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Protein-leucine Ingestion Activates a Regenerative Inflammo-Myogenic Transcriptome in Skeletal Muscle Following Intense Endurance Exercise. - Physiological genomics
Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested either 70/15/180/30g protein/leucine/carbohydrate/fat (15LEU), 23/5/180/30g (5LEU) or 0/0/274/30g (CON) beverages during the first 90 min of a 240-min recovery period. Vastus lateralis muscle samples (30 and 240-min post-exercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by Protein-leucine in a dose-dependent manner impacting the inflammatory response, muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with geneset functions involving cell-cycle arrest (Z-score 2.0-2.7; P<0.01), leukocyte maturation (1.7; P=0.007), cell viability (2.4; P=0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development programme correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL1Î²-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0-2.6; <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF-ÎºÎ², SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (-1.8-2.4; P<0.01), increased apoptosis of myeloid and muscle cells (2.2-3.0; P<0.002) and cell metabolism (2.0-2.4; P<0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity.Copyright Â© 2015, Physiological Genomics.
Live to cheat another day: bacterial dormancy facilitates the social exploitation of Î²-lactamases. - The ISME journal
The breakdown of antibiotics by Î²-lactamases may be cooperative, since resistant cells can detoxify their environment and facilitate the growth of susceptible neighbours. However, previous studies of this phenomenon have used artificial bacterial vectors or engineered bacteria to increase the secretion of Î²-lactamases from cells. Here, we investigated whether a broad-spectrum Î²-lactamase gene carried by a naturally occurring plasmid (pCT) is cooperative under a range of conditions. In ordinary batch culture on solid media, there was little or no evidence that resistant bacteria could protect susceptible cells from ampicillin, although resistant colonies could locally detoxify this growth medium. However, when susceptible cells were inoculated at high densities, late-appearing phenotypically susceptible bacteria grew in the vicinity of resistant colonies. We infer that persisters, cells that have survived antibiotics by undergoing a period of dormancy, founded these satellite colonies. The number of persister colonies was positively correlated with the density of resistant colonies and increased as antibiotic concentrations decreased. We argue that detoxification can be cooperative under a limited range of conditions: if the toxins are bacteriostatic rather than bacteridical; or if susceptible cells invade communities after resistant bacteria; or if dormancy allows susceptible cells to avoid bactericides. Resistance and tolerance were previously thought to be independent solutions for surviving antibiotics. Here, we show that these are interacting strategies: the presence of bacteria adopting one solution can have substantial effects on the fitness of their neighbours.The ISME Journal advance online publication, 27 October 2015; doi:10.1038/ismej.2015.154.
Wallenberg Syndrome with Associated Motor Weakness in a Two-Week-Postpartum Female. - Case reports in neurology
A 30-year-old, right-handed female presented 2 weeks postpartum with acute-onset severe headache, vertigo, and vomiting. Initial neurologic examination illustrated lingual dysarthria, horizontal nystagmus, right dysmetria on finger-to-nose testing, and weakness of the extremities. Magnetic resonance imaging showed a large, left lateral medullary infarction (Wallenberg syndrome) with cephalad extension into the ipsilateral pons as well as involvement of the left middle cerebellar peduncle. The patient was discharged 3 weeks later to an inpatient rehabilitation facility with gradual improvement of her symptoms.
