, performed by American college football players (n = 18) as they prepared for their competitive season. For each workout, our methods entailed the performance of 3-6 front squat repetitions per set at 55, 65, and 75% of subject's 1 repetition maximum (1RM) load. In addition, a fourth set was done at a heavier load, with a resistance equal to 80 and 83% of their 1RM values, for the first and second workouts, respectively. A triple-axis accelerometer was affixed to a barbell to quantify exercise performance. Per load, the accelerometer measures peak values for the following indices: force, velocity, and power. To assess data reproducibility, inter-workout comparisons were made for 12 performance indices with 4 statistical test-retest measures: intraclass correlation coefficients, coefficients of variation (CVs), and the SEM expressed in both absolute and relative terms. Current results show that the majority of performance indices exceeded intraclass correlation (0.75-0.80) and CV (10-15%) values previously deemed as acceptable levels of data reproducibility. The 2 indices with the greatest variability were power and velocity values obtained at 55% of the 1RM load; thus, it was concluded that higher movement rates at the lightest load were the most difficult aspect of front squat performance to repeat successfully over time. Our practical applications imply lighter loads, with inherently higher rates of barbell movement, yield lower data reproducibility values.

Anthropometry as a predictor of bench press performance done at different loads.

The purpose of our study was to examine the ability of anthropometric variables (body mass, total arm length, biacromial width) to predict bench press performance at both maximal and submaximal loads. Our methods required 36 men to visit our laboratory and submit to anthropometric measurements, followed by lifting as much weight as possible in good form one time (1 repetition maximum, 1RM) in the exercise. They made 3 more visits in which they performed 4 sets of bench presses to volitional failure at 1 of 3 (40, 55, or 75% 1RM) submaximal loads. An accelerometer (Myotest Inc., Royal Oak MI) measured peak force, velocity, and power after each submaximal load set. With stepwise multivariate regression, our 3 anthropometric variables attempted to explain significant amounts of variance for 13 bench press performance indices. For criterion measures that reached significance, separate Pearson product moment correlation coefficients further assessed if the strength of association each anthropometric variable had with the criterion was also significant. Our analyses showed that anthropometry explained significant amounts (p < 0.05) of variance for 8 criterion measures. It was concluded that body mass had strong univariate correlations with 1RM and force-related measures, total arm length was moderately associated with 1RM and criterion variables at the lightest load, whereas biacromial width had an inverse relationship with the peak number of repetitions performed per set at the 2 lighter loads. Practical applications suggest results may help coaches and practitioners identify anthropometric features that may best predict various measures of bench press prowess in athletes.

Prediction of resultant testosterone concentrations from flywheel-based resistive exercise.

INTRODUCTION: Numerous variables impact resultant testosterone concentrations (TC) that foretell the efficacy of workouts. Identifying variables may aid the development of in-flight exercise prescription. METHODS: To identify variables that predict the variance in TC from flywheel ergometer exercise, 17 subjects did 3 workouts in a randomized order. Comprised of 10-repetition leg press sets, workouts entailed either: 1) 3 sets of both concentric and eccentric muscle actions (CE3), and concentric-only actions done for 2) three (CO3), or 3) six (CO6) sets. Venous plasma TC were collected before and at 1 and 30 min postexercise. The last two collection points served as criterion measures. Body mass, delta blood lactate levels, peak angular velocity, average power, and total work from workouts were used to predict the variance in TC. RESULTS: Predictor variables accounted for significant levels of variance at both 1 and 30 min post-exercise for both the CE3 and the concentric-only (CO3 and CO6 bouts combined) workouts using multivariate regression. Inclusion of eccentric variables (only collected from the CE3 bout; r2 = 0.90) predicted nearly twice the variance than the concentric-only (r2 = 0.54) workouts. CONCLUSIONS: Body mass and average power indices were the best predictors of the variance in post-workout TC. Since a flywheel-based device is used to abate in-flight muscle atrophy and strength losses, exercise prescriptions may wish to monitor these indices as they impacted post-workout TC to the greatest extent. Future research should assess why eccentric variables increased the amount of explained variance from flywheel ergometer workouts.

Data reliability from an instrumented vertical jump platform.

A Vertec jump measurement and training system measures vertical jump heights but not additional variables that would reveal how the performance was achieved. Technology advances to equipment now include additional variables that elucidate how jump performance is achieved. However, acceptance of new jump-related equipment is predicated on the reliability of the vertical heights it measures in relation to those assessed by the Vertec. Thus, our study compared vertical jump height reliability data from a newly created instrumented platform to those concurrently derived from the Vertec. Methods required subjects (n = 105) to perform 2 jump trials separated by at least 2 days of rest. Trials began with a warm-up, followed by 3 to 5 maximal-effort jumps. The Vertec was placed directly over the platform so, as jumps occurred, subjects took off and landed on the instrumented device. At the jump apex subjects contacted the highest Vertec slapstick possible to assess maximum height attained. Four height measurements were derived from each jump: 3 platform-based calculations (from subject's take-off, hang time, and landing) and 1 Vertec. The platform-based calculations were compared to Vertec data to assess the reliability of the instrumented device. Intraclass correlation coefficient (0.90), coefficient of variation (17.3%), standard error of measurement (0.9 cm), and smallest real difference (3.7 cm) results showed heights calculated from platform take-offs were most reliable to Vertec values. It was concluded take-off from the platform yielded jump heights that are a viable alternative to those derived from the Vertec. Practical applications suggest coaches may use the platform to derive reliable vertical jump data in addition to other variables to better understand the performance of their athletes.

beta(2)-Adrenergic agonist administration and strength training.

beta(2)-Adrenergic agonists (beta(2)AA) produce myriad effects throughout the human body. Prescribed concurrently with theophylline for the bronchodilatory effects they offer in the treatment of asthma and chronic obstructive pulmonary disease, beta(2)AA actions include many beneficial and adverse changes when administered to animals at supraphysiological doses. Beneficial changes include improved musculoskeletal health and function, which can be maintained because adverse changes are reduced if oral beta(2)AA are given at therapeutic dosages in humans with concurrent resistive exercise administration. Combined oral beta(2)AA-resistive exercise treatments have been shown to produce gains in musculoskeletal health and function in numerous healthy and disuse atrophy human models. The mechanism(s) by which beta(2)AA exert their effects are a function of multiple factors, not the least of which includes the type of model receiving the drug treatment. Combined oral beta(2)AA-resistive exercise treatments in humans showed that adverse effects were greatly reduced when prudent and safer drug administration practices were employed (eg, screening subjects for tolerance before drug treatment). Results from human research trials suggest that administration of the combined treatment improves musculoskeletal function and performance with minimal health risk if proper precautions are followed. A related issue is administration of the combined treatment as an ergogenic aid to athletic performance. Given the results presented in this article, physicians should be wary of potential drug abuse and administer beta(2)AA only under appropriate circumstances when such a treatment is warranted.