Explore the vast range of titles available.

BMP-7 and obesity Originally identified as a bone inducer, BMP-7 also has potent renal- and neuro-regenerative effects. Now it is reported to regulate energy homeostasis by promoting differentiation of brown, but not white, fat cells. BMP-7 switches on regulators of brown fat, including PRDM16 (see the cover story) and adipogenic transcription factors, and stimulates mitochondrial biogenesis. Ectopic expression of BMP-7 in mice increases brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain. These results have obvious therapeutic implications for the treatment of obesity. A member of the family of bone morphogenetic proteins, BMP-7, promotes the differentiation of brown, not white, fat cells. BMP-7 switches on regulators of brown fat, among which there is PRDM16, adipogenic transcription factors, and mitochondrial biogenesis. BMP-7 can persuade mesenchymal progenitor cells to become brown adipocytes. Without BMP-7 less brown fat develops. Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity 1 . Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood 2 , 3 . Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4 ) and PGC-1α (peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α; ref. 5 ), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARγ and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.

Controlled release drug delivery systems are well established as oral and implantable dosage forms. However, the controlled release paradigm can also be used to present complex soluble signals responsible for cellular organization during development. Endochondral ossification (EO), the developmental process of bone formation from a cartilage matrix is controlled by several soluble signals with distinct functions that vary in structure, molecular weight and stability. This makes delivering them from a single vehicle rather challenging. Herein, a gelatin-based delivery system suitable for the delivery of small molecules as well as recombinant human (rh) proteins (rhWNT3A, rhFGF2, rhVEGF, rhBMP4) is reported. The release behavior and biological activity of the released molecules was validated using analytical and biological assays, including cell reporter systems. The simplicity of fabrication of the gelatin device should foster its adaptation by the diverse scientific community interested in interrogating developmental processes, in vivo.

The Earth’s atmosphere and oceans are largely determined by periodic patterns of solar radiation, from daily and seasonal, to orbital variations over thousands of years. Dynamical processes alter these cycles with feedbacks and delays, so that the observed climate response is a combination of cyclical features and sudden regime changes. A primary example is the shift from a glacial (ice age) state to interglacial, which is driven by a 100-thousand year orbital cycle, while the transition occurs over a period of hundreds of years. Traditional methods of statistical analysis such as Fourier and wavelet transforms are very good at describing cyclical behavior, but lack any characterization of singular events and regime changes. More recently, researchers have tested techniques in the statistical discipline of change point detection. This paper explores the unique advantages of a piecewise linear regression change point detection algorithm to identify events, regime shifts, and the direction of cyclical trends in geophysical data. It evaluates the reasons for choosing this particular change detection algorithm over other techniques by applying the technique to both observational and model data sets. A comparison of the proposed change detection algorithm to the more established statistical techniques shows the benefits and drawbacks of each method.

We determined the equation of state (EOS) of three silicate liquid compositions by shock compression of preheated samples up to 127 GPa. Diopside (Di; Ca2Mg2SiO6) at 1773 K, anorthite (An; CaAl2Si2O8) at 1923 K and the eutectic composition Di64An36 at 1673 K were previously studied by shock compression to 38 GPa. The new data extend the EOS of each composition nearly to the Earth's core‐mantle boundary. The previously reported anomaly at 25 GPa for Di64An36 eutectic was not reproduced; rather all data for this composition fit within error a straight line Hugoniot in particle velocity vs. shock velocity. Di also displays a linear Hugoniot consistent with ultrasonic data and a third‐order finite strain EOS. The full anorthite data set is complex; we examine a model with a transition between two structural states and a fourth‐order finite strain model excluding two points that may not display relaxed behavior. We also report an experiment on room‐temperature solid Di64An36 aggregate that clearly demonstrates increase upon compression of the Grüneisen parameter of this liquid, much as experiment and theory have shown for forsterite and enstatite liquids. We construct isentropes and isotherms from our Hugoniots using Mie‐Grüneisen thermal pressure and evaluate the model of ideal mixing of volumes. Volume may mix almost linearly at high temperature, but deviates strongly when calculated along an isotherm; it remains difficult to reach a firm conclusion. We compare the densities of liquids to lower mantle solids. Our results suggest that basaltic liquids rich in CaO and Al2O3 are notably denser than liquids in the MgO‐SiO2 binary and, subject to uncertainties in the behavior of FeO and in corrections for thermal pressure, such liquids may be the most likely candidates for achieving negative buoyancy in the lowermost mantle.

