Synthesis of new DPP-4 inhibitors based on a novel tricyclic scaffold

A novel molecular scaffold has been synthesized and its synthesis and incorporation into new analogues of biologically active molecules will be discussed. A comparison of the inhibitory activity of these compounds to the known type-2 diabetes compound (sitagliptin) against dipeptidyl peptidase-4 (DPP-4) will be shown

AdaptiveVLE: an integrated framework for personalised online education using MPS JetBrains domain-specific modelling environment

This paper contains the design and development of an Adaptive Virtual Learning Environment (AdaptiveVLE) framework to assist educators of all disciplines with creating adaptive VLEs tailored to their needs and to contribute towards the creation of a more generic framework for adaptive systems. Fully online education is a major trend in education technology of our times. However, it has been criticised for its lack of personalisation and therefore not adequately addressing individual students’ needs. Adaptivity and intelligence are elements that could substantially improve the student experience and enhance the learning taking place. There are several attempts in academia and in industry to provide adaptive VLEs and therefore personalise educational provision. All these attempts require a multiple-domain (multi-disciplinary) approach from education professionals, software developers, data scientists to cover all aspects of the system. An integrated environment that can be used by all the multiple-domain users mentioned above and will allow for quick experimentation of different approaches is currently missing. Specifically, a transparent approach that will enable the educator to configure the data collected and the way it is processed without any knowledge of software development and/or data science algorithms implementation details is required. In our proposed work, we developed a new language/framework using MPS JetBrains Domain-Specific Language (DSL) development environment to address this problem. Our work consists of the following stages: data collection configuration by the educator, implementation of the adaptive VLE, data processing, adaptation of the learning path. These stages correspond to the adaptivity stages of all adaptive systems such as monitoring, processing and adaptation. The extension of our framework to include other application areas such as business analytics, health analytics, etc. so that it becomes a generic framework for adaptive systems as well as more usability testing for all applications will be part of our future work

Classification Algorithms Framework (CAF) to enable Intelligent Systems using JetBrains MPS domain-specific languages environment

This paper describes the design and development of a Classification Algorithms Framework (CAF) using the JetBrains MPS domain-specific languages (DSLs) development environment. It is increasingly recognized that the systems of the future will contain some form of adaptivity therefore making them intelligent systems as opposed to the static systems of the past. These intelligent systems can be extremely complex and difficult to maintain. Descriptions at higher-level of abstraction (system-level) have long been identified by industry and academia to reduce complexity. This research presents a Framework of Classification Algorithms at system-level that enables quick experimentation with several different algorithms from Naive Bayes to Logistic Regression. It has been developed as a tool to address the requirements of British Telecom’s (BT’s) data-science team. The tool has been presented at BT and JetBrains MPS and feedback has been collected and evaluated. Beyond the reduction in complexity through the system-level description, the most prominent advantage of this research is its potential applicability to many application contexts. It has been designed to be applicable for intelligent applications in several domains from business analytics, eLearning to eHealth, etc. Its wide applicability will contribute to enabling the larger vision of Artificial Intelligence (AI) adoption in context

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

‘I think I'm more free with them'—Conflict, Negotiation and Change in Intergenerational Relations in African Families Living in Britain

While the family is increasingly being recognised as pivotal to migration, there remain too few studies examining how migration impacts on intergenerational relationships. Although traditional intergenerational gaps are intensified by migration, arguably there has been an over-emphasis on the divisions between ‘traditional’ parents and ‘modern’ children at the expense of examining the ways in which both generations adapt. As Foner and Dreby [2011. “Relations Between the Generations in Immigrant Families.” Annual Review of Sociology 37: 545–564] stress, the reality of post-migration intergenerational relations is inevitably more complex, requiring the examination of both conflict and cooperation. This article contributes to this growing literature by discussing British data from comparative projects on intergenerational relations in African families (in Britain, France and South Africa). It argues that particular understandings can be gained from examining the adaptation of parents and parenting strategies post-migration and how the reconfiguration of family relations can contribute to settlement. By focusing on how both parent and child generations engage in conflict and negotiation to redefine their relationships and expectations, it offers insight into how families navigate and integrate the values of two cultures. In doing so, it argues that the reconfiguration of gender roles as a result of migration offers families the space to renegotiate their relationships and make choices about what they transmit to the next generation

Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins

Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m2) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 × 10−7), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 × 10−6) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 × 10−4). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoprotein

Waking up the gut in critically ill patients

Multiorgan failure frequently develops in critically ill patients. While therapeutic efforts in such patients are often focused on the lungs, on the cardiovascular system as well as on the kidneys, it is important to also consider the functional alterations in gut motility and hormone secretion. Given the central regulatory functions of many gut hormones, such as glucagon-like peptide 1, glucagon-like peptide 2, ghrelin and others, exogenous supplementation of some of these factors may be beneficial under conditions of critical illness. From a pragmatic point of view, the most feasible way towards a restoration of gut hormone secretion in critically ill patients is to provide enteral nutritional supply as soon as possible

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.Systematic review and meta-analysis.We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias