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Arjun Patra,1,2,* Swaha Satpathy,1,2,* Anitha K Shenoy,1 Jason A Bush,3 Mohsin Kazi,4 Muhammad Delwar Hussain1,* 1College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, CA, USA; 2Institute of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), India; 3Department of Biology, California State University, Fresno, CA, USA; 4Kayyali Chair for Pharmaceutical Industries, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia *These authors contributed equally to this work Background: Quercetin (QCT), a naturally occurring flavonoid has a wide array of pharmacological properties such as anticancer, antioxidant and anti-inflammatory activities. QCT has low solubility in water and poor bioavailability, which limited its use as a therapeutic molecule. Polymeric micelles (PMs) is a novel drug delivery system having characteristics like smaller particle size, higher drug loading, sustained drug release, high stability, increased cellular uptake and improved therapeutic potential. In the present study, we have formulated and characterized mixed PMs (MPMs) containing QCT for increasing its anticancer potential. Methods: The MPMs were prepared by thin film hydration method, and their physicochemical properties were characterized. The in vitro anticancer activity of the MPMs were tested in breast (MCF-7 and MDA-MB-231, epithelial and metastatic cancer cell lines, respectively), and ovarian (SKOV-3 and NCI/ADR, epithelial and multi-drug resistant cell lines, respectively) cancer. Results: The optimal MPM formulations were obtained from Pluronic polymers, P123 and P407 with molar ratio of 7:3 (A16); and P123, P407 and TPGS in the molar ratio of 7:2:1 (A22). The size of the particles before lyophilization (24.83±0.44 nm) and after lyophilization (37.10±4.23 nm), drug loading (8.75±0.41%), and encapsulation efficiency (87.48±4.15%) for formulation A16 were determined. For formulation A22, the particle size before lyophilization, after lyophilization, drug loading and encapsulation efficiency were 26.37±2.19 nm, 45.88±13.80 nm, 9.01±0.11% and 90.07±1.09%, respectively. The MPMs exhibited sustained release of QCT compared to free QCT as demonstrated from in vitro release experiments. The solubility of QCT was markedly improved compared to pure QCT. The MPMs were highly stable in aqueous media as demonstrated by their low critical micelle concentration. The concentration which inhibited 50% growth (IC50) values of both micellar preparations in all the cancer cell lines were significantly less compared to free QCT. Conclusion: Both the MPMs containing QCT could be used for effective delivery to different type of cancer and may be considered for further development. Keywords: quercetin, mixed polymeric micelle, Pluronics, TPGS, breast cancer, ovarian cancer, multidrug resistant cancer

Regional fat distribution (RFD) has been associated with metabolic derangements in populations with obesity. For example, upper body fat patterning is associated with higher levels of free testosterone (FT) and lower levels of sex-hormone binding globulin (SHBG). We sought to determine the extent to which this relationship was true in a healthy (i.e., non-obese) female population and whether RFD influenced androgen responses to resistance exercise. This study examined the effects of RFD on total testosterone (TT), FT, and SHBG responses to an acute resistance exercise test (ARET) among 47 women (22 +/- 3 years; 165 +/- 6 cm; 62 +/- 8 kg; 25 +/- 5 %BF; 23 +/- 3 BMI). RFD was characterized by 3 separate indices: waist-to-hip ratio (WHR), ratio of upper arm fat to mid-thigh fat assessed with magnetic resonance imaging (MRI ratio), and ratio of subscapular to triceps ratio (SB/TRi ratio). Skinfolds were measured for the triceps, chest, subscapular, mid-axillary, suprailaic, abdomen, and thigh regions. The ARET consisted of 6 sets of 10 RM squats separated by 2-min rest periods. Blood was obtained pre- and post- ARET. TT, FT, and SHBG concentrations were determined by radioimmunoassay. Subjects were divided into tertiles from the indices of RFD, and statistical analyses were performed by an ANOVA with repeated measures (RFD and exercise as main effects). Significant (p ² .05) increases following the AHRET were observed for TT (approximately 25%), FT (approximately 25%), and SHBG (4%). With multiple regression analysis, anthropometric measures significantly predicted pre- concentrations of FT, post-concentrations of TT, and pre-concentrations of SHBG. The SB/TRi and MRI ratios but not the WHR, were discriminant for hormonal concentrations among the tertiles. In young, healthy women, resistance exercise can induce transient increases in testosterone, and anthropometric markers of adiposity correlate with testosterone concentrations. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the efficacy of the BOUNCE parent-daughter intervention in promoting selected physical fitness measures and activity. METHODS: Thirty-seven Latino and African American parent-daughter pairs participated. The intervention entailed physical activities, nutrition classes, and self-esteem activities. Child's height, weight, waist circumference, body fat %, blood pressure, physical fitness, and activity were assessed pre- and postintervention. RESULTS: A repeated-measures ANOVA yielded significant results [F(4,26) = 793.003, P < 0.001]. Post hoc analyses demonstrated significant (P < 0.05) changes in BMI, waist circumference, physical fitness, and activity. CONCLUSIONS: The BOUNCE intervention was effective in promoting fitness and activity in minority girls. [ABSTRACT FROM AUTHOR]

Abstract Background A localized hypoxic environment occurs during tumor growth necessitating an angiogenic response or tumor necrosis results. Novel cancer treatment strategies take advantage of tumor-induced vascularisation by combining standard chemotherapeutic agents with angiogenesis-inhibiting agents. This has extended the progression-free interval and prolonged survival in patients with various types of cancer. We postulated that the expression levels of angiogenesis-related proteins from various primary tumor cultures would be greater under hypoxic conditions than under normoxia. Methods Fifty cell sources, including both immortalized cell lines and primary carcinoma cells, were incubated under normoxic conditions for 48 hours. Then, cells were either transferred to a hypoxic environment (1% O2) or maintained at normoxic conditions for an additional 48 hours. Cell culture media from both conditions was collected and analyzed via an ELISA-based assay to determine expression levels of 11 angiogenesis-related factors: VEGF, PDGF-AA, PDGF-AA/BB, IL-8, bFGF/FGF-2, EGF, IP-10/CXCL10, Flt-3 ligand, TGF-β1, TGF-β2, and TGF-β3. Results A linear correlation between normoxic and hypoxic growth conditions exists for expression levels of eight of eleven angiogenesis-related proteins tested including: VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-β1, TGF-β2, EGF, and IP-10. For VEGF, the target of current therapies, this correlation between hypoxia and higher cytokine levels was greater in primary breast and lung carcinoma cells than in ovarian carcinoma cells or tumor cell lines. Of interest, patient cell isolates differed in the precise pattern of elevated cytokines. Conclusion As linear correlations exist between expression levels of angiogenic factors under normoxic and hypoxic conditions in vitro, we propose that explanted primary cells may be used to probe the in vivo hypoxic environment. Furthermore, differential expression levels for each sample across all proteins examined suggests it may be possible to build a predictor for angiogenesis-related anticancer agents, as each sample has a unique expression profile. Further studies should be performed to correlate in vitro protein expression levels of angiogenesis-related factors with in vivo patient response.

