@article{GalimbertiDell'OssoFenoglioetal.2012, author = {Galimberti, Daniela and Dell'Osso, Bernardo and Fenoglio, Chiara and Villa, Chiara and Cortini, Francesca and Serpente, Maria and Kittel-Schneider, Sarah and Weigl, Johannes and Neuner, Maria and Volkert, Juliane and Leonhard, C. and Olmes, David G. and Kopf, Juliane and Cantoni, Claudia and Ridolfi, Elisa and Palazzo, Carlotta and Ghezzi, Laura and Bresolin, Nereo and Altamura, A.C. and Scarpini, Elio and Reif, Andreas}, title = {Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0032164}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131910}, pages = {e32164}, year = {2012}, abstract = {Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n=271) or BPD (n=237) as compared with 574 age-, gender-and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls. A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2\%, P<0.001, OR: 0.63, 95\% CI: 0.49-0.80), rs4792938 (30.7 versus 39.7\%, P=0.005, OR: 0.70, 95\% CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P=0.007, OR: 0.71, 95\% CI: 0.56-0.91). Mean +/- SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69 +/- 3.97 and 116.14 +/- 5.80 ng/ml, respectively, versus 180.81 +/- 18.39 ng/ml P<0.001) and were not correlated with age. In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results.}, language = {en} } @article{NaseemDandekar2012, author = {Naseem, Muhammad and Dandekar, Thomas}, title = {The Role of Auxin-Cytokinin Antagonism in Plant-Pathogen Interactions}, series = {PLOS Pathogens}, volume = {8}, journal = {PLOS Pathogens}, number = {11}, doi = {10.1371/journal.ppat.1003026}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131901}, pages = {e1003026}, year = {2012}, abstract = {No abstract available.}, language = {en} } @article{SamimiFinkPaeth2012, author = {Samimi, C. and Fink, A. H. and Paeth, H.}, title = {The 2007 flood in the Sahel: causes, characteristics and its presentation in the media and FEWS NET}, series = {Natural Hazards and Earth System Sciences}, volume = {12}, journal = {Natural Hazards and Earth System Sciences}, number = {2}, doi = {10.5194/nhess-12-313-2012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131790}, pages = {313 -- 325}, year = {2012}, abstract = {During the rainy season in 2007, reports about exceptional rains and floodings in the Sahel were published in the media, especially in August and September. Institutions and organizations like the World Food Programme (WFP) and FEWS NET put the events on the agenda and released alerts and requested help. The partly controversial picture was that most of the Sahel faced a crisis caused by widespread floodings. Our study shows that the rainy season in 2007 was exceptional with regard to rainfall amount and return periods. In many areas the event had a return period between 1 and 50 yr with high spatial heterogeneity, with the exception of the Upper Volta basin, which yielded return periods of up to 1200 yr. Despite the strong rainfall, the interpretation of satellite images show that the floods were mainly confined to lakes and river beds. However, the study also proves the difficulties in assessing the meteorological processes and the demarcation of flooded areas in satellite images without ground truthing. These facts and the somewhat vague and controversial reports in the media and FEWS NET demonstrate that it is crucial to thoroughly analyze such events at a regional and local scale involving the local population.}, language = {en} } @article{FernandezRodriguezQuilesBlancoetal.2012, author = {Fern{\´a}ndez-Rodr{\´i}guez, Juana and Quiles, Francisco and Blanco, Ignacio and Teul{\´e}, Alex and Feliubadal{\´o}, L{\´i}dia and del Valle, Jes{\´u}s and Salinas, M{\´o}nica and Izquierdo, {\´A}ngel and Darder, Esther and Schindler, Detlev and Capell{\´a}, Gabriel and Brunet, Joan and L{\´a}zaro, Conxi and Angel Pujana, Miguel}, title = {Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {84}, doi = {10.1186/1471-2407-12-84}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131772}, year = {2012}, abstract = {Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.}, language = {en} } @article{SchneiderTautzGruenewaldetal.2012, author = {Schneider, Christof W. and Tautz, J{\"u}rgen and Gr{\"u}newald, Bernd and Fuchs, Stefan}, title = {RFID Tracking of Sublethal Effects of Two Neonicotinoid Insecticides on the Foraging Behavior of Apis mellifera}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0030023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131753}, pages = {e30023}, year = {2012}, abstract = {The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15-6 ng/bee) and clothianidin (0.05-2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of >= 0.5 ng/bee (clothianidin) and >= 1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.}, language = {en} } @article{PilsKoppPetersonetal.2012, author = {Pils, Stefan and Kopp, Kathrin and Peterson, Lisa and Tascon, Julia Delgado and Nyffenegger-Jann, Naja J. and Hauck, Christof R.