An in-depth examination of the implementation of the Disability Equality Duty in England

This seven-month study examined the implementation of the Disability Equality Duty (DED) in England. The DED, introduced through the Disability Discrimination Act 2005, applies to public authorities in England, Wales and Scotland

BRAHMS: Novel middleware for integrated systems computation

Biological computational modellers are becoming increasingly interested in building large, eclectic models, including components on many different computational substrates, both biological and non-biological. At the same time, the rise of the philosophy of embodied modelling is generating a need to deploy biological models as controllers for robots in real-world environments. Finally, robotics engineers are beginning to find value in seconding biomimetic control strategies for use on practical robots. Together with the ubiquitous desire to make good on past software development effort, these trends are throwing up new challenges of intellectual and technological integration (for example across scales, across disciplines, and even across time) - challenges that are unmet by existing software frameworks. Here, we outline these challenges in detail, and go on to describe a newly developed software framework, BRAHMS. that meets them. BRAHMS is a tool for integrating computational process modules into a viable, computable system: its generality and flexibility facilitate integration across barriers, such as those described above, in a coherent and effective way. We go on to describe several cases where BRAHMS has been successfully deployed in practical situations. We also show excellent performance in comparison with a monolithic development approach. Additional benefits of developing in the framework include source code self-documentation, automatic coarse-grained parallelisation, cross-language integration, data logging, performance monitoring, and will include dynamic load-balancing and 'pause and continue' execution. BRAHMS is built on the nascent, and similarly general purpose, model markup language, SystemML. This will, in future, also facilitate repeatability and accountability (same answers ten years from now), transparent automatic software distribution, and interfacing with other SystemML tools. (C) 2009 Elsevier Ltd. All rights reserved

Using Neonatal Skin to Study the Developmental Programming of Aging

Numerous studies have examined how both negative and positive maternal exposures (environmental contaminants, nutrition, exercise, etc.) impact offspring risk for age-associated diseases such as obesity, type 2 diabetes, hypertension, and others. The purpose of this study was to introduce the foreskin as a novel model to examine developmental programming in human neonates, particularly in regard to adipogenesis and insulin receptor signaling, major contributors to age-associated diseases such as obesity and diabetes. Neonatal foreskin was collected following circumcision and primary dermal fibroblasts were isolated to perform adipocyte differentiation and insulin stimulation experiments. Human neonatal foreskin primary fibroblasts take up lipid when stimulated with a differentiation cocktail and demonstrate insulin signaling when stimulated with insulin. Thus, we propose that foreskin tissue can be used to study developmental exposures and programming that occur in the neonate as it relates to age-associated diseases such as obesity and diabetes

Sea surface temperature in global analyses: gains from the copernicus imaging microwave radiometer

Sea surface temperatures (SSTs) derived from passive microwave (PMW) observations benefit global ocean and SST analyses because of their near-all-weather availability. Present PMW SSTs have a real aperture-limited spatial resolution in excess of 50 km, limiting the spatial fidelity with which SST features, reflecting ocean dynamics, can be captured. This contrasts with the target resolution of global analyses of 5 to 10 km. The Copernicus Imaging Microwave Radiometer (CIMR) is a mission concept under consideration as a high-priority candidate mission for the expansion of the Copernicus space programme. This instrument would be capable of real aperture resolution < 15 km with low total uncertainties in the range 0.4–0.8 K for channels between 1.4 and 36.5 GHz, and a dual-view arrangement that further reduces noise. This paper provides a comparative study of SST uncertainty and feature resolution with and without the availability of CIMR in the future SST-observing satellite constellation based on a detailed simulation of CIMR plus infrared observations and the processing of global SST analyses with 0.05◦ final grid resolution. Simulations of CIMR data including structured errors were added to an observing system consisting of the Sea and Land Surface Temperature Radiometer (SLSTR) on Sentinel-3A and the Advanced Very High Resolution Radiometer (AVHRR) on MetOp-A. This resulted in a large improvement in the global root-mean-square error (RMSE) for SST from 0.37 K to 0.21 K for January and 0.40 K to 0.25 K for July. There was a particularly noticeable improvement in the performance of the analysis, as measured by the reduction in RMSE, for dynamical and persistently cloudy areas. Of these, the Aghulas Current showed an improvement of 43% in January and 48% in July, the Gulf Stream showed 70% and 44% improvements, the Southern Ocean showed 57% and 74% improvements, and the Maritime Continent showed 50% and 40% improvements, respectively

Increased Birth Weight is Associated with Altered Gene Expression in Neonatal Foreskin

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n = 7) v. the remainder of the cohort (n = 40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. controls. Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies

JNK1 Phosphorylates SIRT1 and Promotes Its Enzymatic Activity

SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways including the stress protection pathway. SIRT1 deacetylates a number of protein substrates, including histones, FOXOs, PGC-1α, and p53, leading to cellular protection. We identified a functional interaction between cJUN N-terminal kinase (JNK1) and SIRT1 by coimmunoprecipitation of endogenous proteins. The interaction between JNK1 and SIRT1 was identified under conditions of oxidative stress and required activation of JNK1 via phosphorylation. Modulation of SIRT1 activity or protein levels using nicotinamide or RNAi did not modify JNK1 activity as measured by its ability to phosphorylate cJUN. In contrast, human SIRT1 was phosphorylated by JNK1 on three sites: Ser27, Ser47, and Thr530 and this phosphorylation of SIRT1 increased its nuclear localization and enzymatic activity. Surprisingly, JNK1 phosphorylation of SIRT1 showed substrate specificity resulting in deacetylation of histone H3, but not p53. These findings identify a mechanism for regulation of SIRT1 enzymatic activity in response to oxidative stress and shed new light on its role in the stress protection pathway