The primary purpose of this study was to assess the efficacy of a family-based exploratory community study titled BOUNCE (Behavior Opportunities Uniting Nutrition, Counseling, and Exercise) to increase physical fitness and activity in low-income Latino mothers and daughters. The BOUNCE study consisted of a 12-week exercise (e.g., Latin dance), nutrition education, and counseling intervention. The design included a two-arm parallel group assignment to an experimental group (EG; included 26 mother-daughter dyads) and comparison group (CG; included 20 mother-daughter dyads). Pre- and postintervention 20-Meter Endurance Shuttle Run Test and accelerometry were used to measure children's aerobic capacity and physical activity, respectively. For the mothers, the Rockport Walk test and Non-Exercise Physical Activity Rating test were employed to assess aerobic fitness and physical activity. Anthropometric, demographic, and dietary assessments were also collected pre- and postintervention. Differences in outcome measures between groups were tested using repeated measures analysis of covariance. The BOUNCE intervention had a significant effect on EG Latino daughters' aerobic capacity (P = 0.044). Although not statistically significant, EG daughters reported a higher reduction of high fat food and sweetened beverages and an increase in fruit and vegetable consumption compared to CG daughters. Similarly, EG mothers reported more strategies to increase fruit/vegetable consumption and reduce fat intake compared to CG mothers. No changes in physical activity or BMI were observed between EG and CG mother-daughter dyads. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the warm-up effects of a treadmill walking warm-up (TW) with a dynamic warm-up (DW) on the responses to cardiopulmonary exercise testing (CPET) in youth. A sample of 16 active youth (age 13.6 ± 1.8 yr) were tested for peak oxygen uptake (VO 2 peak) using the Fitkids treadmill test protocol on 2 nonconsecutive days following different 6-min warm-up procedures. The TW consisted of walking on a treadmill at 2.2 mph and 0% grade whereas the DW consisted of 12 bodyweight exercises with a 2 kg medicine ball. Maximal heart rate (HR) was significantly higher following DW vs TW (200.8 ± 6.16 vs. 197.9 ± 7.3 bpm, respectively; p < 0.05), whereas no significant differences were found between DW and TW for VO 2 peak (50.5 ± 9.9 vs 50.6 ± 11.1 ml/kg/min), maximal minute ventilation (V E ; 93.0 ±21.4 vs. 92.7 ±21.2 L/min), maximal respiratory exchange ratio (1.19 ± 0.08 vs 1.22 ± 0.08), and total exercise test time (668.1 ± 103.5 vs 686.3 ± 97.0 s), respectively. During the Fitkids treadmill test protocol HR and V E were significantly higher following DW vs TW at stage 1, stage 2, stage 3 and stage 4, and oxygen uptake was significantly higher following DW vs TW during stage 1 (all p < 0.05). Findings indicate a DW elicits a higher maximal HR and higher submaximal HR, V E , and oxygen uptake values than TW during CPET in youth, although no differences in VO 2 peak were observed.

Abstract: Today's youth are weaker than previous generations, and measurable reductions in physical fitness are beginning to emerge. Without targeted initiatives that recognize the foundational importance of resistance training, weaker children and adolescents may be more likely to experience the inevitable consequences of neuromuscular dysfunction and less likely to experience the pleiotropic benefits of exercise and sport. Early exposure to strength-building activities is needed to prepare today's youth for ongoing participation in varied physical activities throughout this developmental phase of life. The novel iceberg of physical development is a metaphoric image that illustrates the sequential and cumulative influence of muscular strength on motor skills and physical abilities. Efforts to enhance the physical capacity of youth should include resistive skills that improve basic movement patterns and enhance motoric competence. A shift in our conceptual thinking about youth resistance training is needed to alter the current trajectory toward physical inactivity and related comorbidities., (Copyright © 2023 by the American College of Sports Medicine.)

Studies investigating the acute effect of postprandial exercise (PPE) on glucose responses exhibit significant heterogeneity in terms of participant demographic, exercise protocol, and exercise timing post-meal. As such, this study aimed to further analyze the existing literature on the impact of PPE on glycemic control in overweight individuals and individuals with obesity and type 2 diabetes (T2DM). A literature search was conducted through databases such as PubMed, CINAHL, and Google Scholar. Thirty-one original research studies that met the inclusion criteria were selected. A random-effect meta-analysis was performed to compare postprandial glucose area under the curve (AUC) and 24 h mean glucose levels between PPE and the time-matched no-exercise control (CON). Subgroup analyses were conducted to explore whether the glucose-lowering effect of PPE could be influenced by exercise duration, exercise timing post-meal, and the disease status of participants. This study revealed a significantly reduced glucose AUC (Hedges' g = -0.317; SE = 0.057; p < 0.05) and 24 h mean glucose levels (Hedges' g = -0.328; SE = 0.062; p < 0.05) following PPE compared to CON. The reduction in glucose AUC was greater ( p < 0.05) following PPE lasting >30 min compared to ≤30 min. The reduction in 24 h mean glucose levels was also greater ( p < 0.05) following PPE for ≥60 min compared to <60 min post-meal and in those with T2DM compared to those without T2DM. PPE offers a viable approach for glucose management and can be performed in various forms so long as exercise duration is sufficient. The glucose-lowering effect of PPE may be further enhanced by initiating it after the first hour post-meal. PPE is a promising strategy, particularly for patients with T2DM. This manuscript is registered with Research Registry (UIN: reviewregistry1693).

Abstract: Kang, J, Ratamess, NA, Faigenbaum, AD, Bush, JA, Finnerty, C, DiFiore, M, Garcia, A, and Beller, N. Time-of-day effects of exercise on cardiorespiratory responses and endurance performance-A systematic review and meta-analysis. J Strength Cond Res 37(10): 2080-2090, 2023-The time-of-day effect of exercise on human function remains largely equivocal. Hence, this study aimed to further analyze the existing evidence concerning diurnal variations in cardiorespiratory responses and endurance performance using a meta-analytic approach. Literature search was conducted through databases, including PubMed, CINAHL, and Google Scholar. Article selection was made based on inclusion criteria concerning subjects' characteristics, exercise protocols, times of testing, and targeted dependent variables. Results on oxygen uptake (V̇ o2 ), heart rate (HR), respiratory exchange ratio, and endurance performance in the morning (AM) and late afternoon or evening (PM) were extracted from the chosen studies. Meta-analysis was conducted with the random-effects model. Thirty-one original research studies that met the inclusion criteria were selected. Meta-analysis revealed higher resting V̇ o2 (Hedges' g = -0.574; p = 0.040) and resting HR (Hedges' g = -1.058; p = 0.002) in PM than in AM. During exercise, although V̇ o2 remained indifferent between AM and PM, HR was higher in PM at submaximal (Hedges' g = -0.199; p = 0.046) and maximal (Hedges' g = -0.298; p = 0.001) levels. Endurance performance as measured by time-to-exhaustion or the total work accomplished was higher in PM than in AM (Hedges' g = -0.654; p = 0.001). Diurnal variations in V̇ o2 appear less detectable during aerobic exercise. The finding that exercising HR and endurance performance were greater in PM than in AM emphasizes the need to consider the effect of circadian rhythm when evaluating athletic performance or using HR as a criterion to assess fitness or monitor training., (Copyright © 2023 National Strength and Conditioning Association.)

