TY - JOUR A1 - Thormann, Birthe A1 - Ahrens, Dirk A1 - Armijos, Diego Marín A1 - Peters, Marcell K. A1 - Wagner, Thomas A1 - Wägele, Johann W. T1 - Exploring the Leaf Beetle Fauna (Coleoptera: Chrysomelidae) of an Ecuadorian Mountain Forest Using DNA Barcoding JF - PLoS ONE N2 - Background Tropical mountain forests are hotspots of biodiversity hosting a huge but little known diversity of insects that is endangered by habitat destruction and climate change. Therefore, rapid assessment approaches of insect diversity are urgently needed to complement slower traditional taxonomic approaches. We empirically compare different DNA-based species delimitation approaches for a rapid biodiversity assessment of hyperdiverse leaf beetle assemblages along an elevational gradient in southern Ecuador and explore their effect on species richness estimates. Methodology/Principal Findings Based on a COI barcode data set of 674 leaf beetle specimens (Coleoptera: Chrysomelidae) of 266 morphospecies from three sample sites in the Podocarpus National Park, we employed statistical parsimony analysis, distance-based clustering, GMYC- and PTP-modelling to delimit species-like units and compared them to morphology-based (parataxonomic) species identifications. The four different approaches for DNA-based species delimitation revealed highly similar numbers of molecular operational taxonomic units (MOTUs) (n = 284–289). Estimated total species richness was considerably higher than the sampled amount, 414 for morphospecies (Chao2) and 469–481 for the different MOTU types. Assemblages at different elevational levels (1000 vs. 2000 m) had similar species numbers but a very distinct species composition for all delimitation methods. Most species were found only at one elevation while this turnover pattern was even more pronounced for DNA-based delimitation. Conclusions/Significance Given the high congruence of DNA-based delimitation results, probably due to the sampling structure, our study suggests that when applied to species communities on a regionally limited level with high amount of rare species (i.e. ~50% singletons), the choice of species delimitation method can be of minor relevance for assessing species numbers and turnover in tropical insect communities. Therefore, DNA-based species delimitation is confirmed as a valuable tool for evaluating biodiversity of hyperdiverse insect communities, especially when exact taxonomic identifications are missing. KW - leaf beetle KW - Coleoptera: Chrysomelidae KW - Podocarpus National Park KW - DNA-based species delimitation KW - biodiversity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167253 VL - 11 IS - 2 ER - TY - JOUR A1 - Lehners, Nicola A1 - Tabatabai, Julia A1 - Prifert, Christiane A1 - Wedde, Marianne A1 - Puthenparambil, Joe A1 - Weissbrich, Benedikt A1 - Biere, Barbara A1 - Schweiger, Brunhilde A1 - Egerer, Gerlinde A1 - Schnitzler, Paul T1 - Long-Term Shedding of Influenza Virus, Parainfluenza Virus, Respiratory Syncytial Virus and Nosocomial Epidemiology in Patients with Hematological Disorders JF - PLoS ONE N2 - Respiratory viruses are a cause of upper respiratory tract infections (URTI), but can be associated with severe lower respiratory tract infections (LRTI) in immunocompromised patients. The objective of this study was to investigate the genetic variability of influenza virus, parainfluenza virus and respiratory syncytial virus (RSV) and the duration of viral shedding in hematological patients. Nasopharyngeal swabs from hematological patients were screened for influenza, parainfluenza and RSV on admission as well as on development of respiratory symptoms. Consecutive swabs were collected until viral clearance. Out of 672 tested patients, a total of 111 patients (17%) were infected with one of the investigated viral agents: 40 with influenza, 13 with parainfluenza and 64 with RSV; six patients had influenza/RSV or parainfluenza/RSV co-infections. The majority of infected patients (n = 75/111) underwent stem cell transplantation (42 autologous, 48 allogeneic, 15 autologous and allogeneic). LRTI was observed in 48 patients, of whom 15 patients developed severe LRTI, and 13 patients with respiratory tract infection died. Phylogenetic analysis revealed a variety of influenza A(H1N1)pdm09, A(H3N2), influenza B, parainfluenza 3 and RSV A, B viruses. RSV A was detected in 54 patients, RSV B in ten patients. The newly emerging RSV A genotype ON1 predominated in the study cohort and was found in 48 (75%) of 64 RSV-infected patients. Furthermore, two distinct clusters were detected for RSV A genotype ON1, identical RSV G gene sequences in these patients are consistent with nosocomial transmission. Long-term viral shedding for more than 30 days was significantly associated with prior allogeneic transplantation (p = 0.01) and was most pronounced in patients with RSV infection (n = 16) with a median duration of viral shedding for 80 days (range 35–334 days). Long-term shedding of respiratory viruses might be a catalyzer of nosocomial transmission and must be considered for efficient infection control in immunocompromised patients. KW - viral shedding KW - influenza virus KW - parainfluenza virus KW - respiratory syncytial virus KW - hematological disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167243 VL - 11 IS - 2 ER - TY - JOUR A1 - Acqualagna, Laura A1 - Botrel, Loic A1 - Vidaurre, Carmen A1 - Kübler, Andrea A1 - Blankertz, Benjamin T1 - Large-Scale Assessment of a Fully Automatic Co-Adaptive Motor Imagery-Based Brain Computer Interface JF - PLoS ONE N2 - In the last years Brain Computer Interface (BCI) technology has benefited from the development of sophisticated machine leaning methods that let the user operate the BCI after a few trials of calibration. One remarkable example is the recent development of co-adaptive techniques that proved to extend the use of BCIs also to people not able to achieve successful control with the standard BCI procedure. Especially for BCIs based on the modulation of the Sensorimotor Rhythm (SMR) these improvements are essential, since a not negligible percentage of users is unable to operate SMR-BCIs efficiently. In this study we evaluated for the first time a fully automatic co-adaptive BCI system on a large scale. A pool of 168 participants naive to BCIs operated the co-adaptive SMR-BCI in one single session. Different psychological interventions were performed prior the BCI session in order to investigate how motor coordination training and relaxation could influence BCI performance. A neurophysiological indicator based on the Power Spectral Density (PSD) was extracted by the recording of few minutes of resting state brain activity and tested as predictor of BCI performances. Results show that high accuracies in operating the BCI could be reached by the majority of the participants before the end of the session. BCI performances could be significantly predicted by the neurophysiological indicator, consolidating the validity of the model previously developed. Anyway, we still found about 22% of users with performance significantly lower than the threshold of efficient BCI control at the end of the session. Being the inter-subject variability still the major problem of BCI technology, we pointed out crucial issues for those who did not achieve sufficient control. Finally, we propose valid developments to move a step forward to the applicability of the promising co-adaptive methods. KW - large-scale assessment KW - Brain Computer Interface KW - machine leaning KW - fully automatic KW - co-adaptive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167230 VL - 11 IS - 2 ER - TY - JOUR A1 - Hölldobler, Bert T1 - Queen Specific Exocrine Glands in Legionary Ants and Their Possible Function in Sexual Selection JF - PLoS ONE N2 - The colonies of army ants and some other legionary ant species have single, permanently wingless queens with massive post petioles and large gasters. Such highly modified queens are called dichthadiigynes. This paper presents the unusually rich exocrine gland endowment of dichthadiigynes, which is not found in queens of other ant species. It has been suggested these kinds of glands produce secretions that attract and maintain worker retinues around queens, especially during migration. However, large worker retinues also occur in non-legionary species whose queens do not have such an exuberance of exocrine glands. We argue and present evidence in support of our previously proposed hypothesis that the enormous outfit of exocrine glands found in dichthadiigynes is due to sexual selection mediated by workers as the main selecting agents KW - exocrine glands KW - dichthadiigynes KW - legionary ants KW - queens KW - sexual selection KW - army ants Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167057 VL - 11 IS - 3 ER - TY - JOUR A1 - Weidner, Christopher A1 - Rousseau, Morten A1 - Plauth, Annabell A1 - Wowro, Sylvia J. A1 - Fischer, Cornelius A1 - Abdel-Aziz, Heba A1 - Sauer, Sascha T1 - Iberis amara Extract Induces Intracellular Formation of Reactive Oxygen Species and Inhibits