Refine
Has Fulltext
- yes (53)
Is part of the Bibliography
- yes (53)
Year of publication
Document Type
- Journal article (53) (remove)
Language
- English (53)
Keywords
- DNA methylation (4)
- toe (4)
- genetics (3)
- Candida albicans (2)
- NFATc1 (2)
- Staphylococcus aureus (2)
- breed predisposition (2)
- canine (2)
- comparative genomics (2)
- exome sequencing (2)
- gene (2)
- gene regulation (2)
- grading (2)
- immune response (2)
- inflammation (2)
- metabolism (2)
- neisseria meningitidis (2)
- survival (2)
- transcriptome (2)
- (classical and atypical) Werner syndrome (1)
- 3D modeling (1)
- Aspergillus fumigatus (1)
- Autism (1)
- Autism spectrum disorders (1)
- B cell receptors (1)
- Bialowieza (1)
- Biomedical engineering (1)
- CD117 (1)
- CD8+ T cells (1)
- CDC14A (1)
- CNV (1)
- CVID (1)
- ChIPseq (1)
- Chlamydia pneumoniae (1)
- DFNB32 (1)
- DFNB68 (1)
- DNA damage (1)
- DNA methylation dynamics (1)
- DNA recombination (1)
- DNA sequences (1)
- Down syndrome (1)
- EORTC-BN20 (1)
- EORTC-QLQ-C15-PAL (1)
- Environment (1)
- Epigenetics (1)
- European Society for Immunodeficiencies (ESID) (1)
- FRG (1)
- FRG calculations (1)
- Fetal brain development (1)
- Fourthcorner analysis (1)
- Frontal cortex (1)
- Functional modules (1)
- Gene-expression (1)
- Genome (1)
- Genome evolution (1)
- German PID-NET registry (1)
- HCV infection (1)
- High-throughput data (1)
- Human prefrontal cortex (1)
- IL-12B (1)
- IL-12p40 (1)
- IL12B (1)
- ITS2 (1)
- IgG substitution therapy (1)
- Integrated network analysis (1)
- KIT (1)
- Ki67 (1)
- MDSC (1)
- MITE (1)
- Metabolic pathways (1)
- Metabolic profiles (1)
- Methylome (1)
- Microarray analysis (1)
- Milnesium tardigradum (1)
- Multivariate analysis (1)
- Neisseria gonorrhoeae (1)
- Neisseria meningitidis (1)
- ODE (1)
- Ordination methods (1)
- PCR (1)
- PID prevalence (1)
- Pakistan (1)
- Patterns (1)
- Phylogenetics (1)
- RLQ analysis (1)
- RNA (1)
- RNA extraction (1)
- RNA sequence (1)
- RNA-Seq analysis (1)
- S1PR2 (1)
- Schizophrenia (1)
- Stem-cell biotechnology (1)
- T cells (1)
- TIC disorders (1)
- TNFR2 (1)
- Transcription (1)
- Transcriptomics (1)
- Trend test (1)
- Visualization (1)
- abscisic acid (ABA) (1)
- adaption (1)
- alignment (1)
- alu elements (1)
- alzheimers disease (1)
- androgen deprivation therapy (1)
- ants (1)
- ash dieback (1)
- aspergillus fumigatus (1)
- autism (1)
- autoantibodies (1)
- autosomal recessive hearing loss (1)
- autosomal recessive non-synstromic hearing loss (1)
- autotoxicity (1)
- bacterial infection (1)
- bark beetles (1)
- beetle communities (1)
- behavior (1)
- beta-diversity (1)
- bioinformatics and computational biology (1)
- bisulfite pyrosequencing (1)
- blood (1)
- boron (1)
- brain (1)
- brain tumours (1)
- breast cancer (1)
- c-kit (1)
- cancer (1)
- cancer patients (1)
- cancer treatment (1)
- candida genome database (1)
- cell death (1)
- cell vaccines (1)
- cell wall (1)
- cells (1)
- children (1)
- citrus (1)
- classification (1)
- clinical trials (1)
- cluster (1)
- color (1)
- common SNPS (1)
- communities (1)
- community data (1)
- community structure (1)
- community structures (1)
- complex diseases (1)
- complex traits (1)
- computational prediction (1)
- concerted evolution (1)
- conifers (1)
- consanguinity (1)
- costimulation (1)
- cryptic (1)
- cytokine (1)
- cytokines (1)
- cytotoxic T cells (1)
- cytotoxicity (1)
- database (1)
- ddPCR (1)
- decay (1)
- denritic cells (1)
- diboration (1)
- diborenes (1)
- diborynes (1)
- digit (1)
- disruption project (1)
- diversity (1)
- dog (1)
- ecology (1)
- ecosystem function (1)
- epigenetics (1)
- epithelial cells (1)
- european beech forests (1)
- evolution (1)
- expressed sequence tag (1)
- expression (1)
- expression signature (1)
- family (1)
- fetal brain development (1)
- fetal cord blood (1)
- fetal programming (1)
- fibroblasts (1)
- flies (1)
- forest conversion (1)
- forest management (1)
- forests (1)
- frameshift (1)
- frontal cortex (1)
- functional analysis (1)
- functional diversity (1)
- functional modules (1)
- functional renormalization group (1)
- gene expression (1)
- genetic diagnosis (1)
- genetic loci (1)
- genetic variation (1)
- genome sequencing (1)
- genome-wide linkage analysis (1)
- genomic databases (1)
- genomic libraries (1)
- gestational diabetes mellitus (1)
- gilles (1)
- glycophyte Arabidopsis (1)
- gradients (1)
- guard cell (1)
- guild constancy (1)
- haircoat (1)
- halophyte (1)
- halophyte Thellungiella/Eutrema (1)
- hearing loss (1)
- heat shock response (1)
- herbivores (1)
- heterologous (1)
- homologous recombination (1)
- homology modeling (1)
- host cells (1)
- hypthesis (1)
- immune cells (1)
- immune receptors (1)
- immune regulation (1)
- insecticidal knockdown (1)
- insects (1)
- insulin treatment (1)
- integrators (1)
- internal transcribed spacer 2 (1)
- interolog (1)
- ion transport (1)
- isothiocyanates (1)
- juvenile idiopathic arthritis (1)
- kinase signaling (1)
- leishmania major (1)
- liver (1)
- lung cancer (1)
- lymph node metastases (1)
- lymph nodes (1)
- lymphocyte activation (1)
- macrophages (1)
- management (1)
- markers (1)
- meningococcal disease (1)
- metastasis (1)
- metastasis-directed therapy (1)
- methylation (1)
- methylation array (1)
- miniature schnauzer (1)
- missing heritability (1)
- mixed hearing loss (1)
- modules (1)
- molecular cloning (1)