Myotonic dystrophy type 1 (DM1) is caused by a highly structured RNA repeat expansion, r(CUG) exp , harbored in the 3' untranslated region (3' UTR) of dystrophia myotonica protein kinase ( DMPK ) mRNA and drives disease through a gain-of-function mechanism. A panel of low-molecular-weight fragments capable of reacting with RNA upon UV irradiation was studied for cross-linking to r(CUG) exp in vitro , affording perimidin-2-amine diazirine ( 1 ) that bound to r(CUG) exp . The interactions between the small molecule and RNA were further studied by nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. Binding of 1 in DM1 myotubes was profiled transcriptome-wide, identifying 12 transcripts including DMPK that were bound by 1 . Augmenting the functionality of 1 with cleaving capability created a chimeric degrader that specifically targets r(CUG) exp for elimination. The degrader broadly improved DM1-associated defects as assessed by RNA-seq, while having limited effects on healthy myotubes. This study (i) provides a platform to investigate molecular recognition of ligands directly in disease-affected cells; (ii) illustrates that RNA degraders can be more specific than the binders from which they are derived; and (iii) suggests that repeating transcripts can be selectively degraded due to the presence of multiple ligand binding sites., Competing Interests: The authors declare the following competing financial interest(s): M.D.D. is a founder of Expansion Therapeutics., (© 2023 The Authors. Published by American Chemical Society.)

A solid-phase DNA-encoded library (DEL) was studied for binding the RNA repeat expansion r( CUG ) exp , the causative agent of the most common form of adult-onset muscular dystrophy, myotonic dystrophy type 1 (DM1). A variety of uncharged and novel RNA binders were identified to selectively bind r( CUG ) exp by using a two-color flow cytometry screen. The cellular activity of one binder was augmented by attaching it with a module that directly cleaves r( CUG ) exp . In DM1 patient-derived muscle cells, the compound specifically bound r( CUG ) exp and allele-specifically eliminated r( CUG ) exp , improving disease-associated defects. The approaches herein can be used to identify and optimize ligands and bind RNA that can be further augmented for functionality including degradation.

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G 4 C 2 ) exp , causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G 4 C 2 ) exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G 4 C 2 ) exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

Time restricted feeding (TRF) as a form of intermittent fasting (IF) has gained popularity because its ability to reduce body mass (BM) without an emphasis on caloric restriction. However, how this dietary protocol may affect health, fitness, and performance in a relatively healthy cohort remains less clear. The purpose of this article was to systematically review the current literature concerning the effect of TRF on anthropometric, metabolic, and fitness parameters in normal-weight adults and overweight and obese individuals. A systematic search of English literature was conducted through databases including PubMed, CINAHL, and Google Scholar. The search was facilitated by using various combinations of key words related to nutritional interventions, i.e., IF and TRF, and outcomes of interest, i.e., BM, body composition, glucose, insulin, lipid, fitness, and performance. The article selection was made based on the inclusion and exclusion criteria concerning the participants' characteristics, study design, intervention protocols, and targeted dependent variables. Twenty-three full-text longitudinal randomized and nonrandomized controlled studies were selected for this review. Our analysis indicates that TRF can reduce BM and improve nutrient metabolism in both normal- and over-weight individuals. TRF does not appear to alter protein synthesis and fat-free mass nor hamper aerobic fitness and muscular performance among physically active individuals including athletes. In conclusion, TRF as a more easily adaptable form of IF is a promising dietary approach to improving body composition and metabolic health while maintaining fitness and muscular function. However, more research is needed before this dietary protocol can be fully recommended for athletes especially those competing in sports that demand strength and power.Key teaching points and nutritional relevanceTime-restricted feeding (TRF) differs from other fasting protocols due to its emphasis on restricting eating window rather than caloric intake and can be more easily adopted by simply skipping a meal.Its deemphasis on caloric restriction appeals to many young and physically active individuals wanting to optimize body composition but needing sufficient energy to support their physical training and daily activity.Much of what is known regarding the impact of TRF on fitness and athletic performance was derived from studies that use the Ramadan fasting protocol, which differs from TRF in terms of protocol duration and feeding schedule.This review concludes that TRF is a promising dietary approach to improving body composition and metabolic health while maintaining fitness and muscular function in both normal- and over-weight individuals.Due to limited evidence concerning TRF and athletic performance, more research is needed before this dietary protocol can be fully recommended for athletes especially those competing in sports that demand strength and power.

The aim of this study was to compare the warm-up effects of treadmill walking (TW) with a dynamic (DY) bodyweight warm-up on maximal aerobic exercise performance in children. Sixteen children (10.9 ± 1.5 vrs) were tested for peak oxygen uptake (VO 2 peak) on 2 nonconsecutive days following different 6 min warm-up protocols. TW consisted of walking on a motor-driven treadmill at 2.2 mph and 0% grade whereas the DY warm-up consisted of 9 body weight movements including dynamic stretches, lunges, and jumps. Maximal heart rate was significantly higher following DY than TW (193.9 ± 6.2 vs. 191.6 ± 6.1 bpm, respectively; p = 0.008). VO 2 peak (54.8 ± 9.6 vs. 51.8 ± 8.7 mL/kg/min; p = 0.09), maximal minute ventilation (68.9 ± 14.8 vs. 64.9 ± 9.4 L/min; p = 0.27), maximal respiratory exchange ratio (1.12 ± 0.1 vs. 1.11 ± 0.1; p = 0.85) and total exercise time (614.0 ± 77.1 vs. 605 ± 95.0 s; p = 0.55) did not differ significantly between DY and TM warm-ups, respectively. These findings indicate that the design of the warm-up protocol can influence the heart rate response to maximal aerobic exercise and has a tendency to influence VO 2 peak. A DY warm-up could be a viable alternative to a TW warm-up prior to maximal exercise testing in children.

The hexanucleotide repeat expansion GGGGCC [r(G 4 C 2 ) exp ] within intron 1 of C9orf72 causes genetically defined amyotrophic lateral sclerosis and frontotemporal dementia, collectively named c9ALS/FTD. , the repeat expansion causes neurodegeneration via deleterious phenotypes stemming from r(G 4 C 2 ) exp RNA gain- and loss-of-function mechanisms. The r(G 4 C 2 ) exp RNA folds into both a hairpin structure with repeating 1 × 1 nucleotide GG internal loops and a G-quadruplex structure. Here, we report the identification of a small molecule (CB253) that selectively binds the hairpin form of r(G 4 C 2 ) exp . Interestingly, the small molecule binds to a previously unobserved conformation in which the RNA forms 2 × 2 nucleotide GG internal loops, as revealed by a series of binding and structural studies. NMR and molecular dynamics simulations suggest that the r(G 4 C 2 ) exp hairpin interconverts between 1 × 1 and 2 × 2 internal loops through the process of strand slippage. We provide experimental evidence that CB253 binding indeed shifts the equilibrium toward the 2 × 2 GG internal loop conformation, inhibiting mechanisms that drive c9ALS/FTD pathobiology, such as repeat-associated non-ATG translation formation of stress granules and defective nucleocytoplasmic transport in various cellular models of c9ALS/FTD.

The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded G 4 C 2 RNA repeat [r(G 4 C 2 ) exp ] in chromosome 9 open reading frame 72 ( C9orf72 ), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(G 4 C 2 ) exp . The compound was able to selectively bind r(G 4 C 2 ) exp ’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms. In c9ALS patient–derived spinal neurons, the compound selectively degraded the mutant C9orf72 allele with limited off-targets and reduced quantities of toxic dipeptide repeat proteins (DPRs) translated from r(G 4 C 2 ) exp . In vivo work in a rodent model showed that abundance of both the mutant allele harboring the repeat expansion and DPRs were selectively reduced by this compound. These results demonstrate that targeted small-molecule degradation of r(G 4 C 2 ) exp is a strategy for mitigating c9ALS/FTD-associated pathologies and studying disease-associated pathways in preclinical models.

