TY - JOUR A1 - Beyer, Jacob A1 - Goth, Florian A1 - Müller, Tobias T1 - Better integrators for functional renormalization group calculations JF - The European Physical Journal B N2 - We analyze a variety of integration schemes for the momentum space functional renormalization group calculation with the goal of finding an optimized scheme. Using the square lattice t-t' Hubbard model as a testbed we define and benchmark the quality. Most notably we define an error estimate of the solution for the ordinary differential equation circumventing the issues introduced by the divergences at the end of the FRG flow. Using this measure to control for accuracy we find a threefold reduction in number of required integration steps achievable by choice of integrator. We herewith publish a set of recommended choices for the functional renormalization group, shown to decrease the computational cost for FRG calculations and representing a valuable basis for further investigations. KW - functional renormalization group KW - FRG KW - FRG calculations KW - integrators KW - ordinary differential equations KW - ODE Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325131 SN - 1434-6028 VL - 95 IS - 7 ER - TY - JOUR A1 - Maierhofer, Anna A1 - Flunkert, Julia A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Schindler, Detlev A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation JF - PLoS ONE N2 - 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. KW - DNA methylation KW - fibroblasts KW - methylation KW - alu elements KW - DNA damage KW - epigenetics KW - cancer treatment Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170895 VL - 12 IS - 5 ER - TY - JOUR A1 - Conrad, David A1 - Kehl, Alexandra A1 - Müller, Tobias A1 - Klopfleisch, Robert A1 - Aupperle-Lellbach, Heike T1 - Immunohistochemical and molecular genetic analysis of canine digital mast cell tumours JF - Animals N2 - Grading, immunohistochemistry and c-kit mutation status are criteria for assessing the prognosis and therapeutic options of canine cutaneous mast cell tumours (MCTs). As a subset, canine digital MCTs have rarely been explored in this context. Therefore, in this retrospective study, 68 paraffin-embedded canine digital MCTs were analysed, and histological grading was assessed according to Patnaik and Kiupel. The immunohistochemical markers KIT and Ki67 were used, as well as polymerase chain reaction (PCR) for mutational screening in c-kit exons 8, 9, 11 and 14. Patnaik grading resulted in 22.1% grade I, 67.6% grade II and 10.3% grade III tumours. Some 86.8% of the digital MCTs were Kiupel low-grade. Aberrant KIT staining patterns II and III were found in 58.8%, and a count of more than 23 Ki67-positive cells in 52.3% of the cases. Both parameters were significantly associated with an internal tandem duplication (ITD) in c-kit exon 11 (12.7%). French Bulldogs, which tend to form well-differentiated cutaneous MCTs, had a higher proportion of digital high-grade MCTs and ITD in c-kit exon 11 compared with mongrels. Due to its retrospective nature, this study did not allow for an analysis of survival data. Nevertheless, it may contribute to the targeted characterisation of digital MCTs. KW - dog KW - digit KW - toe KW - CD117 KW - Ki67 KW - KIT KW - grading KW - PCR KW - sequencing KW - c-kit Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319199 SN - 2076-2615 VL - 13 IS - 10 ER - TY - JOUR A1 - Luther, Christian H. A1 - Brandt, Philipp A1 - Vylkova, Slavena A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Dittrich, Marcus T1 - Integrated analysis of SR-like protein kinases Sky1 and Sky2 links signaling networks with transcriptional regulation in Candida albicans JF - Frontiers in Cellular and Infection Microbiology N2 - Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype. KW - sky kinases KW - kinase signaling KW - network analysis KW - transcriptome KW - transcriptional regulation KW - phosphoproteome KW - Candida albicans Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311771 SN - 2235-2988 VL - 13 ER - TY - JOUR A1 - Ferber, Elena A1 - Gerhards, Julian A1 - Sauer, Miriam A1 - Krischke, Markus A1 - Dittrich, Marcus