Effect of Leucine Supplementation on Indices of Muscle Damage and Recovery Following Eccentric-Based Resistance Exercise

In vitro, the amino acid leucine has been able to reduce proteolysis and be a potent stimulus for protein synthesis. The purpose of this study was to determine the effect of leucine supplementation on indices of muscle damage and muscular function following eccentric-based resistance exercise. METHODS: Twenty-seven untrained individuals were randomly divided into 3 groups; leucine (L), placebo (P) and control (C). The L and P groups performed 100 depth jumps from 60 cm and 6 sets of 10 repetitions of eccentric-only leg presses. Either leucine (250 mg/kg bm) or placebo was ingested at 3 time points during exercise and each recovery day following exercise. Serum muscle damage markers and muscle function assessment were used to monitor recovery. RESULTS: No significant differences existed between experimental groups for the serum markers of damage. The L group was able to maintain peak force outputs during the muscle function tests CONCLUSIONS: Leucine supplementation may facilitate the recovery process. Leucine may need further examination, as it was unable to shown a between group difference compared to P but did minimize the change in muscle damage markers compared to PRE. Leucine supplementation minimized the decrement in muscle function and maintained force output when compared to a placebo

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy

Satellite cells, the predominant stem cell population in adult skeletal muscle, are activated in response to hypertrophic stimuli and give rise to myogenic progenitor cells (MPCs) within the extracellular matrix (ECM) that surrounds myofibers. This ECM is composed largely of collagens secreted by interstitial fibrogenic cells, which influence satellite cell activity and muscle repair during hypertrophy and aging. Here we show that MPCs interact with interstitial fibrogenic cells to ensure proper ECM deposition and optimal muscle remodeling in response to hypertrophic stimuli. MPC-dependent ECM remodeling during the first week of a growth stimulus is sufficient to ensure long-term myofiber hypertrophy. MPCs secrete exosomes containing miR-206, which represses Rrbp1, a master regulator of collagen biosynthesis, in fibrogenic cells to prevent excessive ECM deposition. These findings provide insights into how skeletal stem and progenitor cells interact with other cell types to actively regulate their extracellular environments for tissue maintenance and adaptation

Myonuclear Transcription is Responsive to Mechanical Load and DNA Content but Uncoupled from Cell Size During Hypertrophy

Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number of transcriptionally active myonuclei and the amount of RNA generated by each myonucleus increased. During late hypertrophy, transcription did not scale with cell size, as smaller myofibers (\u3c 1000 μm2) demonstrated the highest transcriptional activity. Finally, transcription was primarily responsible for changes in the expression of genes known to regulate myofiber size. These findings show that resident myonuclei possess a significant reserve capacity to up-regulate transcription during hypertrophy and that myofiber transcription is responsive to DNA content but uncoupled from cell size during hypertrophy

Reduced Voluntary Running Performance is Associated with Impaired Coordination as a Result of Muscle Satellite Cell Depletion in Adult Mice

BACKGROUND: Satellite cells, or muscle stem cells, have been thought to be responsible for all muscle plasticity, but recent studies using genetically modified mouse models that allow for the conditional ablation of satellite cells have challenged this dogma. Results have confirmed the absolute requirement of satellite cells for muscle regeneration but surprisingly also showed that they are not required for adult muscle growth. While the function of satellite cells in muscle growth and regeneration is becoming better defined, their role in the response to aerobic activity remains largely unexplored. The purpose of the current study was to assess the involvement of satellite cells in response to aerobic exercise by evaluating the effect of satellite cell depletion on wheel running performance. RESULTS: Four-month-old female Pax7/DTA mice (n = 8-12 per group) were satellite cell depleted via tamoxifen administration; at 6 months of age, mice either remained sedentary or were provided with running wheels for 8 weeks. Plantaris muscles were significantly depleted of Pax7+cells (≥90 % depleted), and 8 weeks of wheel running did not result in an increase in Pax7+ cells, or in myonuclear accretion. Interestingly, satellite cell-depleted animals ran ~27 % less distance and were 23 % slower than non-depleted animals. Wheel running was associated with elevated succinate dehydrogenase activity, muscle vascularization, lipid accumulation, and a significant shift toward more oxidative myosin heavy chain isoforms, as well as an increase in voltage dependent anion channel abundance, a marker of mitochondrial density. Importantly, these changes were independent of satellite cell content. Interestingly, depletion of Pax7+ cells from intra- as well as extrafusal muscle fibers resulted in atrophy of intrafusal fibers, thickening of muscle spindle-associated extracellular matrix, and a marked reduction of functional outcomes including grip strength, gait fluidity, and balance, which likely contributed to the impaired running performance. CONCLUSIONS: Depletion of Pax7-expressing cells in muscle resulted in reduced voluntary wheel running performance, without affecting markers of aerobic adaptation; however, their absence may perturb proprioception via disruption of muscle spindle fibers resulting in loss of gross motor coordination, indicating that satellite cells have a yet unexplored role in muscle function

