@article{VanHauteDietmannKremeretal.2016, author = {Van Haute, Lindsey and Dietmann, Sabine and Kremer, Laura and Hussain, Shobbir and Pearce, Sarah F. and Powell, Christopher A. and Rorbach, Joanna and Lantaff, Rebecca and Blanco, Sandra and Sauer, Sascha and Kotzaeridou, Urania and Hoffmann, Georg F. and Memari, Yasin and Kolb-Kokocinski, Anja and Durbin, Richard and Mayr, Johannes A. and Frye, Michaela and Prokisch, Holger and Minczuk, Michal}, title = {Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms12039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165998}, pages = {12039}, year = {2016}, abstract = {Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m5C) methyltransferase NSun3 and link m5C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m5C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNAMet). Further, we demonstrate that m5C deficiency in mt-tRNAMet results in the lack of 5-formylcytosine (f5C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f5C in human mitochondrial RNA is generated by oxidative processing of m5C.}, language = {en} } @article{NickersonAtalagdeBonoetal.2016, author = {Nickerson, David and Atalag, Koray and de Bono, Bernard and Geiger, J{\"o}rg and Goble, Carole and Hollmann, Susanne and Lonien, Joachim and M{\"u}ller, Wolfgang and Regierer, Babette and Stanford, Natalie J. and Golebiewski, Martin and Hunter, Peter}, title = {The Human Physiome: how standards, software and innovative service infrastructures are providing the building blocks to make it achievable}, series = {Interface Focus}, volume = {6}, journal = {Interface Focus}, number = {2}, doi = {10.1098/rsfs.2015.0103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189584}, pages = {13 Seiten}, year = {2016}, abstract = {Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.}, language = {en} } @article{AlbersBernsteinBrachmannetal.2016, author = {Albers, Gregory W. and Bernstein, Richard A. and Brachmann, Johannes and Camm, John and Easton, J. Donald and Fromm, Peter and Goto, Shinya and Granger, Christopher B. and Hohnloser, Stefan H. and Hylek, Elaine and Jaffer, Amir K. and Krieger, Derk W. and Passman, Rod and Pines, Jesse M. and Reed, Shelby D. and Rothwell, Peter M. and Kowey, Peter R.}, title = {Heart Rhythm Monitoring Strategies for Cryptogenic Stroke: 2015 Diagnostics and Monitoring Stroke Focus Group Report}, series = {Journal of the American Heart Association}, volume = {5}, journal = {Journal of the American Heart Association}, number = {e00294}, doi = {10.1161/JAHA.115.002944}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165709}, pages = {1-11}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{ReynoldsHofmeisterCliffeetal.2016, author = {Reynolds, David L. and Hofmeister, Brigitte T. and Cliffe, Laura and Siegel, T. Nicolai and Andersson, Britta A. and Beverley, Stephen M. and Schmitz, Robert J. and Sabatini, Robert}, title = {Base J represses genes at the end of polycistronic gene clusters in Leishmania major by promoting RNAP II termination}, series = {Molecular Microbiology}, volume = {101}, journal = {Molecular Microbiology}, number = {4}, doi = {10.1111/mmi.13408}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187727}, pages = {559-574}, year = {2016}, abstract = {The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription.}, language = {en} } @article{PlauthGeikowskiCichonetal.2016, author = {Plauth, Annabell and Geikowski, Anne and Cichon, Susanne and Wowro, Sylvia J. and Liedgens, Linda and Rousseau, Morten and Weidner, Christopher and Fuhr, Luise and Kliem, Magdalena and Jenkins, Gail and Lotito, Silvina and Wainwright, Linda J. and Sauer, Sascha}, title = {Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress}, series = {Free Radical Biology and Medicine}, volume = {99}, journal = {Free Radical Biology and Medicine}, doi = {10.1016/j.freeradbiomed.2016.08.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187186}, pages = {608-622}, year = {2016}, abstract = {Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general < 50 mu M), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After induction of oxidative stress by using 0.78\% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24\% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.}, language = {en} } @article{AppelScholzKocabeyetal.2016, author = {Appel, Mirjam and Scholz, Claus-J{\"u}rgen and Kocabey, Samet and Savage, Sinead and K{\"o}nig, Christian and Yarali, Ayse}, title = {Independent natural genetic variation of punishment- versus relief-memory}, series = {Biology Letters}, volume = {12}, journal = {Biology Letters}, number = {12}, doi = {10.1098/rsbl.2016.0657}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186554}, pages = {20160657}, year = {2016}, abstract = {A painful event establishes two opponent memories: cues that are associated with pain onset are remembered negatively, whereas cues that coincide with the relief at pain offset acquire positive valence. Such punishment-versus relief-memories are conserved across species, including humans, and the balance between them is critical for adaptive behaviour with respect to pain and trauma. In the fruit fly, Drosophila melanogaster as a study case, we found that both punishment-and relief-memories display natural variation across wild-derived inbred strains, but they do not covary, suggesting a considerable level of dissociation in their genetic effectors. This provokes the question whether there may be heritable inter-individual differences in the balance between these opponent memories in man, with potential psycho-clinical implications.}, language = {en} } @article{GroteKrysciakPetersenetal.2016, author = {Grote, Jessica and Krysciak, Dagmar and Petersen, Katrin and G{\"u}llert, Simon and Schmeisser, Christel and F{\"o}rstner, Konrad U. and Krishnan, Hari B. and Schwalbe, Harald and Kubatova, Nina and Streit, Wolfgang R.}, title = {The Absence of the N-acyl-homoserine-lactone Autoinducer Synthase Genes tral and ngrl Increases the Copy Number of the Symbiotic Plasmid in Sinorhizobium fredii NGR234}, series = {Frontiers in Microbiology}, volume = {7}, journal = {Frontiers in Microbiology}, number = {1858}, doi = {10.3389/fmicb.2016.01858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165185}, year = {2016}, abstract = {Plant-released flavonoids induce the transcription of symbiotic genes in rhizobia and one of the first bacterial responses is the synthesis of so called Nod factors. They are responsible for the initial root hair curling during onset of root nodule development. This signal exchange is believed to be essential for initiating the plant symbiosis with rhizobia affiliated with the Alphaproteobacteria. Here, we provide evidence that in the broad host range strain Sinorhizobium fredii NGR234 the complete lack of quorum sensing molecules results in an elevated copy number of its symbiotic plasmid (pNGR234a). This in turn triggers the expression of symbiotic genes and the production of Nod factors in the absence of plant signals. Therefore, increasing the copy number of specific plasmids could be a widespread mechanism of specialized bacterial populations to bridge gaps in signaling cascades.}, language = {en} } @article{VermaRaiKaushiketal.2016, author = {Verma, Nidhi and Rai, Amit Kumar and Kaushik, Vibha and Br{\"u}nnert, Daniela and Chahar, Kirti Raj and Pandey, Janmejay and Goyal, Pankaj}, title = {Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {33949}, doi = {10.1038/srep33949}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167621}, year = {2016}, abstract = {Gefitinib, an EGFR tyrosine kinase inhibitor, is used as FDA approved drug in breast cancer and non-small cell lung cancer treatment. However, this drug has certain side effects and complications for which the underlying molecular mechanisms are not well understood. By systems biology based in silico analysis, we identified off-targets of gefitinib that might explain side effects of this drugs. The crystal structure of EGFR-gefitinib complex was used for binding pocket similarity searches on a druggable proteome database (Sc-PDB) by using IsoMIF Finder. The top 128 hits of putative off-targets were validated by reverse docking approach. The results showed that identified off-targets have efficient binding with gefitinib. The identified human specific off-targets were confirmed and further analyzed for their links with biological process and clinical disease pathways using retrospective studies and literature mining, respectively. Noticeably, many of the identified off-targets in this study were reported in previous high-throughput screenings. Interestingly, the present study reveals that gefitinib may have positive effects in reducing brain and bone metastasis, and may be useful in defining novel gefitinib based treatment regime. We propose that a system wide approach could be useful during new drug development and to minimize side effect of the prospective drug.}, language = {en} } @article{RoeschPanjeSterzingetal.2016, author = {Roesch, J. and Panje, C. and Sterzing, F. and Mantel, F. and Nestle, U. and Andratschke, N. and Guckenberger, M.}, title = {SBRT for centrally localized NSCLC - What is too central?}, series = {Radiation Oncology}, volume = {11}, journal = {Radiation Oncology}, number = {157}, doi = {10.1186/s13014-016-0732-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167459}, year = {2016}, abstract = {Purpose Current guidelines recommend stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in medically inoperable patients. There are excellent outcome and toxicity data for SBRT of peripheral lung tumors. However, the discussion on SBRT for centrally located tumors is controversial. This study evaluated current clinical practice regarding SBRT of centrally located lung tumors, to identify common fractionation schedules and commonly accepted contraindications for SBRT. Methods A questionnaire consisting of two parts was introduced at the annual meeting of the DEGRO working group on stereotactic radiotherapy, representing centers in Germany and Switzerland. The first part of the questionnaire covered general information about the centers, whereas the second part specifically addressed SBRT of centrally located lung tumors, using case examples of nine primary NSCLC patients. Reconstructions of a contrast enhanced CT, as well as PET-Imaging for each case were demonstrated to the participants. Results Twenty-six centers participated in the meeting. The majority was academic (73\%), participated in interdisciplinary thoracic oncology tumorboards (88\%) and offered SBRT for lung tumors (96\%). Two centers questioned the indication of SBRT for central lung tumors because of lack of evidence. The majority of centers had experience in SBRT for central lung tumors (88\%) and half of the centers reported more than ten cases treated during a median period of five years. Most fractionation schedules used PTV encompassing doses of 48-60 Gy in eight fractions with maximum doses of 125-150\%. A clear indication for SBRT treatment was seen by more than 85\% of centers in three of the nine patients in whom tumors were small and not closer than 2 cm to the main bronchus. Prior pneumonectomy or immediate adjacency to hilar/mediastinal structures were not considered as contraindications for SBRT. In cases where the tumor exceeded 4 cm in diameter or was located closer than 4 cm to the carina 50-80\% of centers saw an indication for SBRT. One case, with a 7 cm tumor reaching to the carina would have been treated with SBRT only by one center. Conclusion Within DEGRO working group on stereotactic radiotherapy, SBRT for small (<4 cm) early stage NSCLC is a common indication, if the minimal distance to the main bronchi is at least 2 cm. The controversy on the treatment of larger and more central tumors will hopefully be solved by ongoing prospective clinical trials.}, language = {en} } @article{VolckmarHanPuetteretal.2016, author = {Volckmar, Anna-Lena and Han, Chung Ting and P{\"u}tter, Carolin and Haas, Stefan and Vogel, Carla I. G. and Knoll, Nadja and Struve, Christoph and G{\"o}bel, Maria and Haas, Katharina and Herrfurth, Nikolas and Jarick, Ivonne and Grallert, Harald and Sch{\"u}rmann, Annette and Al-Hasani, Hadi and Hebebrand, Johannes and Sauer, Sascha and Hinney, Anke}, title = {Analysis of Genes Involved in Body Weight Regulation by Targeted Re-Sequencing}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0147904}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167274}, pages = {e0147904}, year = {2016}, abstract = {Introduction Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. Methods We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. Results and Conclusion We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.}, language = {en} }