The interrogation and manipulation of biological systems by small molecules is a powerful approach in chemical biology. Ideal compounds selectively engage a target and mediate a downstream phenotypic response. Although historically small molecule drug discovery has focused on proteins and enzymes, targeting RNA is an attractive therapeutic alternative, as many disease-causing or -associated RNAs have been identified through genome-wide association studies. As the field of RNA chemical biology emerges, the systematic evaluation of target validation and modulation of target-associated pathways is of paramount importance. In this Review, through an examination of case studies, we outline the experimental characterization, including methods and tools, to evaluate comprehensively the impact of small molecules that target RNA on cellular phenotype.

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached., (Copyright © 2021 Painter et al.)

Genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide GGGGCC repeat expansions [r(G 4 C 2 ) exp ] within the C9orf72 gene. In these diseases, neuronal loss occurs through an interplay of deleterious phenotypes, including r(G 4 C 2 ) exp RNA gain-of-function mechanisms. Herein, we identified a benzimidazole derivative, CB096, that specifically binds to a repeating 1 × 1 GG internal loop structure, 5'C G G/3'G G C, that is formed when r(G 4 C 2 ) exp folds. Structure-activity relationship (SAR) studies and molecular dynamics (MD) simulations were used to define the molecular interactions formed between CB096 and r(G 4 C 2 ) exp that results in the rescue of disease-associated pathways. Overall, this study reveals a unique structural feature within r(G 4 C 2 ) exp that can be exploited for the development of lead medicines and chemical probes.

An equation that uses heart rate index (HRI) defined as HR/HRrest to predict oxygen uptake (VO 2 ) in METs (e.g., METs = 6 × HRI - 5) has been developed retrospectively from aggregate data of 60 published studies. However, the prediction error of this model as used by an individual has not been established. Therefore, the purpose of this study was to examine the predictive validity of the HRI equation by comparing submaximal and maximal VO 2 predicted by the equation (VO 2 -Pred) with that measured by indirect calorimetry (VO 2 -Meas). Sixty healthy adults (age 20.5 ± 2.4 yr., body mass 69.4 ± 13.4 kg, height 1.7 ± 0.1 m) underwent a VO 2 max test and an experimental trial consisting of a 15-min resting measurement and three successive 10-min treadmill exercise bouts performed at 40%, 60% and 80% of VO 2 max. VO 2 and HR were recorded during both the submaximal and maximal exercises and used to obtain VO 2 -Pred and VO 2 -Meas for each intensity and for VO 2 max. Validation was carried out by paired t-test, regression analysis, and Bland-Altman plots. A modest but significant ( p < 0.05) correlation was observed between VO 2 -Meas and VO 2 -Pred at 40% ( r = 0.58), 60% ( r = 0.53), and 80% of VO 2 max ( r = 0.56) and at VO 2 max ( r = 0.50). No differences between VO 2 -Pred and VO 2 -Meas were found at 40% (5.53 ± 1.21 vs. 5.28 ± 0.98 METs, respectively) of VO 2 max, but VO 2 -Pred was higher ( p < 0.05) than VO 2 -Meas at 60% (8.42 ± 1.77 vs. 7.96 ± 1.39 METs, respectively) and 80% (10.79 ± 2.13 vs. 10.29 ± 1.81 METs, respectively) of VO 2 max. In contrast, VO 2 -Pred was lower ( p < 0.05) than VO 2 -Meas at VO 2 max (12.32 ± 2.30 vs. 13.38 ± 2.24 METs, respectively). Standard errors of the estimate were 0.81, 1.20, 1.54, and 1.97 METs at 40%, 60%, 80% of VO 2 max and at VO 2 max, respectively. These results suggest that further investigation aimed to establish the accuracy of using HRI to predict VO 2 is warranted.

Ketogenic diets (KDs) have received increasing attention among athletes and physically active individuals. However, the question as to whether and how the diet could benefit this healthy cohort remains unclear. Purpose: This study was designed to systematically review the existing evidence concerning the effect of KDs on body composition, aerobic and anaerobic capacity, muscle development, and sports performance in normal-weight individuals including athletes. Methods: A systematic search of English literature was conducted through electronic databases including PubMed, EBSCOhost, and Google Scholar. Upon the use of search criteria, 23 full-text original human studies involving non-obese participants were included in this review. For more stratified and focused analysis, these articles were further categorized based on the outcomes being examined including 1) body mass (BM) and %fat, 2) substrate utilization, 3) blood substrate and hormonal responses, 4) aerobic capacity and endurance performance, and 5) strength, power, and anaerobic capacity. Results: Our review indicates that a non-calorie-restricted KD carried out for ≥3 weeks can produce a modest reduction in BM and %fat, while maintaining fat-free mass. This diet leads to augmented use of fat as fuel, but this adaptation doesn't seem to improve endurance performance. Additionally, ad libitum KDs combined with resistance training will pose no harm to developing strength and power, especially when protein intake is increased modestly. Conclusions: It appears that a non-calorie-restricted KD provides minimal ergogenic benefits in normal-weight individuals including athletes, but can be used for optimizing BM and body composition without compromising aerobic and anaerobic performance. Key teaching pointsKetogenic diets have received increasing attention among athletes and physically active individuals.It remains elusive as to whether ketogenic diets could confer ergogenic benefits for those who are normal weight but want to use the diet to improve fitness and performance.An interesting dilemma exists in that ketogenic diets can reduce body mass and %fat and increase fat oxidation, but they can also decrease glycogen stores and limit sports performance.This review concludes that a non-calorie-restricted ketogenic diet provides minimal ergogenic benefits in normal-weight individuals, but can be used to optimize body mass and composition without compromising athletic performance.This finding can be important for esthetic or weight-sensitive athletes because the diet may allow them to reach a target body mass without having to sacrifice athletic performance.The ketogenic diet-induced metabolic adaptations require a state of ketosis, and thus caution should be taken because an excessive increase in ketone bodies can be detrimental to health.

Objective: The present study aimed to examine the interactive effect of exercise and energy balance on energy expenditure and substrate utilization. Method: Seven men and 7 women underwent three 2-day experimental protocols in a random order. Each protocol consisted of no exercise (NE), exercise only (EO), or exercise with a matched energy replacement (ER) on day 1 followed by metabolic testing that occurred after a 12-hour overnight fasting on day 2. Both EO and ER involved treadmill running at 60% maximal oxygen uptake (VO 2 max) that induced an energy expenditure of ∼ 500 kcal. The replacement meal used in ER contained ∼ 500 kcal made up of 45% carbohydrate, 30% fat, and 25% protein. During metabolic testing, oxygen uptake (VO 2 ), heart rate (HR), respiratory exchange ratio (RER), and rates of carbohydrate (COX) and fat oxidation (FOX) were determined in three successive 15-minute periods including rest and exercise at 50% and 70% VO 2 max. Results: No differences in VO 2 and HR were found at rest among NE, EO, and ER. However, RER was lower in EO than NE (0.840 ± 0.014 vs 0.889 ± 0.012, p  < 0.05), COX (g·min -1 ) was lower in ER than NE (0.144 ± 0.016 vs 0.197 ± 0.019, p  < 0.05), and FOX (g·min -1 ) was higher in EO or ER than NE (0.054 ± 0.010 or 0.057 ± 0.009 vs 0.034 ± 0.007, p  < 0.05). No treatment effects were observed for all variables at either intensity. Conclusions: This study demonstrates that an exercise of moderate intensity can increase resting fat oxidation even when the exercise-induced energy expenditure is balanced by energy intake. This finding suggests that muscle action is vital in augmenting fat utilization.

