The Prodomain-bound Form of Bone Morphogenetic Protein 10 Is Biologically Active on Endothelial Cells.

BMP10 is highly expressed in the developing heart and plays essential roles in cardiogenesis. BMP10 deletion in mice results in embryonic lethality because of impaired cardiac development. In adults, BMP10 expression is restricted to the right atrium, though ventricular hypertrophy is accompanied by increased BMP10 expression in a rat hypertension model. However, reports of BMP10 activity in the circulation are inconclusive. In particular, it is not known whether in vivo secreted BMP10 is active or whether additional factors are required to achieve its bioactivity. It has been shown that high-affinity binding of the BMP10 prodomain to the mature ligand inhibits BMP10 signaling activity in C2C12 cells, and it was proposed that prodomain-bound BMP10 (pBMP10) complex is latent. In this study, we demonstrated that the BMP10 prodomain did not inhibit BMP10 signaling activity in multiple endothelial cells, and that recombinant human pBMP10 complex, expressed in mammalian cells and purified under native conditions, was fully active. In addition, both BMP10 in human plasma and BMP10 secreted from the mouse right atrium were fully active. Finally, we confirmed that active BMP10 secreted from mouse right atrium was in the prodomain-bound form. Our data suggest that circulating BMP10 in adults is fully active and that the reported vascular quiescence function of BMP10 in vivo is due to the direct activity of pBMP10 and does not require an additional activation step. Moreover, being an active ligand, recombinant pBMP10 may have therapeutic potential as an endothelial-selective BMP ligand, in conditions characterized by loss of BMP9/10 signaling.This work was supported by British Heart Foundation Grants PG/12/54/29734 (to W. L., P. D. U., and N. W. M.) and CH/09/001/25945 (to N. W. M.). He Jiang was supported by the Cambridge Wellcome Trust 4-year Ph.D Programme in Metabolic and Cardiovascular Disease.This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology via http://dx.doi.org/10.1074/jbc.M115.68329

A school-based intervention incorporating smartphone technology to improve health-related fitness among adolescents: Rationale and study protocol for the NEAT and ATLAS 2.0 cluster randomised controlled trial and dissemination study

Introduction Physical inactivity has been described as a global pandemic. Interventions aimed at developing skills in lifelong physical activities may provide the foundation for an active lifestyle into adulthood. In general, school-based physical activity interventions targeting adolescents have produced modest results and few have been designed to be \u27scaled-up\u27 and disseminated. This study aims to: (1) assess the effectiveness of two physical activity promotion programmes (ie, NEAT and ATLAS) that have been modified for scalability; and (2) evaluate the dissemination of these programmes throughout government funded secondary schools. Methods and analysis The study will be conducted in two phases. In the first phase (cluster randomised controlled trial), 16 schools will be randomly allocated to the intervention or a usual care control condition. In the second phase, the Reach, Effectiveness, Adoption, Implementation and Maintenance (Re-AIM) framework will be used to guide the design and evaluation of programme dissemination throughout New South Wales (NSW), Australia. In both phases, teachers will be trained to deliver the NEAT and ATLAS programmes, which will include: (1) interactive student seminars; (2) structured physical activity programmes; (3) lunch-time fitness sessions; and (4) web-based smartphone apps. In the cluster RCT, study outcomes will be assessed at baseline, 6 months (primary end point) and 12-months. Muscular fitness will be the primary outcome and secondary outcomes will include: objectively measured body composition, cardiorespiratory fitness, flexibility, resistance training skill competency, physical activity, self-reported recreational screen-time, sleep, sugar-sweetened beverage and junk food snack consumption, self-esteem and well-being

Acute effects of reducing sitting time in adolescents: a randomized cross-over study

BACKGROUND: Levels of sitting among adolescents are high, especially during the school day. The acute cognitive and health consequences associated with prolonged sitting are poorly understood in adolescents. This randomized crossover design study examined the acute effects of a simulated school day with reduced sitting or usual sitting on adolescents\u27 cognitive function and cardiometabolic biomarkers. METHODS: Eighteen healthy school aged adolescents were recruited from the community to the study (11 males; 7 females; mean age [SD]&nbsp;=&nbsp;13.5&nbsp;&plusmn;&nbsp;0.9&nbsp;years). Two protocols were developed to simulate an adolescent school day, the amount of time spent sitting was manipulated reflecting: a \u27typical\u27 day (65% of the time spent sitting with two sitting bouts sitting &gt;20&nbsp;min) and a \u27reduced sitting\u27 day (adolescents sat for 50% less time with no bouts of sitting &gt;20 mins). The order that participants were exposed to each condition was randomized (via random number generator). Participants were not fully blinded as they could observe the difference between conditions. Energy intake and moderate to vigorous physical activity (MVPA) were standardized for both conditions and monitored for 48&nbsp;h post-condition for compensatory effects. Cognitive (working memory) and cardiometabolic outcomes (lipids, glucose, insulin, IL-6, apo-A1, apo-B, blood pressure,) were assessed pre and post for both conditions, BMI and body fat were assessed on the morning of the intervention. Data were analyzed using linear mixed models. Standardised effect sizes were calculated. RESULTS: Compared with the typical school day, the reduced sitting day demonstrated significant positive effects for apoB/apoA-1 ratio (adjusted difference&nbsp;&plusmn;&nbsp;SD) -0.02&nbsp;&plusmn;&nbsp;0.03; P&nbsp;=&nbsp;0.03; effect size [Cohen\u27s d]&nbsp;=&nbsp;-0.67. Findings for total cholesterol -0.19&nbsp;&plusmn;&nbsp;0.27; P&nbsp;=&nbsp;0.28; d&nbsp;=&nbsp;-0.71; HDL cholesterol -0.23&nbsp;&plusmn;&nbsp;0.50; P&nbsp;=&nbsp;0.12 d&nbsp;=&nbsp;-0.66; and total cholesterol/HDL ratio 0.25&nbsp;&plusmn;&nbsp;0.53; P&nbsp;=&nbsp;0.25; d&nbsp;=&nbsp;0.51 and for cognition 0.64&nbsp;&plusmn;&nbsp;0.15; P&nbsp;=&nbsp;0.15; d&nbsp;=&nbsp;0.54 were non-significant. There were no compensatory changes in participant energy expenditure or energy intake for 48&nbsp;h post intervention. CONCLUSION: Reducing school day sitting time in adolescents\u27 resulted in significant improvements in apoB/apoA-1 ratio with medium effect sizes for total cholesterol, HDL cholesterol and total cholesterol/HDL ratio. Cognitive function results showed the equivalent of a 6&nbsp;month improvement in effective mental-attentional capacity. <br /