Preprocessing Among the Infalling Galaxy Population of EDisCS Clusters

We present results from a low-resolution spectroscopic survey for 21 galaxy clusters at $0.4 < z < 0.8$ selected from the ESO Distant Cluster Survey. We measured spectra using the low-dispersion prism in IMACS on the Magellan Baade telescope and calculate redshifts with an accuracy of $\sigma_z = 0.007$. We find 1763 galaxies that are brighter than $R = 22.9$ in the large-scale cluster environs. We identify the galaxies expected to be accreted by the clusters as they evolve to $z = 0$ using spherical infall models and find that $\sim30\%$ to $\sim70\%$ of the $z = 0$ cluster population lies outside the virial radius at $z \sim 0.6$. For analogous clusters at $z = 0$, we calculate that the ratio of galaxies that have fallen into the clusters since $z \sim 0.6$ to those that were already in the core at that redshift is typically between $\sim0.3$ and $1.5$. This wide range of ratios is due to intrinsic scatter and is not a function of velocity dispersion, so a variety of infall histories is to be expected for clusters with current velocity dispersions of $300 \lesssim\sigma\lesssim 1200$ km s$^{-1}$. Within the infall regions of $z \sim 0.6$ clusters, we find a larger red fraction of galaxies than in the field and greater clustering among red galaxies than blue. We interpret these findings as evidence of "preprocessing", where galaxies in denser local environments have their star formation rates affected prior to their aggregation into massive clusters, although the possibility of backsplash galaxies complicates the interpretation.Comment: Accepted for publication in Ap

Inducible Depletion of Satellite Cells in Adult, Sedentary Mice Impairs Muscle Regenerative Capacity without Affecting Sarcopenia

A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives. A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis

Validation of the Hidradenitis Suppurativa Investigator Global Assessment

Importance Few simplified instruments exist for use in hidradenitis suppurativa (HS) trials. Objective To assess psychometric properties of the Hidradenitis Suppurativa Investigator Global Assessment (HS-IGA) score using a clinical trial data set. Design, Setting, and Participants This retrospective analysis of a phase 2 randomized double-blind, placebo-controlled, active-reference arm trial (UCB HS0001) included adults with moderate-to-severe HS. Exposures Trial participants were randomized at baseline to receive bimekizumab, adalimumab, or placebo. Main Outcomes and Measures The HS-IGA score at prespecified time points up to 12 weeks after randomization. Results The HS-IGA score showed strong convergent validity with IHS4 and HS-PhGA scores at baseline (Spearman correlation, 0.86 [P < .001] and 0.74 [P < .001], respectively) and at week 12 (Spearman correlation, 0.73 [P < .001] and 0.64 [P < .001], respectively). The HS-IGA scores assessed during predosing visits at screening and baseline showed good test-retest reliability (intraclass correlation coefficient [ICC] = 0.92). At week 12, HS-IGA responders were significantly associated with HiSCR-(50/75/90) responders (χ2 = 18.45; P < .001; χ2 = 18.11; P < .001; and χ2 = 20.83; P < .001, respectively). The HS-IGA score was predictive of HiSCR-50/75/90 and HS-PhGA response at week 12 (AUC, 0.69, 0.73, 0.85, and 0.71, respectively). However, the HS-IGA as a measure of disease activity showed low predictive validity with patient-reported outcomes at week 12. Conclusions and Relevance The HS-IGA score demonstrated good psychometric properties compared with existing measures and may be considered for use as an end point in clinical trials for HS

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London