The purpose of this study was to examine acute hematological and mood perception responses to supplementation with p-synephrine alone and in combination with caffeine during quiet sitting. Sixteen subjects visited the laboratory on 6 occasions and were given (in randomized double-blind manner) 103-mg p-synephrine (S), 233-mg caffeine + 104-mg p-synephrine, 240-mg caffeine, 337-mg caffeine + 46-mg p-synephrine, 325-mg caffeine, or a placebo (PL). The subjects sat quietly for 3 hr while completing mood state questionnaires every 30 min. Venous blood samples were collected at baseline (pre) and 3 hr (post) to determine immune, lipid, and chemistry panels. Compared with PL, no significant supplement differences were observed during the S trial with the exception of differential time effects seen in hematocrit (decrease in PL, no change in S), triglycerides and very low-density lipoproteins (no changes in PL, significant decreases in S), and iron (no change in PL, significant elevation in S). Supplements containing caffeine showed increased feelings of attention, excitement, energy, and vigor. These data indicate that consumption of 103-mg p-synephrine does not negatively impact acute blood parameters, does not augment the effects of caffeine, or produce stimulant-like perceptual mood effects., (Copyright © 2018 John Wiley & Sons, Ltd.)

Ratamess, NA, Kang, J, Kuper, JD, O'Grady, EA, Ellis, NL, Vought, IT, Culleton, E, Bush, JA, and Faigenbaum, AD. Acute cardiorespiratory and metabolic effects of a sandbag resistance exercise protocol. J Strength Cond Res 32(6): 1491-1502, 2018-The purpose of this study was to examine the acute cardiorespiratory and metabolic effects of a sandbag (SB) resistance exercise protocol and compare the responses to time-matched treadmill running protocols. Eight healthy, resistance-trained men (21.1 ± 1.0 years; 86.1 ± 7.8 kg) completed 4 protocols of equal duration in random sequence: (a) SB, (b) treadmill running at 60% of V[Combining Dot Above]O2 reserve (60V[Combining Dot Above]O2R), (c) treadmill running at 80% of V[Combining Dot Above]O2 reserve (80V[Combining Dot Above]O2R), and (d) a control protocol. The SB protocol was 16 minutes in duration and consisted of 3 circuits of 8 multiple-joint exercises (with 11-, 20-, or 48-kg SBs) performed for as many repetitions as possible for 20 seconds followed by a 10-second rest interval before beginning the next exercise. Two minutes of rest was allowed between circuits. Breath-by-breath oxygen consumption (V[Combining Dot Above]O2) and heart rate (HR) were recorded throughout each protocol and for 30 minutes postexercise (PE) and blood lactate was determined before and immediately after each protocol. Blood lactate was significantly higher after SB compared with 60V[Combining Dot Above]O2R and 80V[Combining Dot Above]O2R. Mean and peak HR in SB was significantly higher than 60V[Combining Dot Above]O2R but not different from 80V[Combining Dot Above]O2R. Mean V[Combining Dot Above]O2 and energy expenditure (EE) in SB was significantly lower than 60V[Combining Dot Above]O2R and 80V[Combining Dot Above]O2R during each protocol but significantly higher after SB compared with 60V[Combining Dot Above]O2R and 80V[Combining Dot Above]O2R PE. Compared with 60V[Combining Dot Above]O2R and 80V[Combining Dot Above]O2R, respiratory exchange ratio was significantly higher during SB and through 5 minutes PE, but was significantly lower at 25-30 minutes PE after SB. Sandbag, as performed in this study, provides a superior metabolic stimulus to treadmill running during the PE period; however, the SB results demonstrate inferior EE compared with running at 60V[Combining Dot Above]O2R and 80V[Combining Dot Above]O2R.

Faigenbaum, AD, Kang, J, Ratamess, NA, Farrell, A, Golda, S, Stranieri, A, Coe, J, and Bush, JA. Acute cardiometabolic responses to a novel training rope protocol in children. J Strength Cond Res 32(5): 1197-1206, 2018-The purpose of this study was to quantify the acute cardiometabolic responses to a novel training rope (TR) protocol in children. Fifteen boys (10.6 ± 1.4 years) were tested for peak oxygen uptake (V[Combining Dot Above]O2) on a treadmill and subsequently (2-7 days later) performed a progressive 10-minute protocol of 5 TR exercises (EX): EX1: standing side-to-side waves, EX2: seated alternating waves, EX3: standing alternating waves, EX4: jumping jacks, and EX5: double-arm slams. Participants performed 2 sets of each TR exercise for 30 seconds per set with a 30-second rest interval between sets and exercises. A 12.8-m TR (4.1 kg) was used for all trials, and a metronome was used to standardize cadence. Peak values for V[Combining Dot Above]O2 and HR during the treadmill test were 47.4 ± 8.8 ml·kg·min and 195.1 ± 6.6 b·min, respectively. During the TR protocol, mean V[Combining Dot Above]O2 and HR significantly increased (p ≤ 0.05) from set 1 of EX1 (10.3 ± 2.6 ml·kg·min and 103.2 ± 11.6 b·min, respectively) to set 2 of EX5 (30.0 ± 3.9 ml·kg·min and 168.6 ± 11.8 b·min, respectively). Percentage of peak V[Combining Dot Above]O2 and peak HR values attained during the TR protocol ranged from 21.5 to 64.8% and from 52.9 to 86.4%, respectively. These descriptive data indicate that TR exercise can pose a moderate to vigorous cardiometabolic stimulus in children and with proper supervision and instruction may serve as a worthwhile complement to youth fitness programs.

The purpose was to examine cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during quiet sitting. Sixteen subjects were given (in double-blind manner) either 103 mg of p-synephrine (S), 233 mg of caffeine +104 mg of p-synephrine (LC + S), 240 mg of caffeine (LC), 337 mg of caffeine +46 mg of p-synephrine (HC + S), 325 mg of caffeine (HC), or a placebo. The subjects sat quietly for 3 hr while heart rate (HR) and blood pressure were measured. Only HC + S and HC significantly increased mean systolic blood pressure (SBP) during the second hour and tended to increase mean SBP during the third hour. Mean diastolic blood pressure in S was significantly lower than the other trials during the first and second hours, and mean arterial pressure was significantly lower in S compared to the LC, LC + S, HC, and HC + S trials. No differences were observed in HR. Consumption of p-synephrine may acutely reduce diastolic blood pressure and mean arterial pressure and not affect SBP or HR during quiet sitting. The addition of p-synephrine to caffeine did not augment SBP or HR indicating that consumption of up to 104 mg of p-synephrine does not induce cardiovascular stress during quiet sitting., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objective: The purpose of this study was to examine the metabolic, lipolytic, and cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during resistance exercise (RE)., Methods: Twelve healthy men performed a control RE protocol (6 × 10 repetitions of squats) and were randomly assigned (using a double-blind crossover design with random protocol sequencing) to a supplement sequence: p-synephrine (S; 100 mg), p-synephrine + caffeine (SCF; 100 mg of p-synephrine plus 100 mg of caffeine), or a placebo (P). Subjects reported to the lab at a standard time, consumed a supplement, sat quietly for 45 minutes, performed the RE protocol, and sat quietly for 30 minutes. Blood samples were collected at rest (T1), after sitting quietly for 45 minutes (T2), immediately following RE (T3), and 15 minutes (T4) and 30 minutes (T5) postexercise. Oxygen consumption (VO 2 ) and heart rate (HR) data were collected throughout., Results: Serum glycerol was significantly elevated at T2 only in S and SCF and T3 to T5 in all treatments. Nonesterified fatty acid (NEFA) concentrations did not differ between treatments. Plasma glucose was significantly elevated compared to T1 with highest area under the curve values seen in SCF. Mean VO 2 and energy expenditure (EE) were significantly higher in S and SCF through 30 minutes postexercise. Fat oxidation rates favored S and SCF between 25 and 30 minutes postexercise. Mean HR during RE was significantly highest in SCF., Conclusions: Supplementation with S and SCF increases lipolysis primarily at rest and increases VO 2 , EE, and fat oxidation rates 30 minutes following RE. No HR changes were observed unless caffeine was added.