Increasing physical activity among young children from disadvantaged communities: Study protocol of a group randomised controlled effectiveness trial

Background: Participation in regular physical activity (PA) during the early years helps children achieve healthy body weight and can substantially improve motor development, bone health, psychosocial health and cognitive development. Despite common assumptions that young children are naturally active, evidence shows that they are insufficiently active for health and developmental benefits. Exploring strategies to increase physical activity in young children is a public health and research priority. Methods: Jump Start is a multi-component, multi-setting PA and gross motor skill intervention for young children aged 3–5 years in disadvantaged areas of New South Wales, Australia. The intervention will be evaluated using a two-arm, parallel group, randomised cluster trial. The Jump Start protocol was based on Social Cognitive Theory and includes five components: a structured gross motor skill lesson (Jump In); unstructured outdoor PA and gross motor skill time (Jump Out); energy breaks (Jump Up); activities connecting movement to learning experiences (Jump Through); and a home-based family component to promote PA and gross motor skill (Jump Home). Early childhood education and care centres will be demographically matched and randomised to Jump Start (intervention) or usual practice (comparison) group. The intervention group receive Jump Start professional development, program resources, monthly newsletters and ongoing intervention support. Outcomes include change in total PA (accelerometers) within centre hours, gross motor skill development (Test of Gross Motor Development-2), weight status (body mass index), bone strength (Sunlight MiniOmni Ultrasound Bone Sonometer), self-regulation (Heads-Toes-Knees-Shoulders, executive function tasks, and proxy-report Temperament and Approaches to learning scales), and educator and parent self-efficacy. Extensive quantitative and qualitative process evaluation and a cost-effectiveness evaluation will be conducted. Discussion: The Jump Start intervention is a unique program to address low levels of PA and gross motor skill proficiency, and support healthy lifestyle behaviours among young children in disadvantaged communities. If shown to be efficacious, the Jump Start approach can be expected to have implications for early childhood education and care policies and practices, and ultimately a positive effect on the health and development across the life course

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex

\u27Jump start\u27 childcare-based intervention to promote physical activity in pre-schoolers: six-month findings from a cluster randomised trial

BACKGROUND: Participation in adequate levels of physical activity during the early years is important for health and development. We report the 6-month effects of an 18-month multicomponent intervention on physical activity in early childhood education and care (ECEC) settings in low-income communities. METHODS: A cluster randomised controlled trial was conducted in 43 ECEC settings in disadvantaged areas of New South Wales, Australia. Three-year-old children were recruited and assessed in the first half of 2015 with follow-up 6 months later. The intervention was guided by Social Cognitive Theory and included five components. The primary outcome was minutes per hour in total physical activity during ECEC hours measured using Actigraph accelerometers. Intention-to-treat analysis of the primary outcome was conducted using a generalized linear mixed model. RESULTS: A total of 658 children were assessed at baseline. Of these, 558 (85%) had valid accelerometer data (mean age 3.38y, 52% boys) and 508 (77%) had valid accelerometry data at 6-month follow-up. Implementation of the intervention components ranged from 38 to 72%. There were no significant intervention effects on mins/hr. spent in physical activity (adjusted difference = - 0.17 mins/hr., 95% CI (- 1.30 to 0.97), p = 0.78). A priori sub-group analyses showed a greater effect among overweight/obese children in the control group compared with the intervention group for mins/hr. of physical activity (2.35mins/hr., [0.28 to 4.43], p = 0.036). CONCLUSIONS: After six-months the Jump Start intervention had no effect on physical activity levels during ECEC. This was largely due to low levels of implementation. Increasing fidelity may result in higher levels of physical activity when outcomes are assessed at 18-months

Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention

<p><b>Abstract</b></p> <p>Background</p> <p>The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context.</p> <p>Methods/design</p> <p>A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6–22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined.</p> <p>Discussion</p> <p>The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.</p

Submicron Structures Technology and Research

Contains reports on fifteen research projects.Joint Services Electronics Program (Contract DAALO3-86-K-0002)National Science Foundation (Grant ECS 87-09806)Semiconductor Research Corporation (Contract 87-SP-080)National Science Foundation (Grant ECS 85-03443)U.S. Air Force - Office of Scientific Research (Grant AFOSR 85-0376)National Science Foundation (Grant ECS 85-06565)U.S. Air Force - Office of Scientific Research (Grant AFOSR 85-0154)Lawrence Livermore National Laboratory (Subcontract 2069209)National Aeronautics and Space Adminstration (Grant NGL22-009-683)Collaboration with KMS Fusion, Inc