}, title = {The Adaptor Molecule Nck Localizes the WAVE Complex to Promote Actin Polymerization during CEACAM3-Mediated Phagocytosis of Bacteria}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0032808}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131747}, pages = {e32808}, year = {2012}, abstract = {Background: CEACAM3 is a granulocyte receptor mediating the opsonin-independent recognition and phagocytosis of human-restricted CEACAM-binding bacteria. CEACAM3 function depends on an intracellular immunoreceptor tyrosine-based activation motif (ITAM)-like sequence that is tyrosine phosphorylated by Src family kinases upon receptor engagement. The phosphorylated ITAM-like sequence triggers GTP-loading of Rac by directly associating with the guanine nucleotide exchange factor (GEF) Vav. Rac stimulation in turn is critical for actin cytoskeleton rearrangements that generate lamellipodial protrusions and lead to bacterial uptake. Principal Findings: In our present study we provide biochemical and microscopic evidence that the adaptor proteins Nck1 and Nck2, but not CrkL, Grb2 or SLP-76, bind to tyrosine phosphorylated CEACAM3. The association is phosphorylation-dependent and requires the Nck SH2 domain. Overexpression of the isolated Nck1 SH2 domain, RNAi-mediated knock-down of Nck1, or genetic deletion of Nck1 and Nck2 interfere with CEACAM3-mediated bacterial internalization and with the formation of lamellipodial protrusions. Nck is constitutively associated with WAVE2 and directs the actin nucleation promoting WAVE complex to tyrosine phosphorylated CEACAM3. In turn, dominant-negative WAVE2 as well as shRNA-mediated knock-down of WAVE2 or the WAVE-complex component Nap1 reduce internalization of bacteria. Conclusions: Our results provide novel mechanistic insight into CEACAM3-initiated phagocytosis. We suggest that the CEACAM3 ITAM-like sequence is optimized to co-ordinate a minimal set of cellular factors needed to efficiently trigger actin-based lamellipodial protrusions and rapid pathogen engulfment.}, language = {en} } @article{ZoephelReiherRexeretal.2012, author = {Zoephel, Judith and Reiher, Wencke and Rexer, Karl-Heinz and Kahnt, J{\"o}rg and Wegener, Christian}, title = {Peptidomics of the Agriculturally Damaging Larval Stage of the Cabbage Root Fly Delia radicum (Diptera: Anthomyiidae)}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0041543}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131727}, pages = {e41543}, year = {2012}, abstract = {The larvae of the cabbage root fly induce serious damage to cultivated crops of the family Brassicaceae. We here report the biochemical characterisation of neuropeptides from the central nervous system and neurohemal organs, as well as regulatory peptides from enteroendocrine midgut cells of the cabbage maggot. By LC-MALDI-TOF/TOF and chemical labelling with 4-sulfophenyl isothiocyanate, 38 peptides could be identified, representing major insect peptide families: allatostatin A, allatostatin C, FMRFamide-like peptides, kinin, CAPA peptides, pyrokinins, sNPF, myosuppressin, corazonin, SIFamide, sulfakinins, tachykinins, NPLP1-peptides, adipokinetic hormone and CCHamide 1. We also report a new peptide (Yamide) which appears to be homolog to an amidated eclosion hormone-associated peptide in several Drosophila species. Immunocytochemical characterisation of the distribution of several classes of peptide-immunoreactive neurons and enteroendocrine cells shows a very similar but not identical peptide distribution to Drosophila. Since peptides regulate many vital physiological and behavioural processes such as moulting or feeding, our data may initiate the pharmacological testing and development of new specific peptide-based protection methods against the cabbage root fly and its larva.}, language = {en} } @article{SchwerkPapandreouSchuhmannetal.2012, author = {Schwerk, Christian and Papandreou, Thalia and Schuhmann, Daniel and Nickol, Laura and Borkowski, Julia and Steinmann, Ulrike and Quednau, Natascha and Stump, Carolin and Weiss, Christel and Berger, J{\"u}rgen and Wolburg, Hartwig and Claus, Heike and Vogel, Ulrich and Ishikawa, Hiroshi and Tenenbaum, Tobias and Schroten, Horst}, title = {Polar Invasion and Translocation of Neisseria meningitidis and Streptococcus suis in a Novel Human Model of the Blood-Cerebrospinal Fluid Barrier}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0030069}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131459}, pages = {e30069}, year = {2012}, abstract = {Acute bacterial meningitis is a life-threatening disease in humans. Discussed as entry sites for pathogens into the brain are the blood-brain and the blood-cerebrospinal fluid barrier (BCSFB). Although human brain microvascular endothelial cells (HBMEC) constitute a well established human in vitro model for the blood-brain barrier, until now no reliable human system presenting the BCSFB has been developed. Here, we describe for the first time a functional human BCSFB model based on human choroid plexus papilloma cells (HIBCPP), which display typical hallmarks of a BCSFB as the expression of junctional proteins and formation of tight junctions, a high electrical resistance and minimal levels of macromolecular flux when grown on transwell filters. Importantly, when challenged with the zoonotic pathogen Streptococcus suis or the human pathogenic bacterium Neisseria meningitidis the HIBCPP show polar bacterial invasion only from the physiologically relevant basolateral side. Meningococcal invasion is attenuated by the presence of a capsule and translocated N. meningitidis form microcolonies on the apical side of HIBCPP opposite of sites of entry. As a functionally relevant human model of the BCSFB the HIBCPP offer a wide range of options for analysis of disease-related mechanisms at the choroid plexus epithelium, especially involving human pathogens.