Ratamess, NA, Kang, J, Porfido, TM, Ismaili, CP, Selamie, SN, Williams, BD, Kuper, JD, Bush, JA, and Faigenbaum, AD. Acute resistance exercise performance is negatively impacted by prior aerobic endurance exercise. J Strength Cond Res 30(10): 2667-2681, 2016-The purpose of the present study was to examine acute resistance exercise (RE) performance after 4 different aerobic endurance (AE) protocols. Eleven healthy, resistance-trained men (21.0 ± 1.2 years) performed a control RE protocol and 4 RE protocols 10 minutes after different AE protocols in random sequence. The RE protocol consisted of 5 exercises (high pull, squat, bench press, deadlift, and push press) performed for 3 sets of 6-10 repetitions with 70-80% of one repetition-maximum (1RM) with 3-minute rest intervals in between sets. The AE protocols consisted of treadmill running at velocities corresponding to: (a) 60% of their V[Combining Dot Above]O2 reserve (V[Combining Dot Above]O2R) for 45 minutes (P1); (b) 75% of their V[Combining Dot Above]O2R for 20 minutes (P2); (c) 90-100% of V[Combining Dot Above]O2R in 3-minute intervals (1:1 ratio) for 5 sets (P3); and (d) 75% of V[Combining Dot Above]O2R (4.5 mph) uphill (6-9% grade) for 20 minutes (P4). Completed repetitions, average power and velocity, heart rate (HR), and ratings of perceived exertion (RPE) were assessed each set. Protocols P1-P4 resulted in 9.1-18.6% fewer total repetitions performed compared with the control RE protocol with the squat experiencing the greatest reduction. Average power and velocity were significantly reduced for the high pull, squat, and bench press after most AE protocols. Ratings of perceived exertion values for the high pull and squat were significantly higher in P1-P4 compared with control. Heart rate was significantly higher during RE after P1-P4 compared with control by 4.3-5.5%. These results indicate acute RE performance is significantly compromised in healthy men after AE exercise of different type, intensity, and duration with largest reductions observed after high-intensity interval exercise.

Purpose: This study assessed the effect of whole-body vibration (WBV) of varying frequency and amplitude on metabolic responses during WBV treatment and subsequent aerobic exercise., Methods: Eight men and eight women (21.0 ± 1.9 years) underwent one no-WBV (NV) and six WBV at 30 Hz/low amplitude (30L), 30 Hz/high amplitude (30H), 40 Hz/low amplitude (40L), 40 Hz/high amplitude (40H), 50 Hz/low amplitude (50L), and 50 Hz/high amplitude (50H). During each protocol, subjects performed ten sets of ten body weight squats with 1-min rest period between sets on a vibration platform with a load that represented one of the six frequency-amplitude combinations. Each WBV treatment was immediately followed by 20 min of cycle exercise at 65 % VO2peak. Oxygen uptake (VO2) and rates of carbohydrate (COX) and fat oxidation (FOX) were measured during both the WBV session and subsequent exercise., Results: During WBV, VO2 was higher (p < 0.05) in 40H, 50L and 50H than NV and in 50H than 30L, 30H and 40L. COX was higher (p < 0.05) in 40H, 50L, and 50H than NV, whereas FOX remained indifferent across all protocols. During subsequent exercise, VO2 was higher (p < 0.05) in 50L and 50H than NV and in 50H than 30L. No between-protocol differences were seen for COX or FOX., Conclusion: WBV combined with body weight squats can augment VO2 at 40 Hz of high amplitude and 50 Hz of both low and high amplitudes. This metabolic potentiation remains in effect during subsequent aerobic exercise. WBV did not affect fat oxidation across all vibratory loads.

Background: Little is known concerning the potential ergogenic effects of p-synephrine supplementation. Therefore, the purpose of the present study was to examine the effects of supplementation with p-synephrine alone and in combination with caffeine on free-weight resistance exercise performance., Methods: Twelve healthy, college-aged men performed a control (CT) resistance exercise protocol consisting of 6 sets of squats for up to 10 repetitions per set using 80% of their one repetition-maximum (1RM) with 2 min of rest in between sets. Each subject was randomly assigned (in double-blind, balanced manner) to a treatment sequence consisting of use of 3 supplements: p-synephrine (S; 100 mg), p-synephrine + caffeine (SCF; 100 mg of p-synephrine plus 100 mg of caffeine), or a placebo (P). For each supplement treatment (separated by 1 week), subjects consumed the supplement for 3 days prior to each protocol and the morning of each protocol, and subsequently did not consume any supplements for 3 days following (i.e. wash-out period). On each protocol day, subjects reported to the lab at a standard time, consumed a supplement, sat quietly for 45 min, performed the resistance exercise protocol, and sat quietly for 30 min post exercise. Performance (repetition number, force, velocity and power), blood lactate, and ratings of perceived exertion (RPE) data were collected during each protocol., Results: Supplements SCF and S produced a significantly (P < 0.05) greater number of repetitions performed than CT (by 11.0 ± 8.0%) and P (by 6.0 ± 7.0%) and a 10.6 ± 12.0% greater increase in volume load per protocol than CT and P. Most of the differences were seen during the last 3 sets. Mean power and velocity for all 6 sets were significantly higher in SCF compared to CT and P by ~6.2 ± 8.0%. No supplement effects were observed in RPE or blood lactate, and no adverse side effects were observed or reported., Conclusions: S and SCF augmented resistance exercise performance (total repetitions, volume load) without increasing blood lactate or RPE. The addition of caffeine in SCF increased mean power and velocity of squat performance. These results indicate supplementation with S and SCF can enhance local muscle endurance during resistance exercise.

The purpose of this study was to quantify and compare the acute metabolic responses to battling rope (BR) exercise using 2 different rest intervals. Twelve men and 10 women (age = 20.8 ± 1.3 years) performed a control protocol and 2 BR exercise protocols on separate days (48-72 hours) in random order while connected to a metabolic system. The BR protocol consisted of 8 sets of 30-second intervals (15 seconds of single-arm waves and 15 seconds of double-arm waves) using either a 1-minute (1RI) or 2-minute (2RI) rest interval length. A metronome was used to standardize repetition number/frequency for each exercise, that is, 15 waves for each arm for single-arm waves and 15 repetitions of double-arm waves. The mean oxygen consumption (VO2) values for the entire protocol were significantly higher during the 1RI than 2RI protocol, and values in men were 11.1% (1RI) and 13.5% (2RI) higher than women, respectively, and equated to 52.8 ± 5.5% (men) and 50.0 ± 11.2% (women) of VO2max during 1RI and 40.5 ± 4.5% (men) and 37.7 ± 11.0% (women) of VO2max during 2RI. Energy expenditure values were significantly higher during the 1RI than the 2RI protocol in men (11.93 ± 1.4 vs. 8.78 ± 1.4 kcal·min) and women (7.69 ± 1.3 vs. 5.04 ± 1.7 kcal·min) with values in men statistically higher than women. Blood lactate, mean protocol minute ventilation, and heart rate were significantly higher during the 1RI protocol than the 2RI protocol, and these data were significantly higher in men compared with women. These data demonstrate that BR exercise poses a significant cardiovascular and metabolic stimulus with the mean effects augmented with the use of a short rest interval.

