University of Duisburg-Essen

About: University of Duisburg-Essen is a education organization based out in Essen, Nordrhein-Westfalen, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 16072 authors who have published 39972 publications receiving 1109199 citations.

Interleukin-22 protects intestinal stem cells against genotoxic stress

Abstract: Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Abstract: Background Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis -regulatory elements from FOXG1 , and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis -regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

A multilevel analysis of the effects of external rewards on elementary students' motivation, engagement and learning in an educational game

Abstract: This study investigated the effects of external rewards on fifth graders' motivation, engagement and learning while playing an educational game. We were interested in exploring whether the feedback-rich environment of the game could mitigate the predicted negative effects of external rewards. Data of students' engagement and learning were collected and analyzed at multiple levels. A quasi-experimental design was used to examine the effect of external rewards in one group (n = 50) compared to a control group without such rewards (n = 56). According to the results, the external rewards did not undermine students' motivation (e.g., at proximal and distal levels), however they did not foster disciplinary engagement. On the other hand, students in the reward condition showed significantly larger gains in conceptual understanding (proximal) and non-significantly larger gains in achievement (distal). These results suggest that the predicted negative consequences of external rewards may be addressed in this new generation of learning environments. Future research and contributions of the study are provided.

Dual‐primal FETI methods for linear elasticity

Abstract: Dual-primal FETI methods are nonoverlapping domain decomposition methods where some of the continuity constraints across subdomain boundaries are required to hold throughout the iterations, as in primal iterative substructuring methods, while most of the constraints are enforced by Lagrange multipliers, as in one-level FETI methods. These methods are used to solve the large algebraic systems of equations that arise in elliptic finite element problems. The purpose of this article is to develop strategies for selecting these constraints, which are enforced throughout the iterations, such that good convergence bounds are obtained that are independent of even large changes in the stiffness of the subdomains across the interface between them. The algorithms are described in terms of a change of basis that has proven to be quite robust in practice. A theoretical analysis is provided for the case of linear elasticity, and condition number bounds are established that are uniform with respect to arbitrarily large jumps in the Young's modulus of the material and otherwise depend only polylogarithmically on the number of unknowns of a single subdomain. The strategies have already proven quite successful in large-scale implementations of these iterative methods. © 2006 Wiley Periodicals, Inc.

Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Abstract: Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.