Colon Cancer JF - PLoS ONE N2 - Massively increasing global incidences of colorectal cancer require efficient treatment and prevention strategies. Here, we report unexpected anticancerogenic effects of hydroethanolic Iberis amara extract (IAE), which is known as a widely used phytomedical product for treating gastrointestinal complaints. IAE significantly inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC\(_{50}\)) of 6 and 9 μg/ml, respectively, and further generated inhibitory effects in PC-3 prostate and MCF7 breast cancer cells. Inhibition of proliferation in HT-29 cells was associated with a G2/M phase cell cycle arrest including reduced expression of various regulatory marker proteins. Notably, in HT-29 cells IAE further induced apoptosis by intracellular formation of reactive oxygen species (ROS). Consistent with predictions derived from our in vitro experiments, bidaily oral gavage of 50 mg/kg of IAE over 4 weeks resulted in significant inhibition of tumor growth in a mouse HT-29 tumor xenograft model. Taken together, Iberis amara extracts could become useful alternatives for preventing and treating the progression of colon cancer. KW - iberis amara extract KW - colorectal cancer KW - treatment KW - prevention Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167044 VL - 11 IS - 4 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Champ, Colin E. A1 - Otto, Christoph A1 - Kämmerer, Ulrike T1 - Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis JF - PLoS ONE N2 - Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ\(^{2}\) were MR = 0.85 (95% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors. KW - anti-tumor effects KW - ketogenic dients KW - mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167036 VL - 11 IS - 5 ER - TY - JOUR A1 - Vogtmann, Emily A1 - Hua, Xing A1 - Zeller, Georg A1 - Sunagawa, Shinichi A1 - Voigt, Anita Y. A1 - Hercog, Rajna A1 - Goedert, James J. A1 - Shi, Jianxin A1 - Bork, Peer A1 - Sinha, Rashmi T1 - Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing JF - PLoS ONE N2 - Accumulating evidence indicates that the gut microbiota affects colorectal cancer development, but previous studies have varied in population, technical methods, and associations with cancer. Understanding these variations is needed for comparisons and for potential pooling across studies. Therefore, we performed whole-genome shotgun sequencing on fecal samples from 52 pre-treatment colorectal cancer cases and 52 matched controls from Washington, DC. We compared findings from a previously published 16S rRNA study to the metagenomics-derived taxonomy within the same population. In addition, metagenome-predicted genes, modules, and pathways in the Washington, DC cases and controls were compared to cases and controls recruited in France whose specimens were processed using the same platform. Associations between the presence of fecal Fusobacteria, Fusobacterium, and Porphyromonas with colorectal cancer detected by 16S rRNA were reproduced by metagenomics, whereas higher relative abundance of Clostridia in cancer cases based on 16S rRNA was merely borderline based on metagenomics. This demonstrated that within the same sample set, most, but not all taxonomic associations were seen with both methods. Considering significant cancer associations with the relative abundance of genes, modules, and pathways in a recently published French metagenomics dataset, statistically significant associations in the Washington, DC population were detected for four out of 10 genes, three out of nine modules, and seven out of 17 pathways. In total, colorectal cancer status in the Washington, DC study was associated with 39% of the metagenome-predicted genes, modules, and pathways identified in the French study. More within and between population comparisons are needed to identify sources of variation and disease associations that can be reproduced despite these variations. Future studies should have larger sample sizes or pool data across studies to have sufficient power to detect associations that are reproducible and significant after correction for multiple testing. KW - colorectal cancer KW - gut microbiota KW - whole-genome shotgun sequencing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166904 VL - 11 IS - 5 ER - TY - JOUR A1 - Stock, Nina Katharina A1 - Petráš, Petr A1 - Melter, Oto A1 - Kapounová, Gabriela A1 - Vopalková, Petra A1 - Kubele, Jan A1 - Vaniš, Václav A1 - Tkadlec, Jan A1 - Bukáčková, Eva A1 - Machová, Ivana A1 - Jindrák, Vlastimil T1 - Importance of Multifaceted Approaches in Infection Control: A Practical Experience from an Outbreak Investigation JF - PLoS ONE N2 - Background This study presents the results of a multidisciplinary, nosocomial MRSA outbreak investigation in an 8-bed medical intensive care unit (ICU). The identification of seven MRSA positive patients in the beginning of 2014 led to the closure of the ward for several weeks. A multidisciplinary, retrospective investigation was initiated in order to identify the reason and the source for the outbreak, describe MRSA transmission in the department and identify limitations in infection control. Methods The investigation comprised an epidemiological description of MRSA cases from 2012 to 2014 and a characterization of MRSA isolates, including phage-, spa- and PFGE-typing. Additionally, MRSA screening was performed from the hospital staff and the environment. To identify the reason for the outbreak, work-related, psychological and behavioral factors were investigated by impartial audits and staff interviews. Results Thirty-one MRSA cases were registered during the study period, and 36 isolates were investigated. Molecular typing determined the outbreak strain (phage type 54/812, PFGE type A4, spa type t003) and identified the probable index case. Nasal carriage in one employee and a high environmental contamination with the outbreak strain was documented. Important gaps in nursing procedures and general management were identified. Elevated stress levels and communication problems preceded the outbreak. Compliance with hand hygiene and isolation procedures was evaluated as appropriate. Conclusion This study demonstrates the complexity of controlling hospital-associated infections. The combined use of different typing methods is beneficial for outbreak investigations. Psychological, behavioral and other work-related factors have an important impact on the spread of nosocomial pathogens. These factors should be addressed and integrated in routine infection control practice. KW - multifaceted approaches KW - infection control KW - Methicillin resistant Staphylococcus aureus KW - MRSA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166891 VL - 11 IS - 6 ER - TY - JOUR A1 - Kuntzen, Thomas A1 - Kuhn, Sereina A1 - Kuntzen, Daniela A1 - Seifert, Burkhardt A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection JF - PLoS ONE N2 - Background Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. Methods The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1–4 infection, including 88 patients with available IL28b genotyping. Results Mean ribavirin levels varied between 0.68–5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. Conclusion While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon. KW - ribavirin serum levels KW - antiviral treatment KW - anemia KW - Hepatitis C Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166888 VL - 11 IS - 7 ER - TY - JOUR A1 - Vigorito, Elena A1 - Kuchenbaecker, Karoline B. A1 - Beesley, Jonathan A1 - Adlard, Julian A1 - Agnarsson, Bjarni A. A1 - Andrulis, Irene L. A1 - Arun, Banu K. A1 - Barjhoux, Laure A1 - Belotti, Muriel A1 - Benitez, Javier A1 - Berger, Andreas A1 - Bojesen, Anders A1 - Bonanni, Bernardo A1 - Brewer, Carole A1 - Caldes, Trinidad A1 - Caligo, Maria A. A1 - Campbell, Ian A1 - Chan, Salina B. A1 - Claes, Kathleen B. M. A1 - Cohn, David E. A1 - Cook, Jackie A1 - Daly, Mary B. A1 - Damiola, Francesca A1 - Davidson, Rosemarie A1 - de Pauw, Antoine A1 - Delnatte, Capucine A1 - Diez, Orland A1 - Domchek, Susan M. A1 - Dumont, Martine A1 - Durda, Katarzyna A1 - Dworniczak, Bernd A1 - Easton, Douglas F. A1 - Eccles, Diana A1 - Ardnor, Christina Edwinsdotter A1 - Eeles, Ros A1 - Ejlertsen, Bent A1 - Ellis, Steve A1 - Evans, D. Gareth A1 - Feliubadalo, Lidia A1 - Fostira, Florentia A1 - Foulkes, William D. A1 - Friedman, Eitan A1 - Frost, Debra A1 - Gaddam, Pragna A1 - Ganz, Patricia A. A1 - Garber, Judy A1 - Garcia-Barberan, Vanesa A1 - Gauthier-Villars, Marion A1 - Gehrig, Andrea A1 - Gerdes, Anne-Marie A1 - Giraud, Sophie A1 - Godwin, Andrew K. A1 - Goldgar, David E. A1 - Hake, Christopher R. A1 - Hansen, Thomas V. O. A1 - Healey, Sue A1 - Hodgson, Shirley A1 - Hogervorst, Frans B. L. A1 - Houdayer, Claude A1 - Hulick, Peter J. A1 - Imyanitov, Evgeny N. A1 - Isaacs, Claudine A1 - Izatt, Louise A1 - Izquierdo, Angel A1 - Jacobs, Lauren A1 - Jakubowska, Anna A1 - Janavicius, Ramunas A1 - Jaworska-Bieniek, Katarzyna A1 - Jensen, Uffe Birk A1 - John, Esther M. A1 - Vijai, Joseph A1 - Karlan, Beth Y. A1 - Kast, Karin A1 - Khan, Sofia