Alpha(1)-adrenergic-mediated eNOS phosphorylation in intact arteries

Activation of arterial smooth muscle alpha(1)-adrenergic receptors results in vasoconstriction, as well as a secondary release of nitric oxide and slow vasodilation, presumably through gap junction communication from smooth muscle to endothelium. We hypothesized that this slow vasodilation is due to activation of eNOS through phosphorylation at Ser1179 and dephosphorylation at Thr495. Phosphorylation was measured by western blot using mouse mesenteric arteries that were cannulated and pressurized (75 mm Hg) and treated either by 1) 5 mm of phenylephrine superfusion (10(-5) M) (PE5), 2) 15 min of phenylephrine (PE15), 3) 15 min phenylephrine followed by acetylcholine (10(-4) M) (PE + ACh), or 4) 20 min time control with no treatment (NT) [4-5 arteries pooled per treatment per blot; 5 blots performed]. These treatments allowed correlation between vasomotor changes, namely maximal constriction (PE5), slow vasodilation (PE15), and maximal dilation (PE + ACh), and relative phosphorylation changes. Phosphorylation of eNOS at Ser1179 was increased relative to NT by more than 2-fold at PE5 and remained similarly increased at PE15 and PE + ACh. Phosphotylation of eNOS at Thr495 was less in all treatments relative to NT, but not significantly. Treatment with L-NAME (10(-4) M) or endothelial denudation indicated that the slow dilation in response to phenylephrine was completely due to nitric oxide synthase and was endothelial dependent. These results indicate that eNOS phosphorylation at Ser1179 occurs before the slow dilation and is not actively involved in this vasodilation or dilation to acetylcholine, but may play a permissive role in eNOS activation by other mechanisms. It is not yet known what mechanism is responsible for Ser1179 phosphorylation with phenylephrine stimulation. (C) 2012 Elsevier Inc. All rights reserved

An Azide-Functionalized Nitronyl Nitroxide Radical: Synthesis, Characterization and Staudinger-Bertozzi Ligation Reactivity

An azide-functionalized nitronyl nitroxide was successfully synthesized and its reactivity towards the Staudinger-Bertozzi ligation was explored. While a model reaction in solution showed the conversion of the nitronyl nitroxide to an imino nitroxide radical, the same reaction at the interface of gold nanoparticles allowed for successful covalent incorporation of the nitronyl nitroxide radical onto the nanoparticles

beta-Hydroxy-beta-methylbutyrate free acid reduces markers of exercise-induced muscle damage and improves recovery in resistance-trained men

The purpose of the present study was to determine the effects of short-term supplementation with the free acid form of beta-hydroxy-beta-methylbutyrate (HMB-FA) on indices of muscle damage, protein breakdown, recovery and hormone status following a high-volume resistance training session in trained athletes. A total of twenty resistance-trained males were recruited to participate in a high-volume resistance training session centred on full squats, bench presses and dead lifts. Subjects were randomly assigned to receive either 3 g/d of HMB-FA or a placebo. Immediately before the exercise session and 48 h post-exercise, serum creatine kinase (CK), urinary 3-methylhistadine (3-MH), testosterone, cortisol and perceived recovery status (PRS) scale measurements were taken. The results showed that CK increased to a greater extent in the placebo (329%) than in the HMB-FA group (104%) (P=0.004, d=1.6). There was also a significant change for PRS, which decreased to a greater extent in the placebo (9.1 (SEM 0.4) to 4.6 (SEM 0.5)) than in the HMB-FA group (9.1 (SEM 0.3) to 6.3 (SEM 0.3)) (P=0.005, d = -0.48). Muscle protein breakdown, measured by 3-MH analysis, numerically decreased with HMB-FA supplementation and approached significance (P=0.08, d = 0.12). There were no acute changes in plasma total or free testosterone, cortisol or C-reactive protein. In conclusion, these results suggest that an HMB-FA supplement given to trained athletes before exercise can blunt increases in muscle damage and prevent declines in perceived readiness to train following a high-volume, muscle-damaging resistance-training session

Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection

Additional file 3: Table S2. Clinical Study Participant Characteristics

Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians

Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice

Achieving precision and reproducibility for writing patterns of n-alkanethiol self-assembled monolayers with automated nanografting

Nanografting is a high-precision approach for scanning probe lithography, which provides unique advantages and capabilities for rapidly writing arrays of nanopatterns of thiol self-assembled monolayers (SAMs). Nanografting is accomplished by force-induced displacement of molecules of a matrix SAM, followed immediately by the self-assembly of n-alkanethiol ink molecules from solution. The feedback loop used to control the atomic force microscope tip position and displacement enables exquisite control of forces applied to the surface, ranging from pico to nanonewtons. To achieve high-resolution writing at the nanoscale, the writing speed, direction, and applied force need to be optimized. There are strategies for programing the tip translation, which will improve the uniformity, alignment, and geometries of nanopatterns written using open-loop feedback control. This article addresses the mechanics of automated nanografting and demonstrates results for various writing strategies when nanografting patterns of n-alkanethiol SAMs. © 2008 Wiley Periodicals, Inc

Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Infection with blood-dwelling schistosome worms is a major cause of human disease in many tropical countries. Despite intensive efforts a vaccine has proved elusive, not least because the chronic nature of the infection provides few pointers for vaccine development. The rhesus macaque appears unique among animal models in that adult worms establish but are eventually lost. We investigated whether this was due to pathological or immunological causes by monitoring the fate of a schistosome infection, and were able to rule out escape of worms from the portal system as a result of egg-induced vascular shunts. A substantial worm population established in all animals but there was a wide variation in the numbers recovered at 18 weeks. We observed a strong inverse association between the rapidity and intensity of the IgG response and worm burden. Rather than an acute lethal attack, immune-mediated elimination of worms appeared to be a prolonged process directed against vital components of exposed surfaces, causing worms to starve to death. We suggest that if the mechanisms deployed by the rhesus macaque could be replicated in humans by administration of key recombinant antigens, they would form the basis for a vaccine with both prophylactic and therapeutic properties

The Open Cluster Chemical Analysis and Mapping Survey: Local Galactic Metallicity Gradient with APOGEE using SDSS DR10

The Open Cluster Chemical Analysis and Mapping (OCCAM) Survey aims to produce a comprehensive, uniform, infrared-based dataset for hundreds of open clusters, and constrain key Galactic dynamical and chemical parameters from this sample. This first contribution from the OCCAM survey presents analysis of 141 members stars in 28 open clusters with high-resolution metallicities derived from a large uniform sample collected as part of the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE). This sample includes the first high-resolution metallicity measurements for 22 open clusters. With this largest ever uniformly observed sample of open cluster stars we investigate the Galactic disk gradients of both [M/H] and [alpha/M]. We find basically no gradient across this range in [alpha/M], but [M/H] does show a gradient for R_{GC} < 10 kpc and a significant flattening beyond R_{GC} = 10 kpc. In particular, whereas fitting a single linear trend yields an [M/H] gradient of -0.09 +/- 0.03$ dex/kpc --- similar to previously measure gradients inside 13 kpc --- by independently fitting inside and outside 10 kpc separately we find a significantly steeper gradient near the Sun (7.9 <= R_{GC} <= 10) than previously found (-0.20 +/- 0.08 dex/kpc) and a nearly flat trend beyond 10 kpc (-0.02 +/- 0.09 dex/kpc).Comment: 6 pages, 4 figures, ApJ letters, in pres

Effectiveness and cost-effectiveness of the GoActive intervention to increase physical activity among UK adolescents: A cluster randomised controlled trial

Background: Less than 20% of adolescents globally meet recommended levels of physical activity, and not meeting these recommended levels is associated with social disadvantage and rising disease risk. The determinants of physical activity in adolescents are multilevel and poorly understood, but the school’s social environment likely plays an important role. We conducted a cluster randomised controlled trial to assess the effectiveness of a school-based programme (GoActive) to increase moderate-to-vigorous physical activity (MVPA) among adolescents. Methods and findings: Non-fee-paying, co-educational schools including Year 9 students in the UK counties of Cambridgeshire and Essex were eligible for inclusion. Within participating schools (n = 16), all Year 9 students were eligible and invited to participate. Participants were 2,862 13- to 14-year-olds (84% of eligible students). After baseline assessment, schools were computer-randomised, stratified by school-level pupil premium funding (below/above county-specific median) and county (control: 8 schools, 1,319 participants, mean [SD] participants per school n = 165 [62]; intervention: 8 schools, 1,543 participants, n = 193 [43]). Measurement staff were blinded to allocation. The iteratively developed, feasibility-tested 12-week intervention, aligned with self-determination theory, trained older adolescent mentors and in-class peer-leaders to encourage classes to conduct 2 new weekly activities. Students and classes gained points and rewards for engaging in any activity in or out of school. The primary outcome was average daily minutes of accelerometer-assessed MVPA at 10-month follow-up; a mixed-methods process evaluation evaluated implementation. Of 2,862 recruited participants (52.1% male), 2,167 (76%) attended 10-month follow-up measurements; we analysed the primary outcome for 1,874 participants (65.5%). At 10 months, there was a mean (SD) decrease in MVPA of 8.3 (19.3) minutes in the control group and 10.4 (22.7) minutes in the intervention group (baseline-adjusted difference [95% confidence interval] −1.91 minutes [−5.53 to 1.70], p = 0.316). The programme cost £13 per student compared with control; it was not cost-effective. Overall, 62.9% of students and 87.3% of mentors reported that GoActive was fun. Teachers and mentors commented that their roles in programme delivery were unclear. Implementation fidelity was low. The main methodological limitation of this study was the relatively affluent and ethnically homogeneous sample. Conclusions: In this study, we observed that a rigorously developed school-based intervention was no more effective than standard school practice at preventing declines in adolescent physical activity. Interdisciplinary research is required to understand educational-setting-specific implementation challenges. School leaders and authorities should be realistic about expectations of the effect of school-based physical activity promotion strategies implemented at scale. Trial registration: ISRCTN Registry ISRCTN31583496