Generalized anxiety disorder in primary care: mental health services use and treatment adequacy. - BMC family practice
Generalized Anxiety Disorder (GAD) is a common mental disorder in the primary care setting, marked by persistent anxiety and worries. The aims of this study were to: 1) examine mental health services utilisation in a large sample of primary care patients; 2) explore detection of GAD and minimal standards for pharmacological and psychological treatment adequacy based on recommendation from clinical practice guidelines; 3) examine correlates of treatment adequacy, i.e. predisposing, enabling and needs factors according to the Behavioural Model of Health Care Use.A sample of 373 adults meeting DSM-IV criteria for Generalized Anxiety Disorder in the past 12Â months took part in this study. Data were drawn from the "Dialogue" project, a large primary care study conducted in 67 primary care clinics in Quebec, Canada. Following a mental health screening in medical clinics (nâ€‰=â€‰14833), patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). Multilevel logistic regression models were developed to examine correlates of treatment adequacy for pharmacological and psychological treatments.Results indicate that 52.5Â % of participants were recognized as having GAD by a healthcare professional in the past 12Â months, and 36.2Â % of the sample received a pharmacological (24.4Â %) and/or psychological treatment (19.2Â %) meeting indicators based on clinical practice guidelines recommendations. The detection of GAD by a health professional and the presence of comorbid depression were associated with overall treatment adequacy.This study suggests that further efforts towards GAD detection could lead to an increase in the delivery of evidence-based treatments. Key targets for improvement in treatment adequacy include regular follow up of patients with a GAD medication and access to psychotherapy from the primary care setting.
MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability. - Journal of human genetics
Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.Journal of Human Genetics advance online publication, 22 October 2015; doi:10.1038/jhg.2015.118.
Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases. - PloS one
Tryptic serine proteases of bronchial epithelium regulate ion flux, barrier integrity, and allergic inflammation. Inhibition of some of these proteases is a strategy to improve mucociliary function in cystic fibrosis and asthmatic inflammation. Several inhibitors have been tested in pre-clinical animal models and humans. We hypothesized that these inhibitors inactivate a variety of airway protease targets, potentially with bystander effects. To establish relative potencies and modes of action, we compared inactivation of human prostasin, matriptase, airway trypsin-like protease (HAT), and Î²-tryptase by nafamostat, camostat, bis(5-amidino-2-benzimidazolyl)methane (BABIM), aprotinin, and benzamidine. Nafamostat achieved complete, nearly stoichiometric and very slowly reversible inhibition of matriptase and tryptase, but inhibited prostasin less potently and was weakest versus HAT. The IC50 of nafamostat's leaving group, 6-amidino-2-naphthol, was >104-fold higher than that of nafamostat itself, consistent with suicide rather than product inhibition as mechanisms of prolonged inactivation. Stoichiometric release of 6-amidino-2-naphthol allowed highly sensitive fluorometric estimation of active-site concentration in preparations of matriptase and tryptase. Camostat inactivated all enzymes but was less potent overall and weakest towards matriptase, which, however was strongly inhibited by BABIM. Aprotinin exhibited nearly stoichiometric inhibition of prostasin and matriptase, but was much weaker towards HAT and was completely ineffective versus tryptase. Benzamidine was universally weak. Thus, each inhibitor profile was distinct. Nafamostat, camostat and aprotinin markedly reduced tryptic activity on the apical surface of cystic fibrosis airway epithelial monolayers, suggesting prostasin as the major source of such activity and supporting strategies targeting prostasin for inactivation.
Analysis of Multiple Families with Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion. - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Proximal tubular resistance to parathyroid hormone (PTH) resulting in hypocalcemia and hyperphosphatemia are preeminent abnormalities in pseudohypoparathyroidism type Ib (PHP1B), but resistance toward other hormones as well as variable features of Albright's Hereditary Osteodystrophy (AHO) can occur also. Genomic DNA from PHP1B patients shows epigenetic changes at one or multiple differentially methylated regions (DMRs) within GNAS, the gene encoding GÎ±s and splice variants thereof. In the autosomal dominant disease variant, these methylation abnormalities are caused by deletions in STX16 or GNAS on the maternal allele. The molecular defect(s) leading to sporadic PHP1B (sporPHP1B) remains in most cases unknown and we therefore analyzed 60 sporPHP1B patients and available family members by microsatellite markers, single nucleotide polymorphisms (SNP), multiplex ligation-dependent probe amplification (MLPA), and methylation specific-MLPA (MS-MLPA). All investigated cases revealed broad GNAS methylation changes, but no evidence for inheritance of two paternal chromosome 20q alleles. Some patients with partial epigenetic modifications in DNA from peripheral blood cells showed more complete GNAS methylation changes when testing their immortalized lymphoblastoid cells. Analysis of siblings and children of sporPHP1B patients provided no evidence for an abnormal mineral ion regulation and no changes in GNAS methylation. Only one patient revealed, based on MLPA and microsatellite analyses, evidence for an allelic loss, which resulted in the discovery of two adjacent, maternally inherited deletions (37,597 and 1,427 bp, respectively) that remove the area between GNAS antisense exons 3 and 5, including exon NESP. Our findings thus emphasize that the region comprising antisense exons 3 and 4 is required for establishing all maternal GNAS methylation imprints. The genetic defect(s) leading in sporPHP1B to epigenetic GNAS changes and thus PTH-resistance remains unknown, but it seems unlikely that this disease variant is caused by heterozygous inherited or de novo mutations involving GNAS. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Illustrative case studies in the return of exome and genome sequencing results. - Personalized medicine
Whole genome and exome sequencing tests are increasingly being ordered in clinical practice, creating a need for research exploring the return of results from these tests. A goal of the Clinical Sequencing and Exploratory Research (CSER) consortium is to gain experience with this process to develop best practice recommendations for offering exome and genome testing and returning results. Genetic counselors in the CSER consortium have an integral role in the return of results from these genomic sequencing tests and have gained valuable insight. We present seven emerging themes related to return of exome and genome sequencing results accompanied by case descriptions illustrating important lessons learned, counseling challenges specific to these tests and considerations for future research and practice.
Study of the spin and parity of the Higgs boson in diboson decays with the ATLAS detector. - The European physical journal. C, Particles and fields
Studies of the spin, parity and tensor couplings of the Higgs boson in the [Formula: see text], [Formula: see text] and [Formula: see text] decay processes at the LHC are presented. The investigations are based on [Formula: see text] of pp collision data collected by the ATLAS experiment at [Formula: see text]Â TeV and [Formula: see text]Â TeV. The Standard Model (SM) Higgs boson hypothesis, corresponding to the quantum numbers [Formula: see text], is tested against several alternative spin scenarios, including non-SM spin-0 and spin-2 models with universal and non-universal couplings to fermions and vector bosons. All tested alternative models are excluded in favour of the SM Higgs boson hypothesis at more than 99.9Â % confidence level. Using the [Formula: see text] and [Formula: see text] decays, the tensor structure of the interaction between the spin-0 boson and the SM vector bosons is also investigated. The observed distributions of variables sensitive to the non-SM tensor couplings are compatible with the SM predictions and constraints on the non-SM couplings are derived.
Estimating Incidence of HIV Infection Among Men Who Have Sex with Men, San Francisco, 2004-2014. - AIDS and behavior
After 30Â years of the HIV epidemic in San Francisco there is hope that the number of new infections among men who have sex with men (MSM) is decreasing and that current novel interventions such as treatment as prevention and pre-exposure prophylaxis will hasten the year that the city sees the last of new HIV infections. In addition, new HIV cases/incidence is the key indicator to measure the trajectory of the HIV epidemic. In this analysis we present an alternate age-cohort approach to estimating HIV incidence and compare our results to other indicators of incidence. Data for the present analysis were collected through National HIV Behavioral Surveillance conducted among MSM in San Francisco using time location sampling from 2004 to 2014. We estimated HIV incidence using a model where a closed population of 100 was divided into number infected and uninfected according to the HIV prevalence of the 21-25Â year group and then estimated what incidence over 30Â years would result in the HIV prevalence at age 50+. Incidence estimates were 7 per 1000 person years (PY) (338 cases), 7 per 1000 PY (312), 6 per 1000 PY (285) and 6 per 1000 PY (271) for 2004, 2008, 2011 and 2014, respectively.Our data suggest that recent declines in new HIV diagnoses among MSM in San Francisco maybe due to a reduction in a "back log" of undiagnosed cases and not as large of a decline in new cases or HIV incidence. We hypothesize that the decline in new HIV infections among MSM in San Francisco is much slower than suggested by the decline in new HIV diagnoses.
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