Distinct metabolic programs induced by TGF-β1 and BMP2 in human articular chondrocytes with osteoarthritis

Objectives: Cellular energy metabolism is important for the function of all tissues, including cartilage. Recent studies indicate that superficial and deep subpopulations of articular chondrocytes (ACs) have distinct metabolic profiles. At the cellular and molecular level, osteoarthritis (OA) is characterised by alteration from a healthy homoeostatic state towards a catabolic state. Several molecular pathways, including transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signalling, have been identified as critical players in the pathogenesis and progression of OA. However, the manner in which these factors influence cellular energy metabolism in ACs is not well understood. This study investigates the effect of TGF-β or BMP signalling on energy metabolism in human articular chondrocytes (hACs). Methods: ACs were isolated from residual macroscopically full thickness and intact cartilage from the femoral condyle of human samples obtained from patients with OA. ACs were treated with Vehicle (control), TGF-β1 or BMP2 for 48–72 hours. Metabolic assays were performed to determine glucose consumption, lactate production and adenosine triphosphate (ATP) production, whereas the mitochondrial stress test was performed to determine oxygen consumption rate. Protein was isolated to assess translational activity and was evaluated using Western blot. Results: We showed that TGF-β1, known to maintain chondrocyte homoeostasis, stimulated glycolysis by upregulating key glycolytic factors, such as glucose transporter 1 (Glut1) and hexokinase II, while reducing oxidative phosphorylation in hACs. In contrast, BMP2 enhanced mitochondrial metabolism and oxidative phosphorylation and had a minimal effect on key glycolytic regulators. Conclusions: Our data revealed distinct metabolic programs induced by TGF-β1 and BMP2 in hACs, suggesting that the regulation of cellular metabolism may represent a new mechanism underlying the pathogenesis of OA. The translational potential of this article: The findings define the regulation of energy metabolism as a potential novel therapeutic approach for the treatment of OA

Managed moves: schools collaborating for collective gain

Government guidance in the United Kingdom encourages groups of schools to take collective responsibility for supporting and making provision for excluded pupils and those at risk of exclusion. Managed-moves are one way that some schools and authorities are enacting such guidance. This paper presents the results of an evaluation of one such scheme. The scheme, involving seven neighbouring secondary schools, was nearing its first year of completion. The paper draws primarily on interview data with pupils, parents and school staff to describe a number of positive outcomes associated with the scheme and to explore how these were achieved. We found that while some of these could be attributed directly to the managed-move, others arose from the more inclusive ethos and practices of particular schools. The concepts of tailored support, care and commitment emerged as strong themes that underpinned the various practical ways in which some schools in the cluster were able to re-engage 'at-risk' pupils. As managed moves become more widely practiced it will be important to remember that it is how the move proceeds and develops rather than the move itself that will ultimately make the difference for troubled and troublesome pupils

Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-Carboximidamides

The over production of nitric oxide in the brain by neuronal nitric oxide synthase (nNOS) is associated with a number of neurodegenerative diseases. Although inhibiting nNOS is an important therapeutic goal, it is important not to inhibit endothelial NOS (eNOS) owing to the critical role played by eNOS in maintaining vascular tone. While it has been possible to develop nNOS selective aminopyridine inhibitors, many of the most potent and selective inhibitors exhibit poor bioavailability properties. Our group and others have turned to more biocompatible thiophene-2-carboximidamides (T2C) inhibitors as potential nNOS selective inhibitors. We have used crystallography and computational methods to better understand how and why 2 commercially developed T2C inhibitors exhibit selectivity for human nNOS over human eNOS. As with many of the aminopyridine inhibitors, a critical active site Asp residue in nNOS vs Asn in eNOS is largely responsible for controlling selectivity. We also present thermodynamic integration results to better understand the change in pKa and thus charge of inhibitors once bound to the active site. In addition, relative free energy calculations underscore the importance of enhanced electrostatic stabilization of inhibitors bound to the nNOS active site compared to eNOS

Exploring Individual and Structural Factors Associated with Employment Among Young Transgender Women of Color Using a No-Cost Transgender Legal Resource Center