Numerous studies have shown performance benefits including whole-body vibration (WBV) as a training modality or an acute exercise protocol when used as a component of the resistance training program. Some studies have indicated that performing dynamic exercises as compared with static position exercises while exposed to WBV might be beneficial; however, evidence is lacking. Thus, the purpose of this study was to determine if an acute bout of dynamic versus static squats performed during WBV results in increase in quadriceps force production by means of dynamic isokinetic knee extension and flexion exercise. Nonresistance-trained healthy young men and women (N = 21) of 18-25 years participated in 4 protocols with 2-week rest in-between. Protocol 1 consisted of 5 sets of 10 dynamic squats without vibration; Protocol 2: 5 sets of 30-second static squats without vibration; Protocol 3: 5 sets of 10 dynamic squats with 30-Hz WBV for a total of 2.5 minutes; and Protocol 4: 5 sets of 30-second static squats with 30-Hz WBV for a total of 2.5 minutes. Prestrength tests (1 set of 4 repetitions at 100° · s(-1) for the knee extension exercise) was performed within 5 minutes of starting each protocol, and poststrength testing was performed within 1 minute of completing each protocol. Strength outcomes were analyzed by repeated measures analysis of variance with a significance level set at p ≤ 0.05. A significant decrease in strength was observed after dynamic and static squats without WBV (p = 0.002); an increase in strength after dynamic squats with WBV (p = 0.003); and a decrease in strength after static squats with WBV (p = 0.003). The inclusion of WBV to dynamic resistance exercise can be an added modality to increase strength. Whole-body vibration can have varied effects in altering muscle strength in untrained individuals according to the type of resistance training performed. As a dynamic squat with WBV seems to immediately potentiate neuromuscular functioning, the combination of dynamic exercises and WBV could be used as a potential warm-up procedure before resistance exercise.

Physical education (PE) programs are evolving from a traditional skill-centered model to a health-centered model that focuses on time engaged in moderate to vigorous physical activity (MVPA). However, improvements in muscular fitness and fundamental movement skills are prerequisites for continuous participation in MVPA. The purpose of this study was to examine the effects of integrative strength and skill-based training on measures of physical fitness in children during primary school PE. Children from two fourth grade PE classes were cluster randomized into either a fundamental integrative training (FIT) group (n = 20) or a control (CON) group (n = 21). The 8-week FIT program was performed twice per week during the first ∼ 1 5 minutes of each PE class and consisted of a circuit of strength and skill-based exercises. All participants were assessed for health- and skill-related fitness before and after the intervention. The outcome variables were analyzed via 2 × 2 repeated measures analysis of variance with post hoc analysis. A significant (p ≤ 0.05) interaction of group by time was observed in FIT participants with improvements in aerobic capacity, push-ups, sit and reach flexibility, and single-leg hop. There were no groups by time effects for the sit-up and long jump tests. No injuries were reported. These findings highlight the potential benefits of integrating both health- and skill-related fitness components into primary school PE as evidenced by improvements in measures of aerobic capacity and muscular fitness in children.

To determine if exercise training alters the pattern and magnitude of plasma concentrations of proenkephalin Peptide F and epinephrine, plasma proenkephalin [107-140] Peptide F(ir) and catecholamines were examined pre-training (T-1), and after 4- (T-2), 8- (T-3), and 12-weeks (T-4) of training. 26 healthy men were matched and randomly assigned to one of three groups: heavy resistance strength training (Strength, n=9), high intensity endurance training (Endurance, n=8), or both training modalities combined (Combined, n=9). Blood was collected using a syringe with a cannula inserted into a superficial arm vein with samples collected at rest, after each 7 min stage and 5 and 15 min into recovery. With training, all groups observed shifted plasma Peptide F responses to graded exercise, where significant increases were observed at lower exercise intensities. Increases in plasma epinephrine with exercise were observed in all groups. The Combined group saw increases at 25% at T-3 and for 50% at T-2, T-3, and T-4 which was higher than T-1. The Endurance group demonstrated increases for 50% at T-1, T-2, T-3 but not at T-4. The plasma epinephrine response to graded exercise was reduced in the Strength group. Increases in plasma norepinephrine above rest were observed starting at 50% . The Strength group demonstrated a significant reduction in norepinephrine observed at 100% at T-3 and T-4. Peptide F and catecholamines responses to graded exercise can be altered by different types of physical exercise training. Simultaneous high intensity training may produce adrenal medulla exhaustion when compared to single mode training., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The purpose of this study was to evaluate the effectiveness of the progressive aerobic capacity endurance run (PACER) and a newly designed modified PACER (MPACER) for assessing aerobic fitness in Hispanic children who are obese. Thirty-nine (aged 7-12 years) children who were considered obese (≥ 95 th body mass index [BMI] percentile) and 16 children who were considered normal weight (<85th BMI percentile) participated in this study. Performance outcomes included test duration (in minutes) and exercise heart rate (HR) (first-stage and peak HR) for each test. Ninety-five percent confidence intervals and independent t-tests were used to assess differences in primary outcomes. Mean PACER test duration was 1.6 ± 0.6 and 3.1 ± 1.3 minutes for children who were obese and normal weight, respectively. Modified PACER duration was higher than 3 minutes for the obese (3.6 ± 0.6 minutes) and normal weight (5.3 ± 1.2 minutes) groups. Children first-stage HR, expressed as a percent of peak HR, was above the predicted anaerobic threshold during the PACER, but below the anaerobic threshold during the MPACER. Relative first-stage HR was not significantly different between groups for the PACER, but they were significantly different between groups for the MPACER. In conclusion, the MPACER was a better alternative than the PACER for assessing aerobic fitness in Hispanic children who were normal weight and obese. When validated, this modified field test could be used to assess aerobic fitness in Hispanic children, particularly those who are overweight or obese. Additionally, the study provides evidence in which physical educators, personal trainers, and others most apt to assess aerobic fitness in children who are obese, should modify tests originally designed for the population who are normal weight.

We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. Here, we used chemical genomic and proteomic profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, activates two pathways, one eliciting cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation and driving the transcriptional downregulation of the androgen receptor, and a second pathway that activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response (UPR). SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy.

Proenkephalin Peptide F [107-140] is an enkephalin-containing peptide found predominantly within the adrenal medulla, co-packaged with epinephrine within the chromaffin granules. In vivo studies indicate that Peptide F has classic opioid analgesia effects; in vitro studies suggest potential immune cell interactions. In this investigation we examined patterns of Peptide F concentrations in different bio-compartments of the blood at rest and following sub-maximal cycle exercise to determine if Peptide F interacts with the white blood cell (WBC) bio-compartment during aerobic exercise. Eight physically active men (n=8) performed sub-maximal (80-85% V˙O2peak) cycle ergometer exercise for 30 min. Plasma Peptide F and WBC Peptide F immunoreactivity were examined pre-exercise, mid-exercise and immediately post-, 5-min post-, 15-min post-, 30-min post- and 60-min post-exercise and at similar time-points during a control condition (30 min rest). Peptide F concentrations significantly (p<0.05) increased at 5 and 60 min post-exercise, compared to pre-exercise concentrations. No significant increases in Peptide F concentrations in the WBC fraction were observed during or after exercise. However, a significant decrease was observed at 30 min post-exercise. An ultradian pattern of Peptide F distribution was apparent during rest. Furthermore, concentrations of T cells, B cells, NK cells, and total WBCs demonstrated significant changes in response to aerobic exercise. Data indicated that Peptide F was bound in significant molar concentrations in the WBC fraction and that this biocompartment may be one of the tissue targets for binding interactions. These data indicate that Peptide F is involved with immune cell modulation in the white blood circulatory biocompartment of blood., (Copyright © 2013. Published by Elsevier Inc.)

