@article{StaigerCadotKooteretal.2012, author = {Staiger, Christine and Cadot, Sidney and Kooter, Raul and Dittrich, Marcus and M{\"u}ller, Tobias and Klau, Gunnar W. and Wessels, Lodewyk F. A.}, title = {A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0034796}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131323}, pages = {e34796}, year = {2012}, abstract = {Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer.}, language = {en} } @article{KoetschanKittelmannLuetal.2014, author = {Koetschan, Christian and Kittelmann, Sandra and Lu, Jingli and Al-Halbouni, Djamila and Jarvis, Graeme N. and M{\"u}ller, Tobias and Wolf, Matthias and Janssen, Peter H.}, title = {Internal Transcribed Spacer 1 Secondary Structure Analysis Reveals a Common Core throughout the Anaerobic Fungi (Neocallimastigomycota)}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {3}, doi = {10.1371/journal.pone.0091928}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117058}, pages = {e91928}, year = {2014}, abstract = {The internal transcribed spacer (ITS) is a popular barcode marker for fungi and in particular the ITS1 has been widely used for the anaerobic fungi (phylum Neocallimastigomycota). A good number of validated reference sequences of isolates as well as a large number of environmental sequences are available in public databases. Its highly variable nature predisposes the ITS1 for low level phylogenetics; however, it complicates the establishment of reproducible alignments and the reconstruction of stable phylogenetic trees at higher taxonomic levels (genus and above). Here, we overcame these problems by proposing a common core secondary structure of the ITS1 of the anaerobic fungi employing a Hidden Markov Model-based ITS1 sequence annotation and a helix-wise folding approach. We integrated the additional structural information into phylogenetic analyses and present for the first time an automated sequence-structure-based taxonomy of the ITS1 of the anaerobic fungi. The methodology developed is transferable to the ITS1 of other fungal groups, and the robust taxonomy will facilitate and improve high-throughput anaerobic fungal community structure analysis of samples from various environments.}, language = {en} } @article{RemmeleXianAlbrechtetal.2014, author = {Remmele, Christian W. and Xian, Yibo and Albrecht, Marco and Faulstich, Michaela and Fraunholz, Martin and Heinrichs, Elisabeth and Dittrich, Marcus T. and M{\"u}ller, Tobias and Reinhardt, Richard and Rudel, Thomas}, title = {Transcriptional landscape and essential genes of Neisseria gonorrhoeae}, doi = {10.1093/nar/gku762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113676}, year = {2014}, abstract = {The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes.}, language = {en} } @article{MortonFliesserDittrichetal.2014, author = {Morton, Charles Oliver and Fliesser, Mirjam and Dittrich, Marcus and M{\"u}ller, Tobias and Bauer, Ruth and Kneitz, Susanne and Hope, William and Rogers, Thomas Richard and Einsele, Hermann and L{\"o}ffler, J{\"u}rgen}, title = {Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface}, doi = {10.1371/journal.pone.0098279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112893}, year = {2014}, abstract = {The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.}, language = {en} } @article{WolfChenSongetal.2013, author = {Wolf, Matthias and Chen, Shilin and Song, Jingyuan and Ankenbrand, Markus and M{\"u}ller, Tobias}, title = {Compensatory Base Changes in ITS2 Secondary Structures Correlate with the Biological Species Concept Despite Intragenomic Variability in ITS2 Sequences - A Proof of Concept}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0066726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96450}, year = {2013}, abstract = {Compensatory base changes (CBCs) in internal transcribed spacer 2 (ITS2) rDNA secondary structures correlate with Ernst Mayr's biological species concept. This hypothesis also referred to as the CBC species concept recently was subjected to large-scale testing, indicating two distinct probabilities. (1) If there is a CBC then there are two different species with a probability of ~0.93. (2) If there is no CBC then there is the same species with a probability of ~0.76. In ITS2 research, however, the main problem is the multicopy nature of ITS2 sequences. Most recently, 454 pyrosequencing data have been used to characterize more than 5000 intragenomic variations of ITS2 regions from 178 plant species, demonstrating that mutation of ITS2 is frequent, with a mean of 35 variants per species, respectively per individual organism. In this study, using those 454 data, the CBC criterion is reconsidered in the light of intragenomic variability, a proof of concept, a necessary criterion, expecting no intragenomic CBCs in variant ITS2 copies. In accordance with the CBC species concept, we could demonstrate that the probability that there is no intragenomic CBC is ~0.99.