- molecular medicine (1)
- molecular systematics (1)
- mouse models (1)
- mustard oil bomb (1)
- natural variation (1)
- neophyte trees (1)
- network analysis (1)
- network inference (1)
- networks (1)
- neuropsychiatric disorders (1)
- neutrophils (1)
- non-sense mediated mRNA decay (1)
- norway spruce (1)
- oaks (1)
- older poor readers (1)
- oligmometastases (1)
- oligorecurrence (1)
- ordinary differential equations (1)
- painful (1)
- parasitic diseases (1)
- partitioning analysis RPA (1)
- passes (1)
- pathogen-host interaction (PHI) (1)
- pathogenicity (1)
- pathogens (1)
- phosphoproteome (1)
- phylogenetic tree (1)
- phylogenetic trees (1)
- phylogeny (1)
- pines (1)
- plant evolution (1)
- polar ion transport (1)
- polymorphism (1)
- population genetics (1)
- populations (1)
- potential role (1)
- predation (1)
- premature aging (1)
- primary biliary cholangitis (1)
- primary immunodeficiency (PID) (1)
- primary school (1)
- pristine forests (1)
- profile distances (1)
- prognostic index (1)
- promoter (1)
- prostate cancer (1)
- protein familiy (1)
- protein interaction database (1)
- protein-interaction networks (1)
- protein-protein interaction (1)
- protocadherin gamma cluster (1)
- quinoa (1)
- radiation oncology (1)
- radiation therapy (1)
- rare (1)
- reactive electrophilic species (1)
- reading comprehension (1)
- recombinant proteins (1)
- reconstruction (1)
- redox homeostasis (1)
- registry for primary immunodeficiency (1)
- regulatory T cell (1)
- relA (1)
- ribosomal RNA (1)
- salt stress (1)
- salt tolerance (1)
- second line therapy (1)
- secondary structure (1)
- secretion (1)
- segmental progeria (1)
- sequence alignment (1)
- sequence assembly tools (1)
- sequence databases (1)
- sequencing (1)
- serum (1)
- set (1)
- signal transduction (1)
- sky kinases (1)
- soil (1)
- spiders (1)
- splicing (1)
- stability (1)
- stalk cell (1)
- standard schnauzer (1)
- steatosis (1)
- stereotactic body radiotherapy (1)
- stomata (1)
- stringent response (1)
- substrate quality (1)
- subungual (1)
- sulforaphane (1)
- syllable-based intervention (1)
- symptoms (1)
- systematics (1)
- systems biology (1)
- tardigrada (1)
- temperate forests (1)
- temperature (1)
- throat (1)
- tool (1)
- transcription deficiency (1)
- transcriptional regulation (1)
- transplantation (1)
- transposable elements (1)
- treatment response (1)
- trees (1)
- triple bonds (1)
- trisomy 21 (1)
- tumor (1)
- tumour (1)
- ursodeoxycholic acid (1)
- validation (1)
- virulenceregulatory evolution (1)
- whole exome sequencing (1)
- whole-brain radiotherapy (1)
- word reading fluency (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (38)
- Institut für Humangenetik (14)
- Medizinische Klinik und Poliklinik II (6)
- Institut für Hygiene und Mikrobiologie (3)
- Institut für Molekulare Infektionsbiologie (3)
- Institut für Virologie und Immunbiologie (2)
- Julius-von-Sachs-Institut für Biowissenschaften (2)
- Kinderklinik und Poliklinik (2)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (1)
- Comprehensive Cancer Center Mainfranken (1)
EU-Project number / Contract (GA) number
- 669054 (1)
Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.
The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration.
Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.
TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. \(In\) \(vitro\), TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported \(in\) \(vitro\) expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. \(In\) \(vivo\) application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation.
Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.
Background:
Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.
Results:
Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.
Conclusions:
Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.
Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.
In transparent orthographies, persistent reading fluency difficulties are a major cause of poor reading skills in primary school. The purpose of the present study was to investigate effects of a syllable-based reading intervention on word reading fluency and reading comprehension among German-speaking poor readers in Grade 4. The 16-session intervention was based on analyzing the syllabic structure of words to strengthen the mental representations of syllables and words that consist of these syllables. The training materials were designed using the 500 most frequent syllables typically read by fourth graders. The 75 poor readers were randomly allocated to the treatment or the control group. Results indicate a significant and strong effect on the fluency of recognizing single words, whereas text-level reading comprehension was not significantly improved by the training. The specific treatment effect provides evidence that a short syllable-based approach works even in older poor readers at the end of primary school.
Background:
Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies.
Methods and results:
Using Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM.
Conclusions:
Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.
Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.
Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.
Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.
Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.