}, language = {en} } @article{GassenBrechtefeldSchandryetal.2012, author = {Gassen, Alwine and Brechtefeld, Doris and Schandry, Niklas and Arteaga-Salas, J. Manuel and Israel, Lars and Imhof, Axel and Janzen, Christian J.}, title = {DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {20}, doi = {10.1093/nar/gks801}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131449}, pages = {10302 - 10311}, year = {2012}, abstract = {Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes.}, language = {en} } @article{HafnerHoubenBaeurleetal.2012, author = {Hafner, Christian and Houben, Roland and Baeurle, Anne and Ritter, Cathrin and Schrama, David and Landthaler, Michael and Becker, J{\"u}rgen C.}, title = {Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {2}, doi = {10.1371/journal.pone.0031255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131398}, pages = {e31255}, year = {2012}, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88\% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4\%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.}, language = {en} } @article{vanKoolwijkRamdasIkrametal.2012, author = {van Koolwijk, Leonieke M. E. and Ramdas, Wishal D. and Ikram, M. Kamran and Jansonius, Nomdo M. and Pasutto, Francesca and Hys, Pirro G. and Macgregor, Stuart and Janssen, Sarah F. and Hewitt, Alex W. and Viswanathan, Ananth C. and ten Brink, Jacoline B. and Hosseini, S. Mohsen and Amin, Najaf and Despriet, Dominiek D. G. and Willemse-Assink, Jacqueline J. M. and Kramer, Rogier and Rivadeneira, Fernando and Struchalin, Maksim and Aulchenko, Yurii S. and Weisschuh, Nicole and Zenkel, Matthias and Mardin, Christian Y. and Gramer, Eugen and Welge-L{\"u}ssen, Ulrich and Montgomery, Grant W. and Carbonaro, Francis and Young, Terri L. and Bellenguez, C{\´e}line and McGuffin, Peter and Foster, Paul J. and Topouzis, Fotis and Mitchell, Paul and Wang, Jie Jin and Wong, Tien Y. and Czudowska, Monika A. and Hofman, Albert and Uitterlinden, Andre G. and Wolfs, Roger C. W. and de Jong, Paulus T. V. M. and Oostra, Ben A. and Paterson, Andrew D. and Mackey, David A. and Bergen, Arthur A. B. and Reis, Andre and Hammond, Christopher J. and Vingerling, Johannes R. and Lemij, Hans G. and Klaver, Caroline C. W. and van Duijn, Cornelia M.}, title = {Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {5}, doi = {10.1371/journal.pgen.1002611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131378}, pages = {e1002611}, year = {2012}, abstract = {Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.}, language = {en} } @article{StaigerCadotKooteretal.2012, author = {Staiger, Christine and Cadot, Sidney and Kooter, Raul and Dittrich, Marcus and M{\"u}ller, Tobias and Klau, Gunnar W. and Wessels, Lodewyk F. A.}, title = {A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0034796}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131323}, pages = {e34796}, year = {2012}, abstract = {Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer.}, language = {en} } @article{GrassmannFritscheKeilhaueretal.2012, author = {Grassmann, Felix and Fritsche, Lars G. and Keilhauer, Claudia N. and Heid, Iris M. and Weber, Bernhard H. F.}, title = {Modelling the Genetic Risk in Age-Related Macular Degeneration}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0037979}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131315}, pages = {e37979}, year = {2012}, abstract = {Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95\% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95\% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95\% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5\% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2\% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9\% and a specificity of 99.9\% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4\% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2\% of individuals in the two lowest GRS categories which represent almost 50\% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.}, language = {en} } @article{JainJavdanFegeretal.2012, author = {Jain, Preetesh and Javdan, Mohammad and Feger, Franziska K. and Chiu, Pui Yan and Sison, Cristina and Damle, Rajendra N. and Bhuiya, Tawfiqul A. and Sen, Filiz and Abruzzo, Lynne V. and Burger, Jan A. and Rosenwald, Andreas and Allen, Steven L. and Kolitz, Jonathan E. and Rai, Kanti R. and Chiorazzi, Nicholas and Sherry, Barbara}, title = {Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance}, series = {Haematologica}, volume = {97}, journal = {Haematologica}, number = {4}, doi = {10.3324/haematol.2011.047316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131290}, pages = {599 - 607}, year = {2012}, abstract = {Background The levels and clinical relevance of Th17 cells and other interleukin-17-producing cells have not been analyzed in chronic lymphocytic leukemia. The objective of this study was to quantify blood and tissue levels of Th17 and other interleukin-17-producing cells in patients with this disease and correlate blood levels with clinical outcome. Design and Methods: Intracellular interleukin-17A was assessed in blood and splenic mononuclear cells from patients with chronic lymphocytic leukemia and healthy subjects using flow cytometry. Interleukin-17A-producing cells were analyzed in formalin-