}, language = {en} } @article{KarimiFreundWageretal.2021, author = {Karimi, Sohail M. and Freund, Matthias and Wager, Brittney M. and Knoblauch, Michael and Fromm, J{\"o}rg and M. Mueller, Heike and Ache, Peter and Krischke, Markus and Mueller, Martin J. and M{\"u}ller, Tobias and Dittrich, Marcus and Geilfus, Christoph-Martin and Alfaran, Ahmed H. and Hedrich, Rainer and Deeken, Rosalia}, title = {Under salt stress guard cells rewire ion transport and abscisic acid signaling}, series = {New Phytologist}, volume = {231}, journal = {New Phytologist}, number = {3}, doi = {10.1111/nph.17376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259635}, pages = {1040-1055}, year = {2021}, abstract = {Soil salinity is an increasingly global problem which hampers plant growth and crop yield. Plant productivity depends on optimal water-use efficiency and photosynthetic capacity balanced by stomatal conductance. Whether and how stomatal behavior contributes to salt sensitivity or tolerance is currently unknown. This work identifies guard cell-specific signaling networks exerted by a salt-sensitive and salt-tolerant plant under ionic and osmotic stress conditions accompanied by increasing NaCl loads. We challenged soil-grown Arabidopsis thaliana and Thellungiella salsuginea plants with short- and long-term salinity stress and monitored genome-wide gene expression and signals of guard cells that determine their function. Arabidopsis plants suffered from both salt regimes and showed reduced stomatal conductance while Thellungiella displayed no obvious stress symptoms. The salt-dependent gene expression changes of guard cells supported the ability of the halophyte to maintain high potassium to sodium ratios and to attenuate the abscisic acid (ABA) signaling pathway which the glycophyte kept activated despite fading ABA concentrations. Our study shows that salinity stress and even the different tolerances are manifested on a single cell level. Halophytic guard cells are less sensitive than glycophytic guard cells, providing opportunities to manipulate stomatal behavior and improve plant productivity.}, language = {en} } @article{GrassingerFlorenMuelleretal.2021, author = {Grassinger, Julia Maria and Floren, Andreas and M{\"u}ller, Tobias and Cerezo-Echevarria, Argi{\~n}e and Beitzinger, Christoph and Conrad, David and T{\"o}rner, Katrin and Staudacher, Marlies and Aupperle-Lellbach, Heike}, title = {Digital lesions in dogs: a statistical breed analysis of 2912 cases}, series = {Veterinary Sciences}, volume = {8}, journal = {Veterinary Sciences}, number = {7}, issn = {2306-7381}, doi = {10.3390/vetsci8070136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242690}, year = {2021}, abstract = {Breed predispositions to canine digital neoplasms are well known. However, there is currently no statistical analysis identifying the least affected breeds. To this end, 2912 canine amputated digits submitted from 2014-2019 to the Laboklin GmbH \& Co. KG for routine diagnostics were statistically analyzed. The study population consisted of 155 different breeds (most common: 634 Mongrels, 411 Schnauzers, 197 Labrador Retrievers, 93 Golden Retrievers). Non-neoplastic processes were present in 1246 (43\%), tumor-like lesions in 138 (5\%), and neoplasms in 1528 cases (52\%). Benign tumors (n = 335) were characterized by 217 subungual keratoacanthomas, 36 histiocytomas, 35 plasmacytomas, 16 papillomas, 12 melanocytomas, 9 sebaceous gland tumors, 6 lipomas, and 4 bone tumors. Malignant neoplasms (n = 1193) included 758 squamous cell carcinomas (SCC), 196 malignant melanomas (MM), 76 soft tissue sarcomas, 52 mast cell tumors, 37 non-specified sarcomas, 29 anaplastic neoplasms, 24 carcinomas, 20 bone tumors, and 1 histiocytic sarcoma. Predisposed breeds for SCC included the Schnauzer (log OR = 2.61), Briard (log OR = 1.78), Rottweiler (log OR = 1.54), Poodle (log