A1 - Kwong, Ava A1 - Laitman, Yael A1 - Lester, Jenny A1 - Lesueur, Fabienne A1 - Liljegren, Annelie A1 - Lubinski, Jan A1 - Mai, Phuong L. A1 - Manoukian, Siranoush A1 - Mazoyer, Sylvie A1 - Meindl, Alfons A1 - Mensenkamp, Arjen R. A1 - Montagna, Marco A1 - Nathanson, Katherine L. A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Niederacher, Dieter A1 - Olah, Edith A1 - Olopade, Olufunmilayo I. A1 - Ong, Kai-ren A1 - Osorio, Ana A1 - Park, Sue Kyung A1 - Paulsson-Karlsson, Ylva A1 - Pedersen, Inge Sokilde A1 - Peissel, Bernard A1 - Peterlongo, Paolo A1 - Pfeiler, Georg A1 - Phelan, Catherine M. A1 - Piedmonte, Marion A1 - Poppe, Bruce A1 - Pujana, Miquel Angel A1 - Radice, Paolo A1 - Rennert, Gad A1 - Rodriguez, Gustavo C. A1 - Rookus, Matti A. A1 - Ross, Eric A. A1 - Schmutzler, Rita Katharina A1 - Simard, Jacques A1 - Singer, Christian F. A1 - Slavin, Thomas P. A1 - Soucy, Penny A1 - Southey, Melissa A1 - Steinemann, Doris A1 - Stoppa-Lyonnet, Dominique A1 - Sukiennicki, Grzegorz A1 - Sutter, Christian A1 - Szabo, Csilla I. A1 - Tea, Muy-Kheng A1 - Teixeira, Manuel R. A1 - Teo, Soo-Hwang A1 - Terry, Mary Beth A1 - Thomassen, Mads A1 - Tibiletti, Maria Grazia A1 - Tihomirova, Laima A1 - Tognazzo, Silvia A1 - van Rensburg, Elizabeth J. A1 - Varesco, Liliana A1 - Varon-Mateeva, Raymonda A1 - Vratimos, Athanassios A1 - Weitzel, Jeffrey N. A1 - McGuffog, Lesley A1 - Kirk, Judy A1 - Toland, Amanda Ewart A1 - Hamann, Ute A1 - Lindor, Noralane A1 - Ramus, Susan J. A1 - Greene, Mark H. A1 - Couch, Fergus J. A1 - Offit, Kenneth A1 - Pharoah, Paul D. P. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. T1 - Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers JF - PLoS ONE N2 - Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. KW - fine-scale mapping KW - ovarian cancer KW - genetics KW - BRCA1 KW - BRCA2 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166869 VL - 11 IS - 7 ER - TY - JOUR A1 - Harks, Inga A1 - Jockel-Schneider, Yvonne A1 - Schlagenhauf, Ulrich A1 - May, Theodor W. A1 - Gravemeier, Martina A1 - Prior, Karola A1 - Petersilka, Gregor A1 - Ehmke, Gregor T1 - Impact of the Daily Use of a Microcrystal Hydroxyapatite Dentifrice on De Novo Plaque Formation and Clinical/Microbiological Parameters of Periodontal Health. A Randomized Trial JF - PLoS ONE N2 - Aim This 12-week prospective, randomized, double-blind, two-center trial evaluated the impact of a microcrystalline zinc hydroxyapatite (mHA) dentifrice on plaque formation rate (PFR) in chronic periodontitis patients. We hypothesized that mHA precipitates cause delayed plaque development when compared to a fluoridated control (AmF/SnF\(_{2}\)), and therefore would improve periodontal health. Material & Methods At baseline and after 4 and 12 weeks, PFR and other clinical and microbiological parameters were recorded. Seventy periodontitis patients received a mHA or AmF/SnF\(_{2}\) dentifrice as daily oral care without hygiene instructions. Four weeks after baseline, participants received full mouth debridement and continued using the dentifrices for another 8 weeks. Results Primary outcome PFR did not change statistically significantly from baseline to weeks 4 and 12, neither in mHA (n = 33; 51.7±17.2% vs. 48.5±16.65% vs. 48.4±19.9%) nor in AmF/SnF2-group (n = 34; 52.3±17.5% vs. 52.5±21.3% vs. 46.1±21.8%). Secondary clinical parameters such as plaque control record, gingival index, bleeding on probing, and pocket probing depth improved, but between-group differences were not statistically significant. Microbiological analyses showed similar slight decreases in colony-forming units in both groups. Conclusion In patients with mild-to-moderate periodontitis, periodontal therapy and use of a mHA-or AmF/SnF\(_{2}\) dentifrice without instructions induced comparable improvements in periodontal health but did not significantly reduce the PFR. KW - microcrystalline zinc hydroxyapatiteimpact KW - plaque formation KW - periodontal health Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166853 VL - 11 IS - 7 ER - TY - JOUR A1 - Hellenbrand, Wiebke A1 - Claus, Heike A1 - Schink, Susanne A1 - Marcus, Ulrich A1 - Wichmann, Ole A1 - Vogel, Ulrich T1 - Risk of Invasive Meningococcal Disease in Men Who Have Sex with Men: Lessons Learned from an Outbreak in Germany, 2012-2013 JF - PLoS ONE N2 - Background We undertook investigations in response to an invasive meningococcal disease (IMD) outbreak in men who have sex with men (MSM) in Berlin 2012–2013 to better understand meningococcal transmission and IMD risk in MSM. Methods We retrospectively searched for further IMD cases in MSM in Germany through local health departments and undertook exploratory interviews. We performed antigen sequence typing, characterized fHbp and aniA genes of strains with the outbreak finetype and reviewed epidemiologically or spatiotemporally linked cases from 2002–2014. Results Among the 148 IMD-cases notified from 01.01.2012–30.09.2013 in 18–59 year-old men we identified 13 MSM in 6 federal states: 11 serogroup C (MenC, all finetype C:P1.5–1,10–8:F3-6), 2 MenB. Interviews with 7 MSM revealed frequent meeting of multiple partners online or via mobile apps and illicit drug use as potential risk factors. MenC incidence was 13-fold higher in MSM than non-MSM. MenC isolates from 9/11 MSM had a novel fHbp allele 766. All C:P1.5–1,10–8:F3-6 strains from MSM versus 16/23 from non-MSM had intact aniA genes (p = 0.04). Although definitive evidence for transmission among MSM in epidemiological or spatiotemporal clusters in 2002–2014 was lacking, clusters were more frequent in men aged 20–49 years. Molecular analysis of C:P1.5–1,10–8:F3-6 strains revealed cases with intact aniA since 2007, mainly associated with fHbp361, fHbp766 and fHbp813, all involving one or more MSM. Conclusions MenC incidence was elevated in MSM during the study period. Multiple casual sexual contacts and illicit drug use were common in affected MSM. In all strains from MSM we detected an intact aniA gene coding for a nitrite reductase, which permits survival in microanaerobic environments and could play a role in meningococcal transmission in MSM through urogenital colonization. Furthermore, meningococcal transmission among MSM may be sustained over large areas and thus require modified spatiotemporal scanning algorithms for timely detection and control. KW - invasive meningococcal disease KW - men who have sex with men KW - Germany Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166842 VL - 11 IS - 8 ER - TY - JOUR A1 - Maarouf, Mohammad A1 - Neudorfer, Clemens A1 - El Majdoub, Faycal A1 - Lenartz, Doris A1 - Kuhn, Jens A1 - Sturm, Volker T1 - Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series JF - PLoS ONE N2 - Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31–48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed “partial response” on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. KW - deep brain stimulation KW - obsessive-compulsive disorder Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166830 VL - 11 IS - 8 ER - TY - JOUR A1 - Heurich, Marco A1 - Zeis, Klara A1 - Küchenhoff, Helmut A1 - Müller, Jörg A1 - Belotti, Elisa A1 - Bufka, Luděk A1 - Woelfing, Benno T1 - Selective Predation of a Stalking Predator on Ungulate Prey JF - PLoS ONE N2 - Prey selection is a key factor shaping animal populations and evolutionary dynamics. An optimal forager should target prey that offers the highest benefits in terms of energy content at the lowest costs. Predators are therefore expected to select for prey of optimal size. Stalking predators do not pursue their prey long, which may lead to a more random choice of prey individuals. Due to difficulties in assessing the composition of available prey populations, data on prey selection of stalking carnivores are still scarce. We show how the stalking predator Eurasian lynx (Lynx lynx) selects prey individuals based on species identity, age, sex and individual behaviour. To address the difficulties in assessing prey population structure, we confirm inferred selection patterns by using two independent data sets: (1) data of 387 documented kills of radio-collared lynx were compared to the prey population structure retrieved from systematic camera trapping using Manly’s standardized selection ratio alpha and (2) data on 120 radio-collared roe deer were analysed using a Cox proportional hazards model. Among the larger red deer prey, lynx selected against adult males—the largest and potentially most dangerous prey individuals. In roe deer lynx preyed selectively on males and did not select for a specific age class. Activity during high risk periods reduced the risk of falling victim to a lynx attack. Our results suggest that the stalking predator lynx actively selects for size, while prey behaviour induces selection by encounter and stalking success rates. KW - stalking predators KW - prey selection KW - Lynx lynx Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166827 VL - 11 IS - 8 ER - TY - JOUR A1 - Scherer, Sandra D. A1 - Bauer, Jochen A1 - Schmaus, Anja A1 - Neumaier, Christian A1 - Herskind, Carsten A1 - Veldwijk, Marlon R. A1 - Wenz, Frederik A1 - Sleeman, Jonathan P. T1 - TGF-β1 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT) JF - PLoS ONE N2 - In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF-β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations. Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis. KW - TGF-β1 KW - breast cancer KW - intraoperative radiotherapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166811 VL - 11 IS - 9 ER - TY - JOUR A1 - Rücker, Viktoria A1 - Keil, Ulrich A1 - Fitzgerald, Anthony P A1 - Malzahn, Uwe A1 - Prugger, Christof A1 - Ertl, Georg A1 - Heuschmann, Peter U A1 - Neuhauser, Hannelore T1 - Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts JF - PLoS ONE N2 - Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008–11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40–65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk. KW - fatal cardiovascular disease KW - SCORE KW - Germany Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166804 VL - 11 IS - 9 ER - TY - JOUR A1 - Lo Cascio, Christian M. A1 - Goetze, Oliver A1 - Latshang, Tsogyal D. A1 - Bluemel, Sena A1 - Frauenfelder, Thomas A1 - Bloch, Konrad E. T1 - Gastrointestinal Dysfunction in Patients with Duchenne Muscular Dystrophy JF - PLoS ONE N2 - Background In adult patients with Duchenne muscular dystrophy (DMD) life-threatening constipation has been reported. Since gastrointestinal function in DMD has not been rigorously studied we investigated objective and subjective manifestations of gastrointestinal disturbances in DMD patients. Methods In 33 patients with DMD, age 12–41 years, eating behavior and gastrointestinal symptoms were evaluated by questionnaires. Gastric emptying half time (T\(_{1/2}\)) and oro-cecal transit time (OCTT) were evaluated by analyzing \(^{13}\)CO\(_{2}\) exhalation curves after ingestion of \(^{13}\)C labeled test meals. Colonic transit time (CTT) was measured by abdominal radiography following ingestion of radiopaque markers. Results The median (quartiles) T\(_{1/2}\) was 187 (168, 220) minutes, the OCTT was 6.3 (5.0, 7.9) hours, both substantially longer than normal data (Goetze 2005, T\(_{1/2}\): 107±10; Geypens 1999, OCTT 4.3±0.1 hours). The median CTT was 60 (48, 82) hours despite extensive use of laxative measures (Meier 1995, upper limit of normal: 60 hours). T\(_{1/2}\) and OCTT did not correlate with symptoms evaluated by the Gastroparesis Cardinal Symptom Index (GCSI) (Spearman r = -0.3, p = 0.1; and r = -0.15, p = 0.4, respectively). CTT was not correlated with symptoms of constipation assessed by ROME III criteria (r = 0.12, p = 0.5). Conclusions DMD patients have a markedly disturbed gastrointestinal motor function. Since objective measures of impaired gastrointestinal transport are not correlated with symptoms of gastroparesis or constipation our findings suggest that measures assuring adequate intestinal transport should be taken independent of the patient’s perception in order to prevent potentially life threatening constipation, particularly in older DMD patients. KW - gastrointestinal dysfunction KW - Duchenne muscular dystrophy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166793 VL - 11 IS - 10 ER - TY - JOUR A1 - Holtfrerich, Sarah K. C. A1 - Schwarz, Katharina A. A1 - Sprenger, Christian A1 - Reimers, Luise A1 - Diekhof, Esther K. T1 - Endogenous Testosterone and Exogenous Oxytocin Modulate Attentional Processing of Infant Faces JF - PLoS ONE N2 - Evidence indicates that hormones modulate the intensity of maternal care. Oxytocin is known for its positive influence on maternal behavior and its important role for childbirth. In contrast, testosterone promotes egocentric choices and reduces empathy. Further, testosterone decreases during parenthood which could be an adaptation to increased parental investment. The present study investigated the interaction between testosterone and oxytocin in attentional control and their influence on attention to baby schema in women. Higher endogenous testosterone was expected to decrease selective attention to child portraits in a face-in-the-crowd-paradigm, while oxytocin was expected to counteract this effect. As predicted, women with higher salivary testosterone were slower in orienting attention to infant targets in the context of adult distractors. Interestingly, reaction times to infant and adult stimuli decreased after oxytocin administration, but only in women with high endogenous testosterone. These results suggest that oxytocin may counteract the adverse effects of testosterone on a central aspect of social behavior and maternal caretaking. KW - maternal behavior KW - oxytocin KW - testosterone KW - attention KW - infant faces Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166783 VL - 11 IS - 11 ER - TY - JOUR A1 - Dreschers, Stephan A1 - Saupp, Peter A1 - Hornef, Mathias A1 - Prehn, Andrea A1 - Platen, Christopher A1 - Morschhäuser, Joachim A1 - Orlikowsky, Thorsten W. T1 - Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans JF - PLoS ONE N2 - Background Invasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C.albicans initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO). Hypothesis Phagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLR-mediated immune responses. Methods The ability to phagocytose C. albicans, expression of TLRs, the induction of apoptosis (assessment of sub-G1 and nick-strand breaks) were analyzed by FACS. TLR signalling was induced by agonists such as lipopolysaccharide (LPS), Pam3Cys, FSL-1 and Zymosan and blocked (neutralizing TLR2 antibodies and MYD88 inhibitor). Results Phagocytic indices of PBMO and CBMO were similar. Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of MAP kinase P38 and expression of TNF-α, which were stronger on PBMO compared to CBMO (p < 0.005). Downstream, TLR2 signalling initiated caspase-3-dependent PICD which was found reduced in CBMO (p < 0.05 vs PBMO). Conclusion Our data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO. KW - Candida albicans KW - monocytes KW - immune response KW - PICD Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166778 VL - 11 IS - 11 ER - TY - JOUR A1 - Xu, Li A1 - He, Jianzheng A1 - Kaiser, Andrea A1 - Gräber, Nikolas A1 - Schläger, Laura A1 - Ritze, Yvonne A1 - Scholz, Henrike T1 - A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila JF - PLoS ONE N2 - Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter–in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior. KW - attraction KW - ethanol KW - Drosophila melanogaster KW - serotonin transporter Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166762 VL - 11 IS - 12 ER - TY - JOUR A1 - Künstner, Axel A1 - Hoffmann, Margarete A1 - Fraser, Bonnie A. A1 - Kottler, Verena A. A1 - Sharma, Eshita A1 - Weigel, Detlef A1 - Dreyer, Christine T1 - The Genome of the Trinidadian Guppy, Poecilia reticulata, and Variation in the Guanapo Population JF - PLoS ONE N2 - For over a century, the live bearing guppy, Poecilia reticulata, has been used to study sexual selection as well as local adaptation. Natural guppy populations differ in many traits that are of intuitively adaptive significance such as ornamentation, age at maturity, brood size and body shape. Water depth, light supply, food resources and predation regime shape these traits, and barrier waterfalls often separate contrasting environments in the same river. We have assembled and annotated the genome of an inbred single female from a high-predation site in the Guanapo drainage. The final assembly comprises 731.6 Mb with a scaffold N50 of 5.3 MB. Scaffolds were mapped to linkage groups, placing 95% of the genome assembly on the 22 autosomes and the X-chromosome. To investigate genetic variation in the population used for the genome assembly, we sequenced 10 wild caught male individuals. The identified 5 million SNPs correspond to an average nucleotide diversity (π) of 0.0025. The genome assembly and SNP map provide a rich resource for investigating adaptation to different predation regimes. In addition, comparisons with the genomes of other Poeciliid species, which differ greatly in mechanisms of sex determination and maternal resource allocation, as well as comparisons to other teleost genera can begin to reveal how live bearing evolved in teleost fish. KW - Trinidadian guppy KW - Poecilia reticulata KW - genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166755 VL - 11 IS - 12 ER - TY - JOUR A1 - Ziegler, C. A1 - Richter, J. A1 - Mahr, M. A1 - Gajewska, A. A1 - Schiele, M.A. A1 - Gehrmann, A. A1 - Schmidt, B. A1 - Lesch, K.-P. A1 - Lang, T. A1 - Helbig-Lang, S. A1 - Pauli, P. A1 - Kircher, T. A1 - Reif, A. A1 - Rief, W. A1 - Vossbeck-Elsebusch, A.N. A1 - Arolt, V. A1 - Wittchen, H.