58 research outputs found

    CSM-344 - Two Semantic Embeddings of Z Schemas in Isabelle/HOL

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    This report investigates two semantic embeddings of Z schemas in Isabelle/HOL. The first represents Z values as elements of a type class with polymorphic type constructors and overloaded operators. In contrast, the second embedding uses a Z universe: all Z values are represented as elements of a single monomorphic HOL type

    InterPROM – Interoperables kollaboratives Prozessmanagement in Kooperationen zwischen KMU und Großunternehmen

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    Virtuelle Unternehmensstrukturen benötigen regelmäßig IT-Werkzeuge zur Unterstützung von kooperativen Arbeitsformen. Teamorientiertes Arbeiten in interorganisationalen Kooperationsformen weist bereits besondere Herausforderungen bzgl. Vertrauen, Sicherheit und Kommunikationsstrukturen gegenüber unternehmensinternen teamorientierten Arbeiten auf. Kooperationen von kleinen und mittelständischen Unternehmen (KMU) untereinander, sowie zwischen KMU und Großunternehmen, unterliegen weiteren darüber hinausgehenden Besonderheiten. Beispielsweise ist das Investitionsvolumen für einzelne Kooperationen hier häufig geringer als bei Kooperationen von Großunternehmen untereinander. Vor allem von Großunternehmen wird die dauerhafte oder zumindest die unabhängige Existenz von KMU häufig in Frage gestellt (z. B. durch Liquidation, Insolvenz, Übernahme). Kooperationen können sich daher dynamisch verändern, neue Partner können hinzukommen, bestehende Kooperationen können aus verschiedensten Gründen enden. Kooperative Softwareumgebungen für Kooperationen mit Partnern, von denen einige kleine und mittlere Unternehmen sind, müssen aus diesen Gründen in noch größerem Maße robust gegenüber dem Ausfall einzelner Partner sein

    PROGRESS – prospective observational study on hospitalized community acquired pneumonia

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    Background: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20–29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. Methods: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. Discussion: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. Trial registration: The PROGRESS study was retrospectively registered on May 24th, 2016 with ClinicalTrials.gov: NCT0278201

    Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy

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    With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10−6 ). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets

    Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

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    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

    Evaluative conversations: Translating between diverse stakeholders in regional RRI projects

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    Since the summer of 2020, researchers from ten projects pertaining to the Horizon2020 Science with and for Society (SwafS) call have been meeting virtually as the SwafS14 Monitoring and Evaluation ecosystem. Topics of discussion were the trials and tribulations of their regional Responsible Research and Innovation (RRI) projects as well as their strategies for monitoring and evaluation. In this paper we make a first attempt at presenting these issues as problems of translation between different kinds of stakeholders. After an exploration of the diversity of stakeholders and the process of translation in regional RRI, we suggest evaluative conversations as a way of improving regional RRI. We intend to develop this idea in the future and that these conversations will facilitate more responsible and engaged monitoring and evaluation and contribute to better R&I policies

    52 Genetic Loci Influencing Myocardial Mass.

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    BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets
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