Introduction: In 2007 wildfires ravaged Southern California resulting in the largest evacuation due to a wildfire in American history. We report how these wildfires affected emergency department (ED) visits for respiratory illness., Methods: We extracted data from a Kaiser Permanente database for a single metropolitan community ED. We compared the number of visits due to respiratory illness at time intervals of 2 weeks before and during the time when the fires were burning. We counted the total number of patients with chief complaint of dyspnea, cough, and asthma and final international classification of disease 9 coding diagnosis of asthma, bronchitis, chronic obstructive pulmonary disease and respiratory syndrome, and analyzed data for both total number and proportion of ED visits. We evaluated the data using Early Aberration Reporting System software to determine significant single-visit increases compared to expected counts. We also analyzed the average length of ED stay. Data on air quality were extracted from the http://www.airnow.gov site., Results: There were significant differences between pre-fire and fire period average visit counts for the chief complaints of dyspnea and asthma. Dypnea complaints increased by 3.2 visits per day. During the fire the diagnoses of asthma increased significantly by 2.6 patients per day. Air quality reached air quality index values of 300, indicating very unhealthy conditions. Average ED length of stay times remained unchanged during the fire period compared to the pre-fire period., Conclusion: The 2007 Southern California wildfires caused significant surges in the volume of ED patients seeking treatment for respiratory illness. Disaster plans should prepare for these surges when future wildfires occur.

Integrins are heterodimeric transmembrane receptors involved in sensing and transmitting informational cues from the extracellular environment to the cell. This study explored sub-proteome changes in response to elimination of the β3 integrin using a knockout murine model. Cleavable isotope-coded affinity tagging (cICAT) in combination with sub-cellular fractionation, multiple dimensions of separation and tandem mass spectrometry (MS/MS) were used to characterize differentially expressed proteins among β3 integrin(-/-) (β3(-/-)) mouse embryonic fibroblasts and isogenic wild-type (WT) controls. From a cytosolic protein fraction, 48 proteins were identified, in which expression differed by > 1.5-fold. Predominant ontological groups included actin-binding/cytoskeletal proteins and protease/protease inhibitors. Interestingly, β3 integrin expression was inversely correlated with expression of cathepsin B, a lysosomal cysteine protease, as its expression was greater by over 3.5-fold in the β3(-/-) cells. This inverse correlation was also observed in stable heterologous cells transfected with β3 integrin, where the intracellular expression and activity of cathepsin B was lower compared to control cells. Our data suggests that the composition of the cellular proteome is influenced by integrin expression patterns and reveals a strong functional relationship between β3 integrin and cathepsin B.

Scarring in the skin following surgery or trauma may be associated with adverse aesthetic, functional, growth and psychological effects, such that both physicians and patients regard it as important to minimize the appearance of scars. The prophylactic improvement of cutaneous scar appearance represents a significant opportunity to improve the well-being of patients. Human recombinant transforming growth factor beta 3 (avotermin) is the first in a new class of therapeutic agents to address this medical need. Herein we describe scar-free healing in early embryonic development, including the identification of the cellular and molecular mechanisms underpinning the scarring process. This understanding has led to the discovery of novel therapeutics such as transforming growth factor beta 3, which can be administered to improve scar appearance in human subjects through pharmacological action. We discuss the pioneering development of transforming growth factor beta 3 in this new therapeutic area showing how it has been possible to translate preclinical concepts into clinical application, namely the improvement of scar appearance following surgery., (© 2011 by the Wound Healing Society.)

Cutaneous scarring is an enormous medical problem with approximately 100 million patients acquiring scars each year. Scar prevention/reduction represents a significant, and largely unmet, clinical need. Research into the prophylactic modulation of scar outcome differs from research into other disease processes as the scar is not present at the start of the study; measurements of changes from baseline are impossible. Final scar morphology is influenced by many variables. A fundamental principle that should be observed in the prospective evaluation of scar prevention/reduction therapies is that, if left untreated, wounds in treatment and control groups should have healed with identical scars. Observation of this principle will allow the detection of true treatment effects. The many variables that influence scar morphology mean that the evaluation of potential pharmaceutical products for this indication favors the use of self-controlled designs in clinical trials. In this article, we review variables that affect scar morphology and recommend the self-controlled design for clinical trials aiming to establish proof of efficacy of scar prevention and reduction pharmaceuticals. With no pharmaceutical products currently licensed for this indication, this represents a new therapeutic area. The principles discussed will also have direct relevance to the wider fields of wound healing and regenerative medicine., (© 2011 by the Wound Healing Society.)

Background: Scarring is a major problem following skin injury. In early clinical trials, transforming growth factor β3 (avotermin) improved scar appearance. The aim of this study was to determine whether an injection of avotermin at the time of wound closure is effective in improving scar appearance., Methods: Study RN1001-0042, a double-blind, randomized, within-patient, placebo-controlled trial, investigated the efficacy and safety of four doses of avotermin given once. Patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were enrolled at 20 European centres. A total of 156 patients were randomized to receive one of four doses of avotermin (5, 50, 200 or 500 ng per 100 µl, at 100 µl per linear cm of wound margin), administered by intradermal injection to the groin and distal wound margins of one leg; placebo was administered to the other leg. Scar appearance was evaluated by an independent panel of lay people (lay panel), investigators and patients. The primary efficacy variable was lay panel Total Scar Score (ToScar), derived from visual analogue scale scores for groin scars between 6 weeks and 7 months., Results: Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = 0·036)., Conclusion: Avotermin 500 ng per 100 µl per linear cm of wound margin given once is well tolerated and significantly improves scar appearance., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-β family of cytokines plays a key role in scarring. TGF-β3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-β3) for the improvement of scar appearance following scar revision surgery., Methods: Sixty patients (35 men and 25 women; age, 19 to 78 years; 53 Caucasians; scar length, 5 to 21 cm) received intradermal avotermin (200 ng/100 μl/linear cm wound margin) and placebo to outer wound segments immediately after, and again 24 hours after, complete (group 1) or staged (group 2) scar revision surgery. A within-patient design was chosen to control for interindividual factors that affect scarring. The primary efficacy variable was a total scar score derived from a visual analogue scale, scored by a lay panel from standardized photographs from months 1 through 7 following treatment., Results: : Primary endpoint data from the combined surgical groups showed that avotermin significantly improved scar appearance compared with placebo (total scar score difference, 21.93 mm; p = 0.04). Profilometry showed a greater reduction in scar surface area from baseline with avotermin treatment compared with placebo, significant in group 2 at months 7 and 12 (difference, 41.99 mm and 25.85 mm, respectively; p = 0.03 for both comparisons). Histologic analysis from group 2 showed that, compared with placebo treatment, collagen organization in avotermin-treated scars more closely resembled normal skin in 14 of 19 cases. Avotermin was well tolerated., Conclusion: Avotermin administration following scar revision surgery is well tolerated and significantly improves scar appearance compared with placebo., Clinical Question/level of Evidence: Therapeutic, I.(Figure is included in full-text article.).