-U. A1 - Hamm, A.O. A1 - Deckert, J. A1 - Domschke, K. T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy JF - Translational Psychiatry N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects. KW - Adult KW - Case-Control Studies KW - Cognitive Therapy KW - DNA Methylation KW - Epigenesis KW - Genetic KW - Female KW - Humans KW - Monoamine Oxidase/genetics KW - Panic Disorder/genetics KW - Panic Disorder/therapy KW - Sequence Analysis KW - DNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422 IS - 6 ER - TY - JOUR A1 - Vendelova, Emilia A1 - de Lima, Jeferson Camargo A1 - Lorenzatto, Karina Rodrigues A1 - Monteiro, Karina Mariante A1 - Mueller, Thomas A1 - Veepaschit, Jyotishman A1 - Grimm, Clemens A1 - Brehm, Klaus A1 - Hrčková, Gabriela A1 - Lutz, Manfred B. A1 - Ferreira, Henrique B. A1 - Nono, Justin Komguep T1 - Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions JF - PLoS Neglected Tropical Diseases N2 - Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts. KW - proteomic analysis KW - excretory-secretory KW - Mesocestoides corti Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166742 VL - 10 IS - 10 ER - TY - JOUR A1 - Reynolds, David A1 - Hofmeister, Brigitte T. A1 - Cliffe, Laura A1 - Alabady, Magdy A1 - Siegel, T. Nicolai A1 - Schmitz, Robert J. A1 - Sabatini, Robert T1 - Histone H3 Variant Regulates RNA Polymerase II Transcription Termination and Dual Strand Transcription of siRNA Loci in Trypanosoma brucei JF - PLoS Genetics N2 - Base J, β-D-glucosyl-hydroxymethyluracil, is a chromatin modification of thymine in the nuclear DNA of flagellated protozoa of the order Kinetoplastida. In Trypanosoma brucei, J is enriched, along with histone H3 variant (H3.V), at sites involved in RNA Polymerase (RNAP) II termination and telomeric sites involved in regulating variant surface glycoprotein gene (VSG) transcription by RNAP I. Reduction of J in T. brucei indicated a role of J in the regulation of RNAP II termination, where the loss of J at specific sites within polycistronic gene clusters led to read-through transcription and increased expression of downstream genes. We now demonstrate that the loss of H3.V leads to similar defects in RNAP II termination within gene clusters and increased expression of downstream genes. Gene derepression is intensified upon the subsequent loss of J in the H3.V knockout. mRNA-seq indicates gene derepression includes VSG genes within the silent RNAP I transcribed telomeric gene clusters, suggesting an important role for H3.V in telomeric gene repression and antigenic variation. Furthermore, the loss of H3.V at regions of overlapping transcription at the end of convergent gene clusters leads to increased nascent RNA and siRNA production. Our results suggest base J and H3.V can act independently as well as synergistically to regulate transcription termination and expression of coding and non-coding RNAs in T. brucei, depending on chromatin context (and transcribing polymerase). As such these studies provide the first direct evidence for histone H3.V negatively influencing transcription elongation to promote termination. KW - RNA polymerase KW - Trypanosoma brucei KW - histone H3 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166738 VL - 12 IS - 1 ER - TY - JOUR A1 - Hershko-Shalev, Tal A1 - Odenheimer-Bergman, Ahuva A1 - Elgrably-Weiss, Maya A1 - Ben-Zvi, Tamar A1 - Govindarajan, Sutharsan A1 - Seri, Hemda A1 - Papenfort, Kai A1 - Vogel, Jörg A1 - Altuvia, Shoshy T1 - Gifsy-1 Prophage IsrK with Dual Function as Small and Messenger RNA Modulates Vital Bacterial Machineries JF - PLoS Genetics N2 - While an increasing number of conserved small regulatory RNAs (sRNAs) are known to function in general bacterial physiology, the roles and modes of action of sRNAs from horizontally acquired genomic regions remain little understood. The IsrK sRNA of Gifsy-1 prophage of Salmonella belongs to the latter class. This regulatory RNA exists in two isoforms. The first forms, when a portion of transcripts originating from isrK promoter reads-through the IsrK transcription-terminator producing a translationally inactive mRNA target. Acting in trans, the second isoform, short IsrK RNA, binds the inactive transcript rendering it translationally active. By switching on translation of the first isoform, short IsrK indirectly activates the production of AntQ, an antiterminator protein located upstream of isrK. Expression of antQ globally interferes with transcription termination resulting in bacterial growth arrest and ultimately cell death. Escherichia coli and Salmonella cells expressing AntQ display condensed chromatin morphology and localization of UvrD to the nucleoid. The toxic phenotype of AntQ can be rescued by co-expression of the transcription termination factor, Rho, or RNase H, which protects genomic DNA from breaks by resolving R-loops. We propose that AntQ causes conflicts between transcription and replication machineries and thus promotes DNA damage. The isrK locus represents a unique example of an island-encoded sRNA that exerts a highly complex regulatory mechanism to tune the expression of a toxic protein. KW - prophage KW - Gifsy-1 KW - sRNA KW - IsrK Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166717 VL - 12 IS - 4 ER - TY - JOUR A1 - Isles, Anthony R. A1 - Ingason, Andrés A1 - Lowther, Chelsea A1 - Walters, James A1 - Gawlick, Micha A1 - Stöber, Gerald A1 - Rees, Elliott A1 - Martin, Joanna A1 - Little, Rosie B. A1 - Potter, Harry A1 - Georgieva, Lyudmila A1 - Pizzo, Lucilla A1 - Ozaki, Norio A1 - Aleksic, Branko A1 - Kushima, Itaru A1 - Ikeda, Masashi A1 - Iwata, Nakao A1 - Levinson, Douglas F. A1 - Gejman, Pablo V. A1 - Shi, Jianxin A1 - Sanders, Alan R. A1 - Duan, Jubao A1 - Willis, Joseph A1 - Sisodiya, Sanjay A1 - Costain, Gregory A1 - Werge, Thomas M. A1 - Degenhardt, Franziska A1 - Giegling, Ina A1 - Rujescu, Dan A1 - Hreidarsson, Stefan J. A1 - Saemundsen, Evald A1 - Ahn, Joo Wook A1 - Ogilvie, Caroline A1 - Girirajan, Santhosh D. A1 - Stefansson, Hreinn A1 - Stefansson, Kari A1 - O'Donovan, Michael C. A1 - Owen, Michael J. A1 - Bassett, Anne A1 - Kirov, George T1 - Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders JF - PLoS Genetics N2 - Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling. KW - interstitial duplications KW - schizophrenia KW - developmental delay KW - autism spectrum disorder KW - parental origin KW - genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166706 VL - 12 IS - 5 ER - TY - JOUR A1 - Meier, Doreen A1 - Kruse, Janis A1 - Buttlar, Jann A1 - Friedrich, Michael A1 - Zenk, Fides A1 - Boesler, Benjamin A1 - Forstner, Konrad U. A1 - Hammann, Christian A1 - Nellen, Wolfgang T1 - Analysis of the Microprocessor in Dictyostelium: The Role of RbdB, a dsRNA Binding Protein JF - PLoS Genetics N2 - We identified the dsRNA binding protein RbdB as an essential component in miRNA processing in Dictyostelium discoideum. RbdB is a nuclear protein that accumulates, together with Dicer B, in nucleolar foci reminiscent of plant dicing bodies. Disruption of rbdB results in loss of miRNAs and accumulation of primary miRNAs. The phenotype can be rescued by ectopic expression of RbdB thus allowing for a detailed analysis of domain function. The lack of cytoplasmic dsRBD proteins involved in miRNA processing, suggests that both processing steps take place in the nucleus thus resembling the plant pathway. However, we also find features e.g. in the domain structure of Dicer which suggest similarities to animals. Reduction of miRNAs in the rbdB- strain and their increase in the Argonaute A knock out allowed the definition of new miRNAs one of which appears to belong to a new non-canonical class. KW - microprocessor KW - Dictyostelium discoideum KW - dsRNA binding protein KW - RbdB Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166687 VL - 12 IS - 6 ER - TY - JOUR A1 - Denner, Ansgar A1 - Pellen, Mathieu T1 - NLO electroweak corrections to off-shell top-antitop production with leptonic decays at the LHC JF - Journal of High Energy Phsyics N2 - For the first time the next-to-leading-order electroweak corrections to the full off-shell production of two top quarks that decay leptonically are presented. This calculation includes all off-shell, non-resonant, and interference effects for the 6-particle phase space. While the electroweak corrections are below one per cent for the integrated cross section, they reach up to 15% in the high-transverse-momentum region of distributions. To support the results of the complete one-loop calculation, we have in addition evaluated the electroweak corrections in two different pole approximations, one requiring two on-shell top quarks and one featuring two on-shell W bosons. While the former deviates by up to 10% from the full calculation for certain distributions, the latter provides a very good description for most observables. The increased centre-of-mass energy of the LHC makes the inclusion of electroweak corrections extremely relevant as they are particularly large in the Sudakov regime where new physics is expected to be probed. KW - NLO Computations Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166415 VL - 08 IS - 155 ER - TY - JOUR A1 - Widmann, Annekathrin A1 - Artinger, Marc A1 - Biesinger, Lukas A1 - Boepple, Kathrin A1 - Peters, Christina A1 - Schlechter, Jana A1 - Selcho, Mareike A1 - Thum, Andreas S. T1 - Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae JF - PLoS Genetics N2 - Memory formation is a highly complex and dynamic process. It consists of different phases, which depend on various neuronal and molecular mechanisms. In adult Drosophila it was shown that memory formation after aversive Pavlovian conditioning includes—besides other forms—a labile short-term component that consolidates within hours to a longer-lasting memory. Accordingly, memory formation requires the timely controlled action of different neuronal circuits, neurotransmitters, neuromodulators and molecules that were initially identified by classical forward genetic approaches. Compared to adult Drosophila, memory formation was only sporadically analyzed at its larval stage. Here we deconstruct the larval mnemonic organization after aversive olfactory conditioning. We show that after odor-high salt conditioning larvae form two parallel memory phases; a short lasting component that depends on cyclic adenosine 3’5’-monophosphate (cAMP) signaling and synapsin gene function. In addition, we show for the first time for Drosophila larvae an anesthesia resistant component, which relies on radish and bruchpilot gene function, protein kinase C activity, requires presynaptic output of mushroom body Kenyon cells and dopamine function. Given the numerical simplicity of the larval nervous system this work offers a unique prospect for studying memory formation of defined specifications, at full-brain scope with single-cell, and single-synapse resolution. KW - genetic dissection KW - Drosophila KW - memory formation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166672 VL - 12 IS - 10 ER - TY - JOUR A1 - Denner, Ansgar A1 - Jenniches, Laura A1 - Lang, Jean-Nicolas A1 - Sturm, Christian T1 - Gauge-independent (MS)over-bar renormalization in the 2HDM JF - Journal of High Energy Physics N2 - We present a consistent renormalization scheme for the CP-conserving Two-Higgs-Doublet Model based on (MS)over-bar renormalization of the mixing angles and the soft-Z 2-symmetry-breaking scale M sb in the Higgs sector. This scheme requires to treat tadpoles fully consistently in all steps of the calculation in order to provide gauge-independent S-matrix elements. We show how bare physical parameters have to be defined and verify the gauge independence of physical quantities by explicit calculations in a general R ξ -gauge. The procedure is straightforward and applicable to other models with extended Higgs sectors. In contrast to the proposed scheme, the (MS)over-bar renormalization of the mixing angles combined with popular on-shell renormalization schemes gives rise to gauge-dependent results already at the one-loop level. We present explicit results for electroweak NLO corrections to selected processes in the appropriately renormalized Two-Higgs-Doublet Model and in particular discuss their scale dependence. KW - NLO Computations Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166402 VL - 09 IS - 115 ER - TY - JOUR A1 - Robertson, Kevin A. A1 - Hsieh, Wei Yuan A1 - Forster, Thorsten A1 - Blanc, Mathieu A1 - Lu, Hongjin A1 - Crick, Peter J. A1 - Yutuc, Eylan A1 - Watterson, Steven A1 - Martin, Kimberly A1 - Griffiths, Samantha J. A1 - Enright, Anton J. A1 - Yamamoto, Mami A1 - Pradeepa, Madapura M. A1 - Lennox, Kimberly A. A1 - Behlke, Mark A. A1 - Talbot, Simon A1 - Haas, Jürgen A1 - Dölken, Lars A1 - Griffiths, William J. A1 - Wang, Yuqin A1 - Angulo, Ana A1 - Ghazal, Peter T1 - An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway JF - PLoS Biology N2 - In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway. KW - microRNA KW - sterol pathway KW - multihit targeting KW - interferon signaling Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166666 VL - 14 IS - 3 ER - TY - JOUR A1 - Jakobson, Liina A1 - Vaahtera, Lauri A1 - Tõldsepp, Kadri A1 - Nuhkat, Maris A1 - Wang, Cun A1 - Wang, Yuh-Shuh A1 - Hõrak, Hanna A1 - Valk, Ervin A1 - Pechter, Priit A1 - Sindarovska, Yana A1 - Tang, Jing A1 - Xiao, Chuanlei A1 - Xu, Yang A1 - Talas, Ulvi Gerst A1 - García-Sosa, Alfonso T. A1 - Kangasjärvi, Saijaliisa A1 - Maran, Uko A1 - Remm, Maido A1 - Roelfsema, M. Rob G. A1 - Hu, Honghong A1 - Kangasjärvi, Jaakko A1 - Loog, Mart A1 - Schroeder, Julian I. A1 - Kollist, Hannes A1 - Brosché, Mikael T1 - Natural Variation in Arabidopsis Cvi-0 Accession Reveals an Important Role of MPK12 in Guard Cell CO\(_{2}\) Signaling JF - PLoS Biology N2 - Plant gas exchange is regulated by guard cells that form stomatal pores. Stomatal adjustments are crucial for plant survival; they regulate uptake of CO\(_{2}\) for photosynthesis, loss of water, and entrance of air pollutants such as ozone. We mapped ozone hypersensitivity, more open stomata, and stomatal CO\(_{2}\)-insensitivity phenotypes of the Arabidopsis thaliana accession Cvi-0 to a single amino acid substitution in MITOGEN-ACTIVATED PROTEIN (MAP) KINASE 12 (MPK12). In parallel, we showed that stomatal CO\(_{2}\)-insensitivity phenotypes of a mutant cis (CO\(_{2}\)-insensitive) were caused by a deletion of MPK12. Lack of MPK12 impaired bicarbonate-induced activation of S-type anion channels. We demonstrated that MPK12 interacted with the protein kinase HIGH LEAF TEMPERATURE 1 (HT1)—a central node in guard cell CO\(_{2}\) signaling—and that MPK12 functions as an inhibitor of HT1. These data provide a new function for plant MPKs as protein kinase inhibitors and suggest a mechanism through which guard cell CO\(_{2}\) signaling controls plant water management. KW - MPK12 KW - CO\(_{2}\) signaling KW - Arabidopsis thaliana KW - Cvi-0 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166657 VL - 14 IS - 12 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coleiro, A. A1 - Coniglione, R. A1 - Costantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Fehn, K. A1 - Felis, I. A1 - Fusco, L.A. A1 - Galatà, S. A1 - Gay, P. A1 - Geißelsöder, S. A1 - Geyer, K. A1 - Giordano, V. A1 - Gleixner, A. A1 - Glotin, H. A1 - Gracia-Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A.J. A1 - Hello, Y. A1 - Hernández-Rey, J.J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Hugon, C. A1 - Illuminati, G. A1 - James, C.W. A1 - de Jong, M. A1 - Jongen, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Kießling, D. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J.A. A1 - Mathieu, A. A1 - Melis, K. A1 - Michael, T. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Mueller, C. A1 - Nezri, E. A1 - Pavalas, G.E. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Racca, C. A1 - Riccobene, G. A1 - Roensch, K. A1 - Saldaña, M. A1 - Samtleben, D.F.E. A1 - Sánchez-Losa, A. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schnabel, J. A1 - Schüssler, F. A1 - Seitz, T. A1 - Sieger, C. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Taiuti, M. A1 - Tönnis, C. A1 - Trovato, A. A1 - Tselengidou, M. A1 - Turpin, D. A1 - Vallage, B. A1 - Vallée, C. A1 - Van Elewyck, V. A1 - Vivolo, D. A1 - Wagner, S. A1 - Wilms, J. A1 - Zornoza, J.D. A1 - Zúñiga, J. T1 - Limits on dark matter annihilation in the sun using the ANTARES neutrino telescope JF - Physics Letters B N2 - A search for muon neutrinos originating from dark matter annihilations in the Sun is performed using the data recorded by the ANTARES neutrino telescope from 2007 to 2012. In order to obtain the best possible sensitivities to dark matter signals, an optimisation of the event selection criteria is performed taking into account the background of atmospheric muons, atmospheric neutrinos and the energy spectra of the expected neutrino signals. No significant excess over the background is observed and 90% C.L. upper limits on the neutrino flux, the spin-dependent and spin-independent WIMP-nucleon cross-sections are derived for WIMP masses ranging from 50 GeV to 5 TeV for the annihilation channels WIMP + WIMP→ b\(\overline{b}\), W\(^{+}\)W\(^{−}\) and τ\(^{+}\)τ\(^{−}\). KW - dark matter KW - WIMP KW - neutralino KW - indirect detection KW - neutrino telescope KW - sun Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166642 VL - 759 ER - TY - JOUR A1 - Neufang, S. A1 - Akhrif, A. A1 - Herrmann, C.G. A1 - Drepper, C. A1 - Homola, G.A. A1 - Nowak, J. A1 - Waider, J. A1 - Schmitt, A.G. A1 - Lesch, K.-P. A1 - Romanos, M. T1 - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans JF - Translational Psychiatry N2 - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies. KW - Clinical Genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418 IS - 6 ER - TY - JOUR A1 - Adrián-Martínez, S. A1 - Albert, A. A1 - André, M. A1 - Anghinolfi, M. A1 - Anton, G. A1 - Ardid, M. A1 - Aubert, J.