T. A1 - Müller, Tobias A1 - Berger, Susanne A1 - Fekete, Agnes A1 - Mueller, Martin J. T1 - Chemical Priming by Isothiocyanates Protects Against Intoxication by Products of the Mustard Oil Bomb JF - Frontiers in Plant Science N2 - In Brassicaceae, tissue damage triggers the mustard oil bomb i.e., activates the degradation of glucosinolates by myrosinases leading to a rapid accumulation of isothiocyanates at the site of damage. Isothiocyanates are reactive electrophilic species (RES) known to covalently bind to thiols in proteins and glutathione, a process that is not only toxic to herbivores and microbes but can also cause cell death of healthy plant tissues. Previously, it has been shown that subtoxic isothiocyanate concentrations can induce transcriptional reprogramming in intact plant cells. Glutathione depletion by RES leading to breakdown of the redox potential has been proposed as a central and common RES signal transduction mechanism. Using transcriptome analyses, we show that after exposure of Arabidopsis seedlings (grown in liquid culture) to subtoxic concentrations of sulforaphane hundreds of genes were regulated without depletion of the cellular glutathione pool. Heat shock genes were among the most highly up-regulated genes and this response was found to be dependent on the canonical heat shock factors A1 (HSFA1). HSFA1-deficient plants were more sensitive to isothiocyanates than wild type plants. Moreover, pretreatment of Arabidopsis seedlings with subtoxic concentrations of isothiocyanates increased resistance against exposure to toxic levels of isothiocyanates and, hence, may reduce the autotoxicity of the mustard oil bomb by inducing cell protection mechanisms. KW - autotoxicity KW - heat shock response KW - isothiocyanates KW - mustard oil bomb KW - reactive electrophilic species KW - redox homeostasis KW - sulforaphane Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207104 SN - 1664-462X VL - 11 ER - TY - JOUR A1 - Urban, Lara A1 - Remmele, Christian W. A1 - Dittrich, Marcus A1 - Schwarz, Roland F. A1 - Müller, Tobias T1 - covRNA: discovering covariate associations in large-scale gene expression data JF - BMC Reserach Notes N2 - Objective The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the intrinsic correlation structure of complex annotated gene expression data and discover the covariates that jointly affect expression patterns. Results The Bioconductor package covRNA provides a convenient and fast interface for testing and visualizing complex relationships between sample and gene covariates mediated by gene expression data in an entirely unsupervised setting. The relationships between sample and gene covariates are tested by statistical permutation tests and visualized by ordination. The methods are inspired by the fourthcorner and RLQ analyses used in ecological research for the analysis of species abundance data, that we modified to make them suitable for the distributional characteristics of both, RNA-Seq read counts and microarray intensities, and to provide a high-performance parallelized implementation for the analysis of large-scale gene expression data on multi-core computational systems. CovRNA provides additional modules for unsupervised gene filtering and plotting functions to ensure a smooth and coherent analysis workflow. KW - Multivariate analysis KW - Fourthcorner analysis KW - RLQ analysis KW - Transcriptomics KW - High-throughput data KW - Visualization KW - Ordination methods KW - RNA-Seq analysis KW - Microarray analysis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229258 VL - 13 ER - TY - JOUR A1 - Doll, Julia A1 - Vona, Barbara A1 - Schnapp, Linda A1 - Rüschendorf, Franz A1 - Khan, Imran A1 - Khan, Saadullah A1 - Muhammad, Noor A1 - Alam Khan, Sher A1 - Nawaz, Hamed A1 - Khan, Ajmal A1 - Ahmad, Naseer A1 - Kolb, Susanne M. A1 - Kühlewein, Laura A1 - Labonne, Jonathan D. J. A1 - Layman, Lawrence C. A1 - Hofrichter, Michaela A. H. A1 - Röder, Tabea A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Graves, Tyler D. A1 - Kong, Il-Keun A1 - Nanda, Indrajit A1 - Kim, Hyung-Goo A1 - Haaf, Thomas T1 - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families