Purpose: The purpose of this study was to explore individual and structural factors associated with employment among young transgender women (TW) of color. Methods: Sixty-five trans women of color were recruited from the Transgender Legal Defense and Education Fund to complete a 30-min interviewer-assisted survey assessing sociodemographics, housing, workplace discrimination, job-seeking self-efficacy, self-esteem, perceived public passability, and transactional sex work. Results: Logistic regression models revealed that stable housing (structural factor) and job-seeking self-efficacy (individual factor) were significantly associated with currently being employed. Conclusion: Our findings underscore the need for multilevel approaches to assist TW of color gain employment

Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival

Objectives.We attempted to determine whether a family history of severe cardiovascular disease in patients with the Marfan syndrome is associated with increased aortic dilation or decreased survival, or both.Background.The prognostic importance of a family history of severe cardiovascular disease in patients with the Marfan syndrome has been incompletely examined. We hypothesized that such a family history would correlate with increased aortic dilation and would be associated with decreased survival.Methods.One hundred eight affected patients and 48 unaffected family members from 33 multigenerational families with the Marfan syndrome underwent echocardiographic measurement of the aortic root, arch and mid-abdominal aorta. Date of birth and age at death ascertained from family pedigrees were used to perform life table analysis and estimate survival.Results.Aortic root and arch diameters were significantly greater in patients with a family history of severe cardiovascular disease than in patients without such a family history. Of subjects in the highest quartile for aortic size, >80% had such a family history in contrast to <10% of those in the lowest quartile (chisquare 57.37, p < 0.00001). Mean age at death and cumulative probability of survival were significantly lower in patients with such a family history.Conclusions.Among patients with the Marfan syndrome, aortic dilation is greater and life expectancy shorter in those with a family history of severe cardiovascular manifestations. These data suggest that such a family history is an important risk factor for cardiovascular events in patients with the Marfan syndrome

Pediatric Feeding Disorder: Consensus Definition and Conceptual Framework

Pediatric feeding disorders (PFDs) lack a universally accepted definition. Feeding disorders require comprehensive assessment and treatment of 4 closely related, complementary domains (medical, psychosocial, and feeding skill-based systems and associated nutritional complications). Previous diagnostic paradigms have, however, typically defined feeding disorders using the lens of a single professional discipline and fail to characterize associated functional limitations that are critical to plan appropriate interventions and improve quality of life. Using the framework of the World Health Organization International Classification of Functioning, Disability, and Health, a unifying diagnostic term is proposed: “Pediatric Feeding Disorder” (PFD), defined as impaired oral intake that is not age-appropriate, and is associated with medical, nutritional, feeding skill, and/or psychosocial dysfunction. By incorporating associated functional limitations, the proposed diagnostic criteria for PFD should enable practitioners and researchers to better characterize the needs of heterogeneous patient populations, facilitate inclusion of all relevant disciplines in treatment planning, and promote the use of common, precise, terminology necessary to advance clinical practice, research, and health-care policy

Interoperable human behavior models for simulations

Modern simulations and games have limited capabilities for simulated characters to interact with each other and with humans in rich, meaningful ways. Although significant achievements have been made in developing human behavior models (HBMs) that are able to control a single simulated entity (or a single group of simulated entities), a limiting factor is the inability of HBMs developed by different groups to interact with each other. We present an architecture and multi-level message framework for enabling HBMs to communicate with each other about their actions and their intents, and describe the results of our crowd control demonstration system which applied it to allow three distinct HBMs to interoperate within a single training-oriented simulation. Our hope is that this will encourage the development of standards for interoperability among HBMs which will lead to the development of richer training and analysis simulations.Postprint (author’s final draft

Heme metabolism genes Downregulated in COPD Cachexia.

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss &gt; 5% in the past 12 months or low body mass index (BMI) (&lt; 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance &lt; 350 m), anemia (hemoglobin &lt; 12 g/dl), and low fat-free mass index (FFMI) (&lt; 15 kg/m2 among women and &lt; 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss &gt; 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (&gt; 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR &lt; 0.05) and ECLIPSE (FDR &lt; 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage