Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies

in Epilepsia (2018)

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale ... [more ▼]

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germline and somatic variants remains difficult. Here, we present a state of the art evaluation of reported genes and variants associated with epileptic brain lesions. Methods: We critically re-evaluated the pathogenicity for all neuropathology-associated variants reported to date in PubMed and ClinVar databases including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Results: Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven out of 11 genes to be likely disease-associated according to the reported a disease mechanism, while 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance (VUS), 37 (36.6%) as being likely pathogenic (LP) and 3 (3%) as being pathogenic (P). Significance: We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging and application of current ACMG guidelines is recommended for interpretation and prediction. [less ▲]

Guidelines for Operationalizing Policy Coherence for Development (PCD) as a Methodology for the Design and Implementation of Sustainable Development Strategies

in Sustainability (2020), 12(4055), 1-23

Policy Coherence for Development (PCD) is considered a pillar of the 2030 Sustainable Development Agenda. It aims to promote whole of government approaches to sustainable development. Despite its ... [more ▼]

Policy Coherence for Development (PCD) is considered a pillar of the 2030 Sustainable Development Agenda. It aims to promote whole of government approaches to sustainable development. Despite its prominence in development cooperation discussions, many national development professionals or stakeholders have not heard of PCD, indicating that its effectiveness is significantly limited. This article contends that the impact of PCD has not been maximized because it has been presented as a political objective or a policy tool by multilateral organizations and their member states. Instead, the article argues that PCD should be implemented as a methodology that can be adopted by domestic government and non-governmental actors alike, in order to understand trade-offs and co-benefits within and between policy sectors, thus promoting a participative approach. I-GAMMA is a research project in Mexico that examines data-driven public policy in order to promote PCD. It is based on in-depth reviews of policy documents and interviews with development actors. It is committed to open data, evidence-based policymaking, and collaborative dialogue between academics, government officials, and representatives of civil society organizations in sustainable development discussions. In the results section of this article, the project proposes participative PCD as a methodology for policy analysis through which a plurality of actors can identify mechanisms that either reinforce or undermine sustainable development strategies. This section then applies the methodology to the governance of protected natural areas in Mexico. The discussion section and the conclusions highlight the relevance of this approach for participative policymaking in sustainable development. [less ▲]

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

in Autophagy (2016), 12(1), 1-222

Guillaume II

in Le Naour, Jean-Yves (Ed.) Dictionnaire de la Grande Guerre (2008)

Ein günstiges Zeitfenster: Die Gründung der Universität Luxemburg und der Einfluss internationaler Entwicklungen im Hochschulbereich

in Die Hochschule : Journal für Wissenschaft und Bildung (2015), 24(1), 144-156

guoter, lieber wân. Ästhetische Spielarten der Liebe im Minnesang damals und heute

in Steger, Florian; Fürholzer, Katharina (Eds.) Jahrbuch Literatur und Medizin (2019)

Gut behütet - streng bewacht. Tübin­ger Dienst­mädchen nach der Jahrhundertwende

Book published by Kulturamt (1992)

Gut microbiome signatures of risk and prodromal markers of Parkinson's disease

in Annals of Neurology (2020)

Objective: Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate ... [more ▼]

Objective: Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. Methods: Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. Results: Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical activity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with α- and β-diversity. Physical inactivity and constipation were highest in individuals with the Firmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. Interpretation: Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. [less ▲]

Gut microbiota are related to Parkinson's disease and clinical phenotype

in Movement Disorders (2015), 30(3), 350-358

Gut microbiota in Parkinson's disease: Temporal stability and relations to disease progression

in EBioMedicine (2019), 44

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability ... [more ▼]

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported dif- ferentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach. Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2·25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing. Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients. Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progres- sion, a longer follow-up period is required to confirm these findings. [less ▲]