The PI3K pathway regulates endochondral bone growth through control of hypertrophic chondrocyte differentiation

<p>Abstract</p> <p>Background</p> <p>The majority of our bones develop through the process of endochondral ossification that involves chondrocyte proliferation and hypertrophic differentiation in the cartilage growth plate. A large number of growth factors and hormones have been implicated in the regulation of growth plate biology, however, less is known about the intracellular signaling pathways involved. PI3K/Akt has been identified as a major regulator of cellular proliferation, differentiation and death in multiple cell types.</p> <p>Results and Discussion</p> <p>Employing an organ culture system of embryonic mouse tibiae and LY294002, a pharmacological inhibitor of PI3K, we show that inhibition of the pathway results in significant growth reduction, demonstrating that PI3K is required for normal endochondral bone growth <it>in vitro</it>. PI3K inhibition reduces the length of the proliferating and particularly of the hypertrophic zone. Studies with organ cultures and primary chondrocytes in micromass culture show delayed hypertrophic differentiation of chondrocytes and increased apoptosis in the presence of LY294002. Surprisingly, PI3K inhibition had no strong effect on IGF1-induced bone growth, but partially blocked the anabolic effects of C-type natriuretic peptide.</p> <p>Conclusion</p> <p>Our data demonstrate an essential role of PI3K signaling in chondrocyte differentiation and as a consequence of this, in the endochondral bone growth process.</p

C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and – independent pathways

BACKGROUND: C-type natriuretic peptide (CNP) has recently been identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanisms mediating its effects are not completely understood. RESULTS: We demonstrate in a tibia organ culture system that pharmacological inhibition of p38 blocks the anabolic effects of CNP. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization. Both effects are reversed by p38 inhibition. We also performed Affymetrix microarray analyses on micro-dissected tibiae to identify CNP target genes. These studies confirmed that hypertrophic chondrocytes are the main targets of CNP signaling in the growth plate, since many more genes were regulated by CNP in this zone than in the others. While CNP receptors are expressed at similar levels in all three zones, cGMP-dependent kinases I and II, important transducers of CNP signaling, are expressed at much higher levels in hypertrophic cells than in other areas of the tibia, providing a potential explanation for the spatial distribution of CNP effects. In addition, our data show that CNP induces the expression of NPR3, a decoy receptor for natriuretic peptides, suggesting the existence of a feedback loop to limit CNP signaling. Finally, detailed analyses of our microarray data showed that CNP regulates numerous genes involved in BMP signaling and cell adhesion. CONCLUSION: Our data identify novel target genes of CNP and demonstrate that the p38 pathway is a novel, essential mediator of CNP effects on endochondral bone growth, with potential implications for understanding and treatment of numerous skeletal diseases

Depressive symptoms in people with vision impairment: a cross-sectional study to identify who is most at risk

Objective: To identify the risk factors for significant depressive symptoms in people with visual impairment in England and Wales to provide information on who is most at risk and to whom support services could be targeted in future. Design: A cross-sectional study using baseline data from a pragmatic randomised controlled trial. Setting and participants: 990 participants aged 18 or over attending 1 of 14 low-vision rehabilitation primary care optometry-based clinics in South Wales or two hospital clinics in London. Outcome measure: A score of ≥6 on the Geriatric Depression Scale-15 was classed as clinically significant depressive symptoms. Results: In a multivariable logistic regression model, significant depressive symptoms were associated with age (adjusted OR (AOR)=0.82, 95% CI: 0.66 to 0.90, p&lt;0.001), ethnicity (AOR non-white compared with white=1.72, 95% CI: 1.05 to 2.81, p=0.031), total number of eye conditions (AOR for two vs one condition=0.98, 95% CI: 0.67 to 1.43; three or more vs one condition=0.34, 95% CI: 0.15 to 0.75, p=0.026), self-reported health (AOR for excellent vs poor=0.01, 95% CI: 0.00 to 0.12; very good vs poor=0.06, 95% CI: 0.03 to 0.13; good vs poor=0.14, 95% CI: 0.08 to 0.24; fair vs poor=0.28, 95% CI: 0.18 to 0.46, p&lt;0.001) and self-reported visual functioning (AOR=1.45, 95% CI: 1.31 to 1.61, p&lt;0.001). Conclusion: Younger age, a non-white ethnicity, fewer eye conditions and poorer self-reported health and visual function are risk factors for significant depressive symptoms in this population. Trial registration number: ISRCTN46824140; Pre-results