OR = 1.40), and Dachshund (log OR = 1.30). Jack Russell Terriers (log OR = -2.95) were significantly less affected by SCC than Mongrels. Acral MM were significantly more frequent in Rottweilers (log OR = 1.88) and Labrador Retrievers (log OR = 1.09). In contrast, Dachshunds (log OR = -2.17), Jack Russell Terriers (log OR = -1.88), and Rhodesian Ridgebacks (log OR = -1.88) were rarely affected. This contrasted with the well-known predisposition of Dachshunds and Rhodesian Ridgebacks to oral and cutaneous melanocytic neoplasms. Further studies are needed to explain the underlying reasons for breed predisposition or "resistance" to the development of specific acral tumors and/or other sites.}, language = {en} } @article{DollKolbSchnappetal.2020, author = {Doll, Julia and Kolb, Susanne and Schnapp, Linda and Rad, Aboulfazl and R{\"u}schendorf, Franz and Khan, Imran and Adli, Abolfazl and Hasanzadeh, Atefeh and Liedtke, Daniel and Knaup, Sabine and Hofrichter, Michaela AH and M{\"u}ller, Tobias and Dittrich, Marcus and Kong, Il-Keun and Kim, Hyung-Goo and Haaf, Thomas and Vona, Barbara}, title = {Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms21010311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285142}, year = {2020}, abstract = {CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.}, language = {en} } @article{FlorenKruegerMuelleretal.2015, author = {Floren, Andreas and Kr{\"u}ger, Dirk and M{\"u}ller, Tobias and Dittrich, Marcus and Rudloff, Renate and Hoppe, Bj{\"o}rn and Linsenmair, Karl Eduard}, title = {Diversity and interactions of wood-inhabiting fungi and beetles after deadwood enrichment}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0143566}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145129}, pages = {e0143566}, year = {2015}, abstract = {Freshly cut beech deadwood was enriched in the canopy and on the ground in three cultural landscapes in Germany (Swabian Alb, Hainich-Dun, Schorfheide-Chorin) in order to analyse the diversity, distribution and interaction of wood-inhabiting fungi and beetles. After two years of wood decay 83 MOTUs (Molecular Operational Taxonomic Units) from 28 wood samples were identified. Flight Interception Traps (FITs) installed adjacent to the deadwood enrichments captured 29.465 beetles which were sorted to 566 species. Geographical 'region' was the main factor determining both beetle and fungal assemblages. The proportions of species occurring in all regions were low. Statistic models suggest that assemblages of both taxa differed between stratum and management praxis but their strength varied among regions. Fungal assemblages in Hainich-Dun, for which the data was most comprehensive, discriminated unmanaged from extensively managed and age-class forests (even-aged timber management) while canopy communities differed not from those near the ground. In contrast, the beetle assemblages at the same sites showed the opposite pattern. We pursued an approach in the search for fungus-beetle associations by computing cross correlations and visualize significant links in a network graph. These correlations can be used to formulate hypotheses on mutualistic relationships for example in respect to beetles acting as vectors of fungal spores.}, language = {en} } @article{RauBuggischMaussetal.2022, author = {Rau, Monika and Buggisch, Peter and Mauss, Stefan and Boeker, Klaus H. W. and Klinker, Hartwig and M{\"u}ller, Tobias and Stoehr, Albrecht and Schattenberg, J{\"o}rn M. and Geier, Andreas}, title = {Prognostic impact of steatosis in the clinical course of chronic HCV infection-Results from the German Hepatitis C-Registry}, series = {PLoS ONE}, volume = {17}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0264741}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300549}, year = {2022}, abstract = {Background Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients. Methods The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores. Results At the time of study inclusion 12.3\% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3\%) in contrast to HCV patients +S (26\%). This effect was mainly observed in GT-3 patients (34.4\% vs. 20.6\%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4-24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m\(^{2}\)) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT. Conclusion Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.}, language = {en} }