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Background The purpose of this study was to examine the effects of acute ingestion of a pre-workout dietary supplement (PWS) with and without p- synephrine (S) on perceptions of readiness to perform, cognitive function, exercise performance, and markers of safety. Methods In a randomized, double-blind, and counterbalanced manner; 25 healthy and recreationally active male and female participants ingested a flavored maltodextrin placebo (PLA), a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg) with 2 g of maltodextrin and flavoring; or, the PWS with Citrus aurantium (PWS + S) extract standardized for 30% p -synephrine (20 mg). Participants had heart rate (HR), blood pressure, resting energy expenditure (REE), 12-lead electrocardiograms (ECG), perceptions about readiness to perform, cognitive function (Stroop Color-Word test), bench and leg press performance (2 sets of 10 repetitions at 70% of 1RM and 1 set to failure), and Wingate anaerobic capacity (WAC) sprint performance determined as well as donated blood samples prior to and/or following exercise/supplementation. Data were analyzed by MANOVA with repeated measures as well as mean changes from baseline with 95% confidence intervals (CI). Results No clinically significant differences were observed among treatments in HR, blood pressure, ECG, or general clinical blood panels. There was evidence that PWS and PWS + S ingestion promoted greater changes in REE responses. Participants reported higher perception of optimism about performance and vigor and energy with PWS and PWS + S ingestion and there was evidence that PWS and PWS + S improved changes in cognitive function scores from baseline to a greater degree than PLA after 1 or 2 h. However, the scores in the PWS + S treatment did not exceed PLA or PWS responses at any data point. No statistically significant differences were observed among treatments in total bench press lifting volume, leg press lifting volume or WAC sprint performance. Conclusions Within the confines of this study, ingestion of PWS and/or PWS + S prior to exercise appears to be well-tolerated when consumed by young, healthy individuals. The primary effects appear to be to increase REE responses and improve perceptions about readiness to perform and cognitive function with limited to no effects on muscular endurance and WAC. The addition of 20 mg of p -synephrine to the PWS provided limited to no additive benefits. Trial registration This trial ( NCT02952014 ) was retrospectively registered on September 13th 2016.

Background The purpose of this study was to examine whether ingesting a pre-workout dietary supplement (PWS) with and without synephrine (S) during training affects training responses in resistance-trained males. Methods Resistance-trained males ( N  = 80) were randomly assigned to supplement their diet in a double-blind manner with either a flavored placebo (PLA); a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg); or, the PWS supplement with Citrus aurantium extract containing 20 mg of synephrine (PWS + S) once per day for 8-weeks during training. Participants donated a fasting blood sample and had body composition (DXA), resting heart rate and blood pressure, cognitive function (Stroop Test), readiness to perform, bench and leg press 1 RM, and Wingate anaerobic capacity assessments determined a 0, 4, and 8-weeks of standardized training. Data were analyzed by MANOVA with repeated measures. Performance and cognitive function data were analyzed using baseline values as covariates as well as mean changes from baseline with 95% confidence intervals (CI). Blood chemistry data were also analyzed using Chi-square analysis. Results Although significant time effects were seen, no statistically significant overall MANOVA Wilks’ Lambda interactions were observed among groups for body composition, resting heart and blood pressure, readiness to perform questions, 1RM strength, anaerobic sprint capacity, or blood chemistry panels. MANOVA univariate analysis and analysis of changes from baseline with 95% CI revealed some evidence that cognitive function and 1RM strength were increased to a greater degree in the PWS and/or PWS + S groups after 4- and/or 8-weeks compared to PLA responses. However, there was no evidence that PWS + S promoted greater overall training adaptations compared to the PWS group. Dietary supplementation of PWS and PWS + S did not increase the incidence of reported side effects or significantly affect the number of blood values above clinical norms compared to PLA. Conclusion Results provide some evidence that 4-weeks of PWS and/or PWS + S supplementation can improve some indices of cognitive function and exercise performance during resistance-training without significant side effects in apparently health males. However, these effects were similar to PLA responses after 8-weeks of supplementation and inclusion of synephrine did not promote additive benefits. Trial registration This trial ( NCT02999581 ) was retrospectively registered on December 16th 2016.