Temperature Dependence of Radiation Induced Conductivity in Insulators

We report on measurements of Radiation Induced Conductivity (RIC) of thin film Low Density Polyethylene (LDPE) samples. RIC occurs when incident ionizing radiation deposits energy in a material and excites electrons into conduction states. RIC is calculated as the difference in sample conductivity under an incident flux and “dark current” conductivity under no incident radiation. The primary focus of this study is the temperature dependence of the steady state RIC over a wide range of absorbed dose rates, from cryogenic temperatures to well above room temperature. The measured RIC values are compared to theoretical predictions of dose rate and temperature dependence based on photoconductivity models developed for localized trap states in disordered semiconductors. We also investigated the variation of RIC as a function of material, applied electric field, and incident beam energy parameters

The impact of Cochrane Systematic Reviews : a mixed method evaluation of outputs from Cochrane Review Groups supported by the UK National Institute for Health Research

© 2014 Bunn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: There has been a growing emphasis on evidence-informed decision making in health care. Systematic reviews, such as those produced by the Cochrane Collaboration, have been a key component of this movement. The UK National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs). The aim of this study was to identify the impacts of Cochrane reviews published by NIHR funded CRGs during the years 2007-11. Methods: We sent questionnaires to CRGs and review authors, interviewed guideline developers and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane reviews. We used a framework with four categories (knowledge production, research targeting, informing policy development, and impact on practice/services). Results: A total of 1502 new and updated reviews were produced by the 20 NIHR funded CRGs between 2007-11. The clearest impacts were on policy with a total of 483 systematic reviews cited in 247 sets of guidance; 62 were international, 175 national (87 from the UK) and 10 local. Review authors and CRGs provided some examples of impact on practice or services, for example safer use of medication, the identification of new effective drugs or treatments and potential economic benefits through the reduction in the use of unproven or unnecessary procedures. However, such impacts are difficult to objectively document and the majority of reviewers were unsure if their review had produced specific impacts. Qualitative data suggested that Cochrane reviews often play an instrumental role in informing guidance although a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and guideline developers were barriers to their use. Conclusions: Health and economic impacts of research are generally difficult to measure. We found that to be the case with this evaluation. Impacts on knowledge production and clinical guidance were easier to identify and substantiate than those on clinical practice. Questions remain about how we define and measure impact and more work is needed to develop suitable methods for impact analysis.Peer reviewe

Teachers as writers: a systematic review

This paper is a critical literature review of empirical work from 1990-2015 on teachers as writers. It interrogates the evidence on teachers’ attitudes to writing, their sense of themselves as writers and the potential impact of teacher writing on pedagogy or student outcomes in writing. The methodology was carried out in four stages. Firstly, educational databases keyword searches located 438 papers. Secondly, initial screening identified 159 for further scrutiny, 43 of which were found to specifically address teachers’ writing identities and practices. Thirdly, these sources were screened further using inclusion/exclusion criteria. Fourthly, the 22 papers judged to satisfy the criteria were subject to in-depth analysis and synthesis. The findings reveal that the evidence base in relation to teachers as writers is not strong, particularly with regard to the impact of teachers’ writing on student outcomes. The review indicates that teachers have narrow conceptions of what counts as writing and being a writer and that multiple tensions exist, relating to low self-confidence, negative writing histories, and the challenge of composing and enacting teacher and writer positions in school. However, initial training and professional development programmes do appear to afford opportunities for reformulation of attitudes and sense of self as writer

A Metabolomic Endotype of Bioenergetic Dysfunction Predicts Mortality in Critically Ill Patients with Acute Respiratory Failure

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors\u27 biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition

Product factorability of integral bilinear operators on Banach function spaces

[EN] This paper deals with bilinear operators acting in pairs of Banach function spaces that factor through the pointwise product. We find similar situations in different contexts of the functional analysis, including abstract vector lattices¿orthosymmetric maps, C¿-algebras¿zero product preserving operators, and classical and harmonic analysis¿integral bilinear operators. Bringing together the ideas of these areas, we show new factorization theorems and characterizations by means of norm inequalities. The objective of the paper is to apply these tools to provide new descriptions of some classes of bilinear integral operators, and to obtain integral representations for abstract classes of bilinear maps satisfying certain domination properties.The first author was supported by TUBITAK-The Scientific and Technological Research Council of Turkey, Grant No. 2211/E. 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