Association of the tumor necrosis factor-alpha promoter polymorphism with change in triacylglycerol response to sequential meals

Background: Reported associations between Tumor Necrosis Factor-alpha (TNFA) and the postprandial triacylglycerol (TAG) response have been inconsistent, which could be due to variations in the TNFA gene, meal fat composition or participant’s body weight. Hence, we investigated the association of TNFA polymorphism (−308G → A) with body mass index (BMI) and postprandial lipaemia and also determined the impact of BMI on the association of the polymorphism with postprandial lipaemia. Methods: The study participants (n = 230) underwent a sequential meal postprandial study. Blood samples were taken at regular intervals after a test breakfast (t = 0, 49 g fat) and lunch (t =330 min, 29 g fat) to measure fasting and postprandial lipids, glucose and insulin. The Metabolic Challenge Study (MECHE) comprising 67 Irish participants who underwent a 54 g fat oral lipid tolerance test was used as a replication cohort. The impact of genotype on postprandial responses was determined using general linear model with adjustment for potential confounders. Results: The -308G → A polymorphism showed a significant association with BMI (P = 0.03) and fasting glucose (P = 0.006), where the polymorphism explained 13 % of the variation in the fasting glucose. A 30 % higher incremental area under the curve (IAUC) was observed for the postprandial TAG response in the GG homozygotes than A-allele carriers (P = 0.004) and the genotype explained 19 % of the variation in the IAUC. There was a non-significant trend in the impact of BMI on the association of the genotype with TAG IAUC (P = 0.09). These results were not statistically significant in the MECHE cohort, which could be due to the differences in the sample size, meal composition, baseline lipid profile, allelic diversity and postprandial characterisation of participants across the two cohorts. Conclusions: Our findings suggest that TNFA -308G → A polymorphism may be an important candidate for BMI, fasting glucose and postprandial TAG response. Further studies are required to investigate the mechanistic effects of the polymorphism on glucose and TAG metabolism, and determine whether BMI is an important variable which should be considered in the design of future studies. Trial registration: NCT01172951

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Abstract\ud \ud Background\ud High fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined.\ud \ud \ud Methods\ud Mesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction.\ud \ud \ud Results\ud Vasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice.\ud \ud \ud Conclusion\ud TNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.This work was supported by grants from Fundação de Amparo à Pesquisa\ud do Estado de São Paulo (FAPESP 2013/08216-2-CRID), Coordenação de Aper‑\ud feiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de\ud Desenvolvimento Científico e Tecnológico (CNPq), Brazil

User modeling for intelligent human-computer interaction

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ArchReco: a software tool to assist software design based on context aware recommendations of design patterns

Abstract This work describes the design, development and evaluation of a software Prototype, named ArchReco, an educational tool that employs two types of Context-aware Recommendations of Design Patterns, to support users (CS students or professionals) who want to improve their design skills when it comes to training for High Level Software models. The tool’s underlying algorithms take advantage of Semantic Web technologies, and the usage of Content based analysis for the computation of non-personalized recommendations for Design Patterns. The recommendations’ objective is to support users in functions such as finding the most suitable Design Pattern to use according to the working context, learn the meaning, objectives and usages of each Design Pattern. The current work presents the Semantic Modeling of the Software Design process through the definition of the context that defines the Software Design process and in particular the representation of the Design Patterns as Ontology model, the implemented Context Aware Recommendation Algorithms and the evaluation results extracted from a user based testing for the ArchReco prototype