Table of contents P1 Impact of antioxidant-enriched nutrient bar supplementation on the serum antioxidant markers and physical fitness components of track and field athletes Lalitha Ramaswamy, Supriya Velraja P2 The effects of phosphatidic acid supplementation on fitness levels in resistance trained women Guillermo Escalante, Phil Harvey, Michelle Alencar, Bryan Haddock P3 The effects of phosphatidic acid supplementation on cardiovascular risk factors in resistance trained men Phil Harvey, Guillermo Escalante, Michelle Alencar, Bryan Haddock P4 The efficacy of sodium bicarbonate supplementation on physical capacity and selected biochemical markers in elite wrestlers Krzysztof Durkalec-Michalski, Jan Jeszka, Bogna Zawieja, Tomasz Podgórski P5 Effects of different nutritional strategies in hydration and physical performance in healthy well-trained males Ana Paula Trussardi Fayh, Alexandre Hideki Okano, Amanda Maria de Jesus Ferreira P6 Reduction of plasma creatine concentrations as an indicator of improved bioavailability Ralf Jäger, Martin Purpura, Roger C Harris P7 Effect of three different breakfast meals on energy intake and nutritional status in college-age women Molly M. Krause, Kiley A. Lavanger, Nina O. Allen, Allison E. Lieb, Katie A. Mullen, Joan M. Eckerson P8 Accuracy of the ASA24® Dietary Recall system for assessing actual dietary intake in normal weight college-age women. Kiley A. Lavanger, Molly M. Krause, Nina O. Allen, Allison E. Lieb, Katie A. Mullen, Joan M. Eckerson P9 β-aminoisobutyric acid does not regulate exercise induced UCP-3 expression in skeletal muscle Elisa Morales, Jeffrey Forsse, Thomas Andre, Sarah McKinley, Paul Hwang, Grant Tinsley, Mike Spillane, Peter Grandjean, Darryn Willoughby P10 The ability of collegiate football athletes to adhere to sport-specific nutritional recommendations A. Jagim, G. Wright, J. Kisiolek, M. Meinking, J. Ochsenwald, M. Andre, M.T. Jones, J. M. Oliver P11 A single session of low-volume high intensity interval exercise improves appetite regulation in overweight men Victor Araújo Ferreira, Daniel Costa de Souza, Victor Oliveira Albuquerque dos Santos, Rodrigo Alberto Vieira Browne, Eduardo Caldas Costa, Ana Paula Trussardi Fayh P12 Acute effects of oral peppermint oil ingestion on exercise performance in moderately-active college students Suresh T. Mathews, Haley D. Bishop, Clara R. Bowen, Yishan Liang, Emily A. West, Rebecca R. Rogers, Mallory R. Marshall, John K. Petrella P13 Associations in body fat and liver triglyceride content with serum health markers in sedentary and exercised rats fed a ketogenic diet, Western diet or standard chow over a 6-week period A. Maleah Holland, Wesley C. Kephart, Petey W. Mumford, C. Brooks Mobley, Ryan P. Lowery, Jacob M. Wilson, Michael D. Roberts P14 Physiological changes following competition in male and female physique athletes: A pilot study Eric T. Trexler, Katie R. Hirsch, Bill I. Campbell, Meredith G. Mock, Abbie E. Smith-Ryan P15 Relationship between cognition and hydration status in college students at a large Southwestern university Kate Zemek, Carol Johnston P16 Whey protein-derived exosomes increase protein synthesis in C2C12 myotubes C. Brooks Mobley, Petey W. Mumford, David D. Pascoe, Christopher M. Lockwood, Michael E. Miller, Michael D. Roberts P17 The effect of three different energy drinks on 1.5-mile running performance, oxygen consumption, and perceived exertion Gabriel J. Sanders, Willard Peveler, Brooke Warning, Corey A. Peacock P18 The Ketogenic diet improves rotarod performance in young and older rats Wesley C. Kephart, Petey W. Mumford, Ryan P. Lowery, Michael D. Roberts, Jacob M. Wilson P19 Absorption of bonded arginine silicate compared to individual arginine and silicon components David Sandler, Sara Perez Ojalvo, James Komorowski P20 Effects of a high (2.4 g/kg) vs. low/moderate (1.2 g/kg) protein intake on body composition in aspiring female physique athletes engaging in an 8-week resistance training program Bill I. Campbell, Danielle Aguilar, Andres Vargas, Laurin Conlin, Amey Sanders, Paola Fink-Irizarry, Layne Norton, Ross Perry, Ryley McCallum, Matthew R. Wynn, Jack Lenton P21 Effects of a high (2.4 g/kg) vs. low/moderate (1.2 g/kg) protein intake on maximal strength in aspiring female physique athletes engaging in an 8-week resistance training program Bill I. Campbell, Chris Gai, Seth Donelson, Shiva Best, Daniel Bove, Kaylee Couvillion, Jeff Dolan, Dante Xing, Kyshia Chernesky, Michael Pawela, Andres D. Toledo, Rachel Jimenez P22 Monitoring of female collegiate athletes over a competitive season reveals changes in nutritional biomarkers M. Rabideau, A. Walker, J. Pellegrino, M. Hofacker, B. McFadden, S. Conway, C. Ordway, D. Sanders, R. Monaco, M. S. Fragala, S. M. Arent P23 Comparison of prediction equations to indirect calorimetry in men and women athletes Jason D. Stone, Andreas Kreutzer, Jonathan M. Oliver, Jacob Kisiolek, Andrew R. Jagim P24 Regional variations in sweat-based electrolyte loss and changes in plasma electrolyte content in Division I female athletes over the course of a competitive season M. Hofacker, A. Walker, J. Pellegrino, M. Rabideau, B. McFadden, S. Conway, D. Sanders, C. Ordway, R. Monaco, M. S. Fragala, S. M. Arent P25 In-season changes in plasma amino acid levels in Division I NCAA female athletes Ozlem Tok, Joseph K. Pellegrino, Alan J. Walker, David J. Sanders, Bridget A. McFadden, Meaghan M. Rabideau, Sean P. Conway, Chris E. Ordway, Marissa Bello, Morgan L. Hofacker, Nick S. Mackowski, Anthony J. Poyssick, Eddie Capone, Robert M. Monaco, Maren S. Fragala, Shawn M. Arent P26 Effects of a ketogenic diet with exercise on serum markers of bone metabolism, IGF-1 and femoral bone mass in rats Petey W. Mumford, A. Maleah Holland, Wesley C. Kephart, Ryan P. Lowery, C. Brooks Mobley, Romil K. Patel, Annie Newton, Darren T. Beck, Michael D. Roberts, Jacob M. Wilson, Kaelin C. Young P27 Casein supplementation in trained men and women: morning versus evening Tobin Silver, Anya Ellerbroek, Richard Buehn, Leo Vargas, Armando Tamayo, Corey Peacock, Jose Antonio P28 A high protein diet has no harmful effects: a one-year crossover study in resistance-trained males Anya Ellerbroek, Tobin Silver, Richard Buehn, Leo Vargas, Armando Tamayo, Corey Peacock, Jose Antonio P29 SUP (Stand-up Paddling) athletes: nutritional intake and body composition Adam Pollock, Anya Ellerbroek, Tobin Silver, Corey Peacock, Jose Antonio P30 The effects of 8 weeks of colostrum and bio-active peptide supplementation on body composition in recreational male weight lifters A. Kreutzer, P. Zavala, S. Fleming, M. Jones, J. M. Oliver, A. Jagim P31 Effects of a Popular Women’s Thermogenic Supplement During an Energy-Restricted High Protein Diet on Changes in Body Composition and Clinical Safety Markers Cody T. Haun, Petey W. Mumford, Parker N. Hyde, Ciaran M. Fairman, Wesley C. Kephart, Darren T. Beck, Jordan R. Moon, Michael D. Roberts, Kristina L. Kendall, Kaelin C. Young P32 Three days of caffeine consumption following caffeine withdrawal yields small strength increase in knee flexors Geoffrey M Hudson, Tara Hannings, Kyle Sprow, Loretta DiPietro P33 Comparison of cellular nitric oxide production from various sports nutrition ingredients Doug Kalman, Sara Perez Ojalvo, James Komorowski P34 The effects of 8 weeks of bio-active peptide supplementation on training adaptations in recreational male weight lifters