Original Article

Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. Methods: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). Results: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). Conclusions: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism. (C) 2020 The Author(s). Published by Elsevier GmbH

The LHC Continuous Cryostat Interconnections: The Organization of a Logistically Complex Worksite Requiring Strict Quality Standards and High Output

The interconnections of the Large Hadron Collider (LHC) continuous cryostat have been completed in fall 2007: 1695 interconnections magnet to magnet and 224 interconnections between the continuous cryostat and the cryogenic distribution line have been executed along the 27 km of the LHC. The very tight schedule, the complexity of the interconnection sequence, the strict quality standards applied have required the creation of an ad hoc organization in order to steer and coordinate the activities on the worksite dispersed along the whole accelerator ring. The concatenation of construction and test phases carried out by CERN staff, CERN collaborating institutes and contractors have led to the necessity of a common approach and of a very effective information flow. In this paper, after having recalled the main technical challenges, we review the organizational choices that have been taken and we briefly analyze the development of the worksite in term of allocated resources and production

Development and test of a segmented Time-of-Flight plastic detector

Path planning problems involve computing or finding a collision free path between two positions. A special kind of path planning is complete coverage path planning, where a robot sweeps all area of free space in an environment. There are different methods to cover the complete area; however, they are not designed to optimize the process. This paper proposes a novel method of complete coverage path planning based on genetic algorithms. In order to check the viability of this approach the optimal path is tested in a virtual environment. The simulation results confirm the feasibility of this method

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge

Use of metabolomics for the identification and validation of clinical biomarkers for preterm birth:Preterm SAMBA

Made available in DSpace on 2018-12-11T17:29:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-08-08Background: Spontaneous preterm birth is a complex syndrome with multiple pathways interactions determining its occurrence, including genetic, immunological, physiologic, biochemical and environmental factors. Despite great worldwide efforts in preterm birth prevention, there are no recent effective therapeutic strategies able to decrease spontaneous preterm birth rates or their consequent neonatal morbidity/mortality. The Preterm SAMBA study will associate metabolomics technologies to identify clinical and metabolite predictors for preterm birth. These innovative and unbiased techniques might be a strategic key to advance spontaneous preterm birth prediction. Methods/design: Preterm SAMBA study consists of a discovery phase to identify biophysical and untargeted metabolomics from blood and hair samples associated with preterm birth, plus a validation phase to evaluate the performance of the predictive modelling. The first phase, a case-control study, will randomly select 100 women who had a spontaneous preterm birth (before 37 weeks) and 100 women who had term birth in the Cork Ireland and Auckland New Zealand cohorts within the SCOPE study, an international consortium aimed to identify potential metabolomic predictors using biophysical data and blood samples collected at 20 weeks of gestation. The validation phase will recruit 1150 Brazilian pregnant women from five participant centres and will collect blood and hair samples at 20 weeks of gestation to evaluate the performance of the algorithm model (sensitivity, specificity, predictive values and likelihood ratios) in predicting spontaneous preterm birth (before 34 weeks, with a secondary analysis of delivery before 37 weeks). Discussion: The Preterm SAMBA study intends to step forward on preterm birth prediction using metabolomics techniques, and accurate protocols for sample collection among multi-ethnic populations. The use of metabolomics in medical science research is innovative and promises to provide solutions for disorders with multiple complex underlying determinants such as spontaneous preterm birth.University of Campinas (UNICAMP) School of Medical Sciences Department of Obstetrics and Gynecology, R. Alexander Fleming, 101University of Auckland Gravida: National Centre for Growth and Development Liggins InstituteUniversity College Cork Irish Centre for Fetal and Neonatal Translational Research (INFANT) Department of Obstetrics and GynaecologyUniversity of Auckland South Auckland Clinical School Faculty of Medical and Health SciencesUniversity of Auckland School of Biological SciencesUniversity of Campinas (UNICAMP) LNBio-Brazilian Biosciences National Laboratory and School of Medical SciencesSchool of Medical Sciences University of CampinasLNBioSchool of Medicine of Botucatu UNESPSchool of Medicine Federal University of Rio Grande do SulSchool of Medicine Federal University of PernambucoSchool of Medicine Federal University of CearáKing's College London and King's Health PartnersMaternal and Fetal Health Research Centre University of ManchesterUniversity of LeedsUniversity of AdelaideSchool of Medicine of Botucatu UNES