Submarine groundwater discharge (SGD) is a ubiquitous source of meteoric fresh groundwater and recirculating seawater to the coastal ocean. Due to the hidden distribution of SGD, as well as the hydraulic- and stratigraphy-driven spatial and temporal heterogeneities, one of the biggest challenges to date is the correct assessment of SGD-driven constituent fluxes. Here, we present results from a 3-dimensional seasonal sampling campaign of a shallow subterranean estuary in a high-energy, meso-tidal beach, Spiekeroog Island, Northern Germany. We determined beach topography and analyzed physico-chemical and biogeochemical parameters such as salinity, temperature, dissolved oxygen, Fe(II) and dissolved organic matter fluorescence (FDOM). Overall, the highest gradients in pore water chemistry were found in the cross-shore direction. In particular, a strong physico-chemical differentiation between the tidal high water and low water line was found and reflected relatively stable in- and exfiltrating conditions in these areas. Contrastingly, in between, the pore water compositions in the existing foreshore ridge and runnel system were very heterogeneous on a spatial and temporal scale. The reasons for this observation may be the strong morphological changes that occur throughout the entire year, which affect the exact locations and heights of the ridge and runnel structures and associated flow paths. Further, seasonal changes in temperature and inland hydraulic head, and the associated effect on microbial mediated redox reactions likely overprint these patterns. In the long-shore direction the pore water chemistry varied less than the along the cross-shore direction. Variation in long-shore direction was probably occurring due to topography changes of the ridge-runnel structure and a physical heterogeneity of the sediment, which produced non-uniform groundwater flow conditions. We conclude that on meso-tidal high energy beaches, the rapidly changing beach morphology produces zones with different approximations to steady-state conditions. Therefore, we suggest that zone-specific endmember sampling is the optimal strategy to reduce uncertainties of SGD-driven constituent fluxes.

Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort. This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus. Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35-4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48-4.72]), and hyperglycemia at admission (6-11 mM: OR, 2.93 [95% CI, 1.54-5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58-113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001). Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.

The actin-associated protein Pdlim7 is essential for heart and fin development in zebrafish; however, the expression and function of this PDZ-LIM family member in the mammal has remained unclear. Here, we show that Pdlim7 predominantly localizes to actin-rich structures in mice including the heart, vascular smooth muscle, and platelets. To test the requirement for Pdlim7 in mammalian development and function, we analyzed a mouse strain with global genetic inactivation of Pdlim7. We demonstrate that Pdlim7 loss-of-function leads to significant postnatal mortality. Inactivation of Pdlim7 does not disrupt cardiac development, but causes mild cardiac dysfunction in adult mice. Adult Pdlim7(-/-) mice displayed increased mitral and tricuspid valve annulus to body weight ratios. These structural aberrations in Pdlim7(-/-) mice were supported by three-dimensional reconstructions of adult cardiac valves, which revealed increased surface area to volume ratios for the mitral and tricuspid valve leaflets. Unexpectedly, we found that loss of Pdlim7 triggers systemic venous and arterial thrombosis, leading to significant mortality shortly after birth in Pdlim7(+/-) (11/60) and Pdlim7(-/-) (19/35) mice. In line with a prothrombotic phenotype, adult Pdlim7(-/-) mice exhibit dramatically decreased tail bleed times compared to controls. These findings reveal a novel and unexpected function for Pdlim7 in maintaining proper hemostasis in neonatal and adult mice.

The profile of the electric potential at interfaces is often employed in discussions of classical molecular dynamics models. However, in contrast to the total potential, the contribution of molecular dipoles to the potential depends on the choice of an arbitrary reference point within molecules. We show both analytically and in a simulation how this choice affects the dipole contribution in the bulk. The analytic derivation pinpoints the origin of the changes in the dipole contribution. The simulation verifies the analytic expression and shows the exact influence of the chosen molecular reference. This work highlights the inherent issues of the dipole contribution to the electric potential.

Background Digital and mobile (mHealth) solutions are online or application-based services intended to support individuals with health needs. Despite evidence supporting the use of mHealth for patients with chronic pain, and the increasing desire of these types of solutions by both patients and providers, adoption of mHealth solutions remains limited. Implementation mapping can serve as a practical method to facilitate implementation and adoption of mHealth solutions within healthcare settings. Methods Implementation mapping was used to develop implementation strategies based on contextual determinants organized within the Consolidated Framework for Implementation Research (CFIR) for mHealth eLearning solutions across an integrated, multi-site healthcare system. We describe our experience identifying stakeholders, delineating implementation facilitators and barriers, defining implementation outcomes using RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, outlining initial implementation strategies, and iterating on implementation strategies. Results A total of 30 implementation strategies were identified and implemented. Over the first year, primary and specialty care providers across all the clinical sites (n = 70) placed 2559 orders for the mHealth solution. Most patients reported receiving the mHealth eLearning module (74%), and most patients felt that the tool improved their knowledge regarding their condition (82%) and their ability to provide self-care related to the condition (73%). Conclusion Practical applications of implementation science methods can help enable change within healthcare settings. Implementation mapping is an exercise that can engage stakeholders to facilitate the incorporation of new methods of care delivery, including mHealth solutions.

There is limited evidence on the acceptability, feasibility and cost-effectiveness of task-sharing interventions to narrow the treatment gap for mental disorders in sub-Saharan Africa. The purpose of this article is to describe the rationale, aims and methods of the Africa Focus on Intervention Research for Mental health (AFFIRM) collaborative research hub. AFFIRM is investigating strategies for narrowing the treatment gap for mental disorders in sub-Saharan Africa in four areas. First, it is assessing the feasibility, acceptability and cost-effectiveness of task-sharing interventions by conducting randomised controlled trials in Ethiopia and South Africa. The AFFIRM Task-sharing for the Care of Severe mental disorders (TaSCS) trial in Ethiopia aims to determine the acceptability, affordability, effectiveness and sustainability of mental health care for people with severe mental disorder delivered by trained and supervised non-specialist, primary health care workers compared with an existing psychiatric nurse-led service. The AFFIRM trial in South Africa aims to determine the cost-effectiveness of a task-sharing counselling intervention for maternal depression, delivered by non-specialist community health workers, and to examine factors influencing the implementation of the intervention and future scale up. Second, AFFIRM is building individual and institutional capacity for intervention research in sub-Saharan Africa by providing fellowship and mentorship programmes for candidates in Ethiopia, Ghana, Malawi, Uganda and Zimbabwe. Each year five Fellowships are awarded (one to each country) to attend the MPhil in Public Mental Health, a joint postgraduate programme at the University of Cape Town and Stellenbosch University. AFFIRM also offers short courses in intervention research, and supports PhD students attached to the trials in Ethiopia and South Africa. Third, AFFIRM is collaborating with other regional National Institute of Mental Health funded hubs in Latin America, sub-Saharan Africa and south Asia, by designing and executing shared research projects related to task-sharing and narrowing the treatment gap. Finally, it is establishing a network of collaboration between researchers, non-governmental organisations and government agencies that facilitates the translation of research knowledge into policy and practice. This article describes the developmental process of this multi-site approach, and provides a narrative of challenges and opportunities that have arisen during the early phases. Crucial to the long-term sustainability of this work is the nurturing and sustaining of partnerships between African mental health researchers, policy makers, practitioners and international collaborators.