P. Zavala, S. Fleming, M. Jones, J. Oliver, A. Jagim P35 Effects of MusclePharm Assault Black TM on lower extremity spinal excitability and postactivation potentiation: A pilot study Brian Wallace, Haley Bergstrom, Kelly Wallace P36 Effects of four weeks of Ketogenic Diet alone and combined with High intensity Interval Training or Continuous-Moderate intensity on body composition, lipid profile and physical performance on healthy males Matias Monsalves-Alvarez, Sebastian Oyharçabal, Victoria Espinoza P37 Effect of branched-chain amino acid supplementation on creatine kinase, muscular performance, and perceived muscle soreness following acute eccentric exercise Trisha A. VanDusseldorp, Kurt A. Escobar, Kelly E. Johnson, Nathan Cole, Terence Moriarty, Matthew Stratton, Marvin R. Endito, Christine M. Mermier, Chad M. Kerksick P38 Effects of endurance training on markers of ribosome biogenesis in rodents fed a high fat diet Matthew A. Romero, C. Brooks Mobley, Melissa Linden, Grace Margaret-Eleanor Meers, R. Scott Rector, Michael D. Roberts P39 The effects of acute citrulline-malate on lower-body isokinetic performance in recreationally active individuals Joshua L Gills, Hocheng Lu, Kimberly Parker, Chris Dobbins, Joshua N Guillory, Braden Romer, David Szymanski, Jordan Glenn P40 The effect pre-ingested L-isoleucine and L-leucine on blood glucose responses and glycemic hormones in healthy inactive adults: Preliminary data. Daniel E. Newmire, Eric Rivas, Sarah E. Deemer, Robert Wildman, Victor Ben-Ezra P41 Does protein and source impact substrate oxidation and energy expenditure during and after moderate intensity treadmill exercise? C Kerksick, B Gieske, R Stecker, C Smith, K Witherbee P42 Effects of a pre-workout supplement on peak power and power maintenance during lower and upper body testing Michael T. Lane, M. Travis Byrd, Zachary Bell, Emily Frith, Lauren M.C. Lane P43 Effects of a pre-workout supplement on peak power production during lower and upper body testing in college-age females Michael T. Lane, M. Travis Byrd, Zachary Bell, Emily Frith, Lauren M.C. Lane P44 A comparison of whey versus casein protein supplementation on resting metabolic rate and body composition: a pilot study Corey A. Peacock, Tobin A. Silver, Megan Colas, Mauricio Mena, Winter Rodriguez, Gabriel J. Sanders, Jose Antonio P45 A novel mixed-tocotrienol intervention enhances recovery after eccentric exercise: preliminary findings Andrea Vansickle, Brittany DiFiore, Stephanie Stepp, Grant Slack, Bridget Smith, Kayla

Functional CD8 + T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. PD-1 expression in T cells involved in chronic infections and tumors such as melanoma often correlates with a state of T-cell exhaustion. Here we interrogate CD8 + tumor-infiltrating lymphocytes (TILs) from human breast and melanoma tumors to explore their functional state. Despite expression of exhaustion hallmarks, such as PD-1 expression, human breast tumor CD8 + TILs retain robust capacity for production of effector cytokines and degranulation capacity. In contrast, melanoma CD8 + TILs display dramatic reduction of cytokine production and degranulation capacity. We show that CD8 + TILs from human breast tumors can potently kill cancer cells via bi-specific antibodies. Our data demonstrate that CD8 + TILs in human breast tumors retain polyfunctionality, despite PD-1 expression, and suggest that they may be harnessed for effective immunotherapies. Expression of the checkpoint molecule programmed cell death protein 1 (PD-1) is considered a marker of T cells exhaustion. Here the authors show that CD8T cells isolated from breast cancer patients are perfectly functional despite PD-1 expression while those isolated from melanoma patients are not.

Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting. RNA interference screens were used to identify chromatin-associated factors that impede reprogramming of somatic cells into iPS cells; suppression of the chromatin assembly factor CAF-1 enhances the generation of iPS cells by rendering chromatin more accessible to pluripotency transcription factors. CAF-1 is a barrier to cell fate change Lineage fate determination in development, and reprogramming to a different fate in the laboratory, depend on gene expression programs that are regulated by factors influencing the chromatin landscape. Konrad Hochedlinger and colleagues have performed two RNA-interference-based screens to search for chromatin-associated factors that impede reprogramming. They identify the chromatin assembly factor-1 (CAF-1) complex as an important regulator of this process, acting by rendering the chromatin inaccessible to transcription factors. Suppression of CAF-1 function thus facilitates chromatin access to reprogramming factors, both during reprogramming to pluripotency and in direct fate conversion.

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function. Elements of gene function Three papers in this issue of Nature report on the modENCODE initiative, which aims to characterize functional DNA elements in the fruitfly Drosophila melanogaster and the roundworm Caenorhabditis elegans . Kharchenko et al . present a genome-wide chromatin landscape of the fruitfly, based on 18 histone modifications. They describe nine prevalent chromatin states. Integrating these analyses with other data types reveals individual characteristics of different genomic elements. Graveley et al . have used RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages of the fruitfly. Among the results are scores of new genes, coding and non-coding transcripts, as well as splicing and editing events. Finally, Nègre et al . have produced a map of the regulatory part of the fruitfly genome, defining a vast array of putative regulatory elements, such as enhancers, promoters, insulators and silencers. As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans , this study presents a genome-wide chromatin landscape of the fruitfly, based on 18 histone modifications. Nine prevalent chromatin states are described. Integrating these analyses with other data types reveals individual characteristics of different genomic elements. The work provides a resource of unprecedented scale for future experimental investigations.

Background Complex human health conditions with etiological heterogeneity like Autism Spectrum Disorder (ASD) often pose a challenge for traditional genome-wide association study approaches in defining a clear genotype to phenotype model. Coalitional game theory (CGT) is an exciting method that can consider the combinatorial effect of groups of variants working in concert to produce a phenotype. CGT has been applied to associate likely-gene-disrupting variants encoded from whole genome sequence data to ASD; however, this previous approach cannot take into account for prior biological knowledge. Here we extend CGT to incorporate a priori knowledge from biological networks through a game theoretic centrality measure based on Shapley value to rank genes by their relevance–the individual gene’s synergistic influence in a gene-to-gene interaction network. Game theoretic centrality extends the notion of Shapley value to the evaluation of a gene’s contribution to the overall connectivity of its corresponding node in a biological network. Results We implemented and applied game theoretic centrality to rank genes on whole genomes from 756 multiplex autism families. Top ranking genes with the highest game theoretic centrality in both the weighted and unweighted approaches were enriched for pathways previously associated with autism, including pathways of the immune system. Four of the selected genes HLA-A, HLA-B, HLA-G, and HLA-DRB1–have also been implicated in ASD and further support the link between ASD and the human leukocyte antigen complex. Conclusions Game theoretic centrality can prioritize influential, disease-associated genes within biological networks, and assist in the decoding of polygenic associations to complex disorders like autism.