QSSPN: dynamic simulation of molecular interaction networks describing gene regulation, signalling and whole-cell metabolism in human cells

Motivation: Dynamic simulation of genome-scale molecular interaction networks will enable the mechanistic prediction of genotype–phenotype relationships. Despite advances in quantitative biology, full parameterization of whole-cell models is not yet possible. Simulation methods capable of using available qualitative data are required to develop dynamic whole-cell models through an iterative process of modelling and experimental validation. Results: We formulate quasi-steady state Petri nets (QSSPN), a novel method integrating Petri nets and constraint-based analysis to predict the feasibility of qualitative dynamic behaviours in qualitative models of gene regulation, signalling and whole-cell metabolism. We present the first dynamic simulations including regulatory mechanisms and a genome-scale metabolic network in human cell, using bile acid homeostasis in human hepatocytes as a case study. QSSPN simulations reproduce experimentally determined qualitative dynamic behaviours and permit mechanistic analysis of genotype–phenotype relationships. Availability and implementation: The model and simulation software implemented in Cþþ are available in supplementary material and at http://sysbio3.fhms.surrey.ac.uk/qsspn/. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Measurement Properties of Questionnaires Assessing Complementary and Alternative Medicine Use in Pediatrics: A Systematic Review

Complementary and alternative medicine (CAM) is commonly used by children, but estimates of that use vary widely partly due to the range of questionnaires used to assess CAM use. However, no studies have attempted to appraise measurement properties of these questionnaires. The aim of this systematic review was to critically appraise and summarize measurement properties of questionnaires of CAM use in pediatrics.A search strategy was implemented in major electronic databases in March 2011 and conference websites, scientific journals and experts were consulted. Studies were included if they mentioned a questionnaire assessing the prevalence of CAM use in pediatrics. Members of the team independently rated the methodological quality of the studies (using the COSMIN checklist) and measurement properties of the questionnaires (using the Terwee and Cohen criteria).A total of 96 CAM questionnaires were found in 104 publications. The COSMIN checklist showed that no studies reported adequate methodological quality. The Terwee criteria showed that all included CAM questionnaires had indeterminate measurement properties. According to the Cohen score, none were considered to be a well-established assessment, two approached the level of a well-established assessment, seven were promising assessments and the remainder (n = 87) did not reach the score's minimum standards.None of the identified CAM questionnaires have been thoroughly validated. This systematic review highlights the need for proper validation of CAM questionnaires in pediatrics, which may in turn lead to improved research and knowledge translation about CAM in clinical practice

Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted. Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRA

Associations between inhibitory control, eating behaviours and adiposity in 6 year-old children

BackgroundLower inhibitory control has been associated with obesity. One prediction is that lower inhibitory control underlies eating behaviours that promote increased energy intakes. This study examined the relationships between children’s inhibitory control measured using the Stop Signal Task (SST), body composition and eating behaviours, which included self-served portion size, number of servings, eating rate, and energy intake at lunch and in an eating in the absence of hunger (EAH) task.MethodsThe sample included 255 6-year-old children from an Asian cohort. Stop-signal reaction time (SSRT) was used as an index of inhibitory control. Children participated in a recorded self-served lunchtime meal, followed by the EAH task where they were exposed to energy-dense snacks. Behavioural coding of oral processing was used to estimate eating rates (g/min). BMI, waist circumference and skinfolds were used as indices of adiposity.ResultsChildren with lower inhibitory control tended to self-serve larger food portions (p = 0.054), had multiple food servings (p = 0.006) and significantly faster eating rates (p = 0.041). Inhibitory control did not predict energy intake at lunch (p = 0.17) or during the EAH task (p = 0.45), and was unrelated to measures of adiposity (p &gt; 0.32). Twenty percent of the children in the sample had problems focusing on the SST and were described as ‘restless’. Post-hoc analysis revealed that these children had lower inhibitory control (p &lt; 0.001) and consumed more energy during the EAH task (p = 0.01), but did not differ in any other key outcomes from the rest of the sample (p &gt; 0.1).ConclusionsChildren with lower inhibitory control showed a trend to select larger food portions, had multiple food servings and faster eating rates, but were equally as responsive to snacks served in the absence of hunger as children with better inhibitory control. Inhibitory control may impact a number of eating behaviours, not limited to energy-dense snacks.</p