Elevated Lipid Oxidation Is Associated with Exceeding Gestational Weight Gain Recommendations and Increased Neonatal Anthropometrics: A Cross-Sectional Analysis

BACKGROUND: Deviations from gestational weight gain (GWG) recommendations are associated with unfavorable maternal and neonatal outcomes. There is a need to understand how maternal substrate metabolism, independent of weight status, may contribute to GWG and neonatal outcomes. The purpose of this study was to explore the potential link between maternal lipid oxidation rate, GWG, and neonatal anthropometric outcomes. METHODS: Women (N = 32) with a lean pre-pregnancy BMI were recruited during late pregnancy and substrate metabolism was assessed using indirect calorimetry, before and after consumption of a high-fat meal. GWG was categorized as follows: inadequate, adequate, or excess. Shortly after delivery (within 48 h), neonatal anthropometrics were obtained. RESULTS: Using ANOVA, we found that fasting maternal lipid oxidation rate (grams/minute) was higher (p = 0.003) among women with excess GWG (0.1019 ± 0.0416) compared to women without excess GWG (inadequate = 0.0586 ± 0.0273, adequate = 0.0569 ± 0.0238). Findings were similar when lipid oxidation was assessed post-meal and also when expressed relative to kilograms of fat free mass. Absolute GWG was positively correlated to absolute lipid oxidation expressed in grams/minute at baseline (r = 0.507, p = 0.003), 2 h post-meal (r = 0.531, p = 0.002), and 4 h post-meal (r = 0.546, p = 0.001). Fasting and post-meal lipid oxidation (grams/minute) were positively correlated to neonatal birthweight (fasting r = 0.426, p = 0.015; 2-hour r = 0.393, p = 0.026; 4-hour r = 0.540, p = 0.001) and also to neonatal absolute fat mass (fasting r = 0.493, p = 0.004; 2-hour r = 0.450, p = 0.010; 4-hour r = 0.552, p = 0.001). CONCLUSIONS: A better understanding of the metabolic profile of women during pregnancy may be critical in truly understanding a woman\u27s risk of GWG outside the recommendations. GWG counseling during prenatal care may need to be tailored to women based not just on their weight status, but other metabolic characteristics

Exposure to PCB126 During The Nursing Period Reversibly Impacts Early-Life Glucose Tolerance

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal days (PND) 3, 10, and 17 (n = 9 per group). Offspring body weight, lean and fat mass, and glucose tolerance were recorded every three weeks. PCB126 treatment did not alter dam nor offspring body weight (p \u3e 0.05). PCB126-exposed male and female offspring displayed normal body composition (p \u3e 0.05) relative to vehicle-exposed offspring. However, both male and female offspring that were exposed to PCB126 during the nursing period had significantly impaired glucose tolerance at 3 and 9 weeks of age (p \u3c 0.05). At 6 and 12 weeks of age, no impairments in glucose tolerance existed in offspring (p \u3e 0.05). Our current study demonstrates that exposure to PCB126 through the mother\u27s milk does not affect short- or long-term body composition but impairs glucose tolerance in the short-term

Oxidative Stress Accumulates in Adipose Tissue during Aging and Inhibits Adipogenesis

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.Objective: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as Type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating Type 1 from non-Type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. Research Design and Methods: We studied patients diagnosed ≤30y, currently <50y, in two UK regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised 3 stages: 1) Assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) If UCPCR≥0.2nmol/mmol, measurement of GAD and IA2 islet autoantibodies; 3) If negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. Results: 1407 patients participated (1365 no known genetic cause, 34 monogenic diabetes, 8 cystic-fibrosis-related diabetes). 386/1365(28%) had UCPCR≥0.2nmol/mmol. 216/386(56%) of these patients were negative for GAD and IA2 and underwent molecular genetic testing. 17 new cases of monogenic diabetes were diagnosed (8 common MODY (Sanger sequencing), 9 rarer causes (next generation sequencing)) in addition to the 34 known cases (estimated prevalence of 3.6% (51/1407) (95%CI: 2.7-4.7%)). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. Conclusions: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed ≤30y.This study was funded by the Department of Health and Wellcome Trust Health Innovation Challenge Award (HICF-1009-041; WT-091985). ATH and SE are Wellcome Trust Senior Investigators. ATH is an NIHR Senior Investigator. BS, ATH, MH, SE, and BK are core members of the NIHR Exeter Clinical Research Facility. EP is a Wellcome Trust New Investigator. TM is supported by NIHR CSO Fellowship. JP is partly funded by the NIHR Collaboration for Leadership in Applied Health Research and Care for the South West (PenCLAHRC)