-J. A1 - Avgitas, T. A1 - Baret, B. A1 - Barrios-Martí, J. A1 - Basa, S. A1 - Bertin, V. A1 - Biagi, S. A1 - Bormuth, R. A1 - Bouwhuis, M.C. A1 - Bruijn, R. A1 - Brunner, J. A1 - Busto, J. A1 - Capone, A. A1 - Caramete, L. A1 - Carr, J. A1 - Celli, S. A1 - Chiarusi, T. A1 - Circella, M. A1 - Coleiro, A. A1 - Coniglione, R. A1 - Constantini, H. A1 - Coyle, P. A1 - Creusot, A. A1 - Deschamps, A. A1 - De Bonis, G. A1 - Distefano, C. A1 - Donzaud, C. A1 - Dornic, D. A1 - Drouhin, D. A1 - Eberl, T. A1 - El Bojaddaini, I. A1 - Elsässer, D. A1 - Enzenhöfer, A. A1 - Fehn, K. A1 - Felis, I. A1 - Fusco, L.A. A1 - Galatà, S. A1 - Gay, P. A1 - Geißelsöder, S. A1 - Geyer, K. A1 - Giordano, V. A1 - Gleixner, A. A1 - Glotin, H. A1 - Gracia-Ruiz, R. A1 - Graf, K. A1 - Hallmann, S. A1 - van Haren, H. A1 - Heijboer, A.J. A1 - Hello, Y. A1 - Hernández-Rey, J.J. A1 - Hößl, J. A1 - Hofestädt, J. A1 - Hugon, C. A1 - Illuminati, G. A1 - James, C.W. A1 - de Jong, M. A1 - Kadler, M. A1 - Kalekin, O. A1 - Katz, U. A1 - Kießling, D. A1 - Kouchner, A. A1 - Kreter, M. A1 - Kreykenbohm, I. A1 - Kulikovskiy, V. A1 - Lachaud, C. A1 - Lahmann, R. A1 - Lefèvre, D. A1 - Leonora, E. A1 - Loucatos, S. A1 - Marcelin, M. A1 - Margiotta, A. A1 - Marinelli, A. A1 - Martínez-Mora, J.A. A1 - Mathieu, A. A1 - Michael, T. A1 - Migliozzi, P. A1 - Moussa, A. A1 - Mueller, C. A1 - Nezri, E. A1 - Pavalas, G.E. A1 - Pellegrino, C. A1 - Perrina, C. A1 - Piattelli, P. A1 - Popa, V. A1 - Pradier, T. A1 - Racca, C. A1 - Riccobene, G. A1 - Roensch, K. A1 - Saldaña, M. A1 - Samtleben, D.F.E. A1 - Sánchez-Losa, A. A1 - Sanguineti, M. A1 - Sapienza, P. A1 - Schnabel, J. A1 - Schüssler, F. A1 - Seitz, T. A1 - Sieger, C. A1 - Spurio, M. A1 - Stolarczyk, Th. A1 - Taiuti, M. A1 - Trovato, A. A1 - Tselengidou, M. A1 - Turpin, D. A1 - Tönnis, C. A1 - Vallage, B. A1 - Vallée, C. A1 - Van Elewyck, V. A1 - Visser, E. A1 - Vivolo, D. A1 - Wagner, S. A1 - Wilms, J. A1 - Zornoza, J.D. A1 - Zúñiga, J. T1 - Constraints on the neutrino emission from the Galactic Ridge with the ANTARES telescope JF - Physics Letters B N2 - A highly significant excess of high-energy astrophysical neutrinos has been reported by the IceCube Collaboration. Some features of the energy and declination distributions of IceCube events hint at a North/South asymmetry of the neutrino flux. This could be due to the presence of the bulk of our Galaxy in the Southern hemisphere. The ANTARES neutrino telescope, located in the Mediterranean Sea, has been taking data since 2007. It offers the best sensitivity to muon neutrinos produced by galactic cosmic ray interactions in this region of the sky. In this letter a search for an extended neutrino flux from the Galactic Ridge region is presented. Different models of neutrino production by cosmic ray propagation are tested. No excess of events is observed and upper limits for different neutrino flux spectral indices Γ are set. For Γ=2.4 the 90% confidence level flux upper limit at 100 TeV for one neutrino flavour corresponds to Φ\(^{1f}_{0}\) (100 TeV) = 2.0 · 10\(^{−17}\) GeV\(^{−1}\) cm\(^{−2}\)s\(^{−1}\)sr\(^{−1}\). Under this assumption, at most two events of the IceCube cosmic candidates can originate from the Galactic Ridge. A simple power-law extrapolation of the Fermi-LAT flux to account for IceCube High Energy Starting Events is excluded at 90% confidence level. KW - neutrino emission KW - Galactic Ridge KW - ANTARES telescope Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166608 VL - 760 ER - TY - JOUR A1 - Kim, Seonghoon A1 - Zhang, Bo A1 - Wang, Zhaorong A1 - Fischer, Julian A1 - Brodbeck, Sebastian A1 - Kamp, Martin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Deng, Hui T1 - Coherent Polariton Laser JF - Physical Review X N2 - The semiconductor polariton laser promises a new source of coherent light, which, compared to conventional semiconductor photon lasers, has input-energy threshold orders of magnitude lower. However, intensity stability, a defining feature of a coherent state, has remained poor. Intensity noise many times the shot noise of a coherent state has persisted, attributed to multiple mechanisms that are difficult to separate in conventional polariton systems. The large intensity noise, in turn, limits the phase coherence. Thus, the capability of the polariton laser as a source of coherence light is limited. Here, we demonstrate a polariton laser with shot-noise-limited intensity stability, as expected from a fully coherent state. This stability is achieved by using an optical cavity with high mode selectivity to enforce single-mode lasing, suppress condensate depletion, and establish gain saturation. Moreover, the absence of spurious intensity fluctuations enables the measurement of a transition from exponential to Gaussian decay of the phase coherence of the polariton laser. It suggests large self-interaction energies in the polariton condensate, exceeding the laser bandwidth. Such strong interactions are unique to matter-wave lasers and important for nonlinear polariton devices. The results will guide future development of polariton lasers and nonlinear polariton devices. KW - polariton laser KW - condensed matter physics KW - photonics KW - quantum physics KW - coherent light Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166597 VL - 6 IS - 011026 ER - TY - JOUR A1 - Kernreiter, T. A1 - Governale, M. A1 - Zülicke, U. A1 - Hankiewicz, E. M. T1 - Anomalous Spin Response and Virtual-Carrier-Mediated Magnetism in a Topological Insulator JF - Physical Review X N2 - We present a comprehensive theoretical study of the static spin response in HgTe quantum wells, revealing distinctive behavior for the topologically nontrivial inverted structure. Most strikingly, the q=0 (long-wavelength) spin susceptibility of the undoped topological-insulator system is constant and equal to the value found for the gapless Dirac-like structure, whereas the same quantity shows the typical decrease with increasing band gap in the normal-insulator regime. We discuss ramifications for the ordering of localized magnetic moments present in the quantum well, both in the insulating and electron-doped situations. The spin response of edge states is also considered, and we extract effective Landé g factors for the bulk and edge electrons. The variety of counterintuitive spin-response properties revealed in our study arises from the system’s versatility in accessing situations where the charge-carrier dynamics can be governed by ordinary Schrödinger-type physics; it mimics the behavior of chiral Dirac fermions or reflects the material’s symmetry-protected topological order. KW - spin response KW - magnetism KW - nanophysics KW - topological insulators Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166582 VL - 6 IS - 021010 ER - TY - JOUR A1 - Read, Hannah M. A1 - Mills, Grant A1 - Johnson, Sarah A1 - Tsai, Peter A1 - Dalton, James A1 - Barquist, Lars A1 - Print, Cristin G. A1 - Patrick, Wayne M. A1 - Wiles, Siouxsie T1 - The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium JF - PeerJ N2 - Bioluminescent reporter genes, such as those from fireflies and bacteria, let researchers use light production as a non-invasive and non-destructive surrogate measure of microbial numbers in a wide variety of environments. As bioluminescence needs microbial metabolites, tagging microorganisms with luciferases means only live metabolically active cells are detected. Despite the wide use of bioluminescent reporter genes, very little is known about the impact of continuous (also called constitutive) light expression on tagged bacteria. We have previously made a bioluminescent strain of Citrobacter rodentium, a bacterium which infects laboratory mice in a similar way to how enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) infect humans. In this study, we compared the growth of the bioluminescent C. rodentium strain ICC180 with its non-bioluminescent parent (strain ICC169) in a wide variety of environments. To understand more about the metabolic burden of expressing light, we also compared the growth profiles of the two strains under approximately 2,000 different conditions. We found that constitutive light expression in ICC180 was near-neutral in almost every non-toxic environment tested. However, we also found that the non-bioluminescent parent strain has a competitive advantage over ICC180 during infection of adult mice, although this was not enough for ICC180 to be completely outcompeted. In conclusion, our data suggest that constitutive light expression is not metabolically costly to C. rodentium and supports the view that bioluminescent versions of microbes can be used as a substitute for their non-bioluminescent parents to study bacterial behaviour in a wide variety of environments. KW - bioluminescence KW - lux KW - luciferase KW - biophotonic imaging KW - bioluminescence imaging KW - enteric pathogens KW - animal model KW - reporter genes KW - phenotypic microarray KW - biolog Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166576 VL - 4 IS - e2130 ER - TY - JOUR A1 - Schupp, Nicole A1 - Stopper, Helga A1 - Heidland, August T1 - DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers JF - Oxidative Medicine and Cellular Longevity N2 - Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients’ burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker’s potential to predict clinical outcomes. KW - chronic kidney disease KW - cancer risk KW - DNA damage KW - biomarkers Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166569 VL - 2016 IS - 3592042 ER - TY - JOUR A1 - Lenders, Malte A1 - Weidemann, Frank A1 - Kurschat, Christine A1 - Canaan-Kühl, Sima A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Schmitz, Boris A1 - Reiermann, Stefanie A1 - Krämer, Johannes A1 - Blaschke, Daniela A1 - Wanner, Christoph A1 - Brand, Stefan-Martin A1 - Brand, Eva T1 - Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant JF - Orphanet Journal of Rare Diseases N2 - Background Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option. KW - Fabry disease KW - genotype KW - lyso-Gb3 KW - variant of unknown significance KW - GLA mutation KW - late-onset KW - stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166559 VL - 11 IS - 54 ER - TY - JOUR A1 - Lenders, Malte A1 - Hennermann, Julia B. A1 - Kurschat, Christine A1 - Rolfs, Arndt A1 - Canaan-Kühl, Sima A1 - Sommer, Claudia A1 - Üçeyler, Nurcan A1 - Kampmann, Christoph A1 - Karabul, Nesrin A1 - Giese, Anne-Katrin A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Krämer, Johannes A1 - Weidemann, Frank A1 - Brand, Stefan-Martin A1 - Wanner, Christoph A1 - Brand, Eva T1 - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease JF - Orphanet Journal of Rare Diseases N2 - Background The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. Methods Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. Results Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels. Conclusion The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females. KW - Fabry disease KW - females KW - lyso-Gb3 KW - enzyme replacement therapy KW - guidelines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543 VL - 11 IS - 88 ER - TY - JOUR A1 - Wente, Sarah A1 - Schröder, Simone A1 - Buckard, Johannes A1 - Büttel, Hans-Martin A1 - von Deimling, Florian A1 - Diener, Wilfried A1 - Häussler, Martin A1 - Hübschle, Susanne A1 - Kinder, Silvia A1 - Kurlemann, Gerhard A1 - Kretzschmar, Christoph A1 - Lingen, Michael A1 - Maroske, Wiebke A1 - Mundt, Dirk A1 - Sánchez-Albisua, Iciar A1 - Seeger, Jürgen A1 - Toelle, Sandra P. A1 - Boltshauser, Eugen A1 - Brockmann, Knut T1 - Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study JF - Orphanet Journal of Rare Diseases N2 - Background The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom. Methods We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA. Results Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups. Conclusions Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment. KW - congenital ocular motor apraxia KW - molar tooth sign KW - Joubert syndrome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166534 VL - 11 IS - 104 ER - TY - JOUR A1 - Eisenhardt, Anja E. A1 - Sprenger, Adrian A1 - Röring, Michael A1 - Herr, Ricarda A1 - Weinberg, Florian A1 - Köhler, Martin A1 - Braun, Sandra A1 - Orth, Joachim A1 - Diedrich, Britta A1 - Lanner, Ulrike A1 - Tscherwinski, Natalja A1 - Schuster, Simon A1 - Dumaz, Nicolas A1 - Schmidt, Enrico A1 - Baumeister, Ralf A1 - Schlosser, Andreas A1 - Dengjel, Jörn A1 - Brummer, Tilman T1 - Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles JF - Oncotarget N2 - B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase. KW - BRAF KW - proteomics KW - phosphorylation KW - sorafenib KW - protein-protein interaction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166529 VL - 7 IS - 18 ER - TY - JOUR A1 - Vučićević, Dubravka A1 - Gehre, Maja A1 - Dhamija, Sonam A1 - Friis-Hansen, Lennart A1 - Meierhofer, David A1 - Sauer, Sascha A1 - Ørom, Ulf Andersson T1 - The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation JF - Oncotarget N2 - Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells. KW - PARROT KW - c-Myc KW - long ncRNA KW - upstream regulator Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166519 VL - 7 IS - 23 ER - TY - JOUR A1 - Shi, Yaoyao A1 - Kuai, Yue A1 - Lei, Lizhen A1 - Weng, Yuanyuan A1 - Berberich-Siebelt, Friederike A1 - Zhang, Xinxia A1 - Wang, Jinjie A1 - Zhou, Yuan A1 - Jiang, Xin A1 - Ren, Guoping A1 - Pan, Hongyang A1 - Mao, Zhengrong A1 - Zhou, Ren T1 - The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma JF - Oncotarget N2 - Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis. KW - LITAF KW - BCL6 KW - apoptosis KW - lymphoma KW - B-cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166500 VL - 7 IS - 47 ER - TY - JOUR A1 - Schneider, Anna A1 - Corona, Angela A1 - Spöring, Imke A1 - Jordan, Mareike A1 - Buchholz, Bernd A1 - Maccioni, Elias A1 - Di Santo, Roberto A1 - Bodem, Jochen A1 - Tramontano, Enzo A1 - Wöhrl, Birgitta M. T1 - Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reverse transcriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors JF - Nucleic Acids Research N2 - We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs. KW - ribonuclease H KW - HIV-1 subtype AG KW - azidothymidine KW - reverse transcriptase KW - multi-drug resistance Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166423 VL - 44 IS - 5 ER - TY - JOUR A1 - Cui, Huanhuan A1 - Schlesinger, Jenny A1 - Schoenhals, Sophia A1 - Tonjes, Martje A1 - Dunkel, Ilona A1 - Meierhofer, David A1 - Cano, Elena A1 - Schulz, Kerstin A1 - Berger, Michael F. A1 - Haack, Timm A1 - Abdelilah-Seyfried, Salim A1 - Bulyk, Martha L. A1 - Sauer, Sascha A1 - Sperling, Silke R. T1 - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA JF - Nucleic Acids Research N2 - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. KW - phosphorylation KW - DPF3a KW - HEY repressors KW - DNA KW - cardiac hypertrophy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166391 VL - 44 IS - 6 ER - TY - JOUR A1 - Schwarz, Roland F. A1 - Tamuri, Asif U. A1 - Kultys, Marek A1 - King, James A1 - Godwin, James A1 - Florescu, Ana M. A1 - Schultz, Jörg A1 - Goldman, Nick T1 - ALVIS: interactive non-aggregative visualization and explorative analysis of multiple sequence alignments JF - Nucleic Acids Research N2 - Sequence Logos and its variants are the most commonly used method for visualization of multiple sequence alignments (MSAs) and sequence motifs. They provide consensus-based summaries of the sequences in the alignment. Consequently, individual sequences cannot be identified in the visualization and covariant sites are not easily discernible. We recently proposed Sequence Bundles, a motif visualization technique that maintains a one-to-one relationship between sequences and their graphical representation and visualizes covariant sites. We here present Alvis, an open-source platform for the joint explorative analysis of MSAs and phylogenetic trees, employing Sequence Bundles as its main visualization method. Alvis combines the power of the visualization method with an interactive toolkit allowing detection of covariant sites, annotation of trees with synapomorphies and homoplasies, and motif detection. It also offers numerical analysis functionality, such as dimension reduction and classification. Alvis is user-friendly, highly customizable and can export results in publication-quality figures. It is available as a full-featured standalone version (http://www.bitbucket.org/rfs/alvis) and its Sequence Bundles visualization module is further available as a web application (http://science-practice.com/projects/sequence-bundles). KW - visualization KW - multiple sequence alignments KW - phylogenetic trees KW - Alvis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166374 VL - 44 IS - 8 ER - TY - JOUR A1 - Letunic, Ivica A1 - Bork, Peer T1 - Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees JF - Nucleic Acids Research N2 - Interactive Tree Of Life (http://itol.embl.de) is a web-based tool for the display, manipulation and annotation of phylogenetic trees. It is freely available and open to everyone. The current version was completely redesigned and rewritten, utilizing current web technologies for speedy and streamlined processing. Numerous new features were introduced and several new data types are now supported. Trees with up to 100,000 leaves can now be efficiently displayed. Full interactive control over precise positioning of various annotation features and an unlimited number of datasets allow the easy creation of complex tree visualizations. iTOL 3 is the first tool which supports direct visualization of the recently proposed phylogenetic placements format. Finally, iTOL's account system has been redesigned to simplify the management of trees in user-defined workspaces and projects, as it is heavily used and currently handles already more than 500,000 trees from more than 10,000 individual users. KW - Interactive Tree Of Life (iTOL) KW - phylogenetic trees KW - visualization KW - tool Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166181 VL - 44 IS - W1 ER - TY - JOUR A1 - Telorac, Jonas A1 - Prykhozhij, Sergey V. A1 - Schöne, Stefanie A1 - Meierhofer, David A1 - Sauer, Sascha A1 - Thomas-Chollier, Morgane A1 - Meijsing, Sebastiaan H. T1 - Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements JF - Nucleic Acids Research N2 - Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot. KW - DNA sequencing KW - glucocorticoid receptor KW - DNA binding KW - transcription factors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166330 VL - 44 IS - 13 ER -