JF - Genes N2 - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes. KW - genetic diagnosis KW - consanguinity KW - genome-wide linkage analysis KW - hearing loss KW - Pakistan KW - exome sequencing Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293 SN - 2073-4425 VL - 11 IS - 11 ER - TY - JOUR A1 - Wilde, Anne-Christin Beatrice A1 - Lieb, Charlotte A1 - Leicht, Elise A1 - Greverath, Lena Maria A1 - Steinhagen, Lara Marleen A1 - Wald de Chamorro, Nina A1 - Petersen, Jörg A1 - Hofmann, Wolf Peter A1 - Hinrichsen, Holger A1 - Heyne, Renate A1 - Berg, Thomas A1 - Naumann, Uwe A1 - Schwenzer, Jeannette A1 - Vermehren, Johannes A1 - Geier, Andreas A1 - Tacke, Frank A1 - Müller, Tobias T1 - Real-world clinical management of patients with primary biliary cholangitis — a retrospective multicenter study from Germany JF - Journal of Clinical Medicine N2 - Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients. KW - primary biliary cholangitis KW - autoantibodies KW - ursodeoxycholic acid KW - treatment response KW - second line therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234003 SN - 2077-0383 VL - 10 IS - 5 ER - TY - JOUR A1 - Floren, Andreas A1 - Linsenmair, Karl Eduard A1 - Müller, Tobias T1 - Diversity and functional relevance of canopy arthropods in Central Europe JF - Diversity N2 - Although much is known about the ecology and functional importance of canopy arthropods in temperate forests, few studies have tried to assess the overall diversity and investigate the composition and dynamics of tree-specific communities. This has impeded a deeper understanding of the functioning of forests, and of how to maintain system services. Here, we present the first comprehensive data of whole arthropod communities, collected by insecticidal knockdown (fogging) from 1159 trees in 18 study areas in Central Europe during the last 25 years. The data includes 3,253,591 arthropods from 32 taxa (order, suborder, family) collected on 24 tree species from 18 genera. Fogging collects free-living, ectophytic arthropods in approximately the same number as they occur in the trees. To our knowledge, these are the most comprehensive data available today on the taxonomic composition of arboreal fauna. Assigning all arthropods to their feeding guild provided a proxy of their functional importance. The data showed that the canopy communities were regularly structured, with a clear dominance hierarchy comprised of eight ‘major taxa’ that represented 87% of all arthropods. Despite significant differences in the proportions of taxa on deciduous and coniferous trees, the composition of the guilds was very similar. The individual tree genera, on the other hand, showed significant differences in guild composition, especially when different study areas and years were compared, whereas tree-specific traits, such as tree height, girth in breast height or leaf cover, explained little of the overall variance. On the ordinal level, guild composition also differed significantly between managed and primary forests, with a simultaneous low within-group variability, indicating that management is a key factor determining the distribution of biodiversity and guild composition. KW - temperate forests KW - insecticidal knockdown KW - community structure KW - functional diversity KW - guild constancy KW - forest management KW - pristine forests KW - Bialowieza Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285924 SN - 1424-2818 VL - 14 IS - 8 ER - TY - JOUR A1 - Ampattu, Biju Joseph A1 - Hagmann, Laura A1 - Liang, Chunguang A1 - Dittrich, Marcus A1 - Schlüter, Andreas A1 - Blom, Jochen A1 - Krol, Elizaveta A1 - Goesmann, Alexander A1 - Becker, Anke A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Schoen, Christoph T1 - Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence JF - BMC Genomics N2 - 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. KW - neisseria meningitidis KW - MITE KW - virulenceregulatory evolution KW - systems biology KW - metabolism KW - cryptic KW - genetic variation KW - stringent response KW - relA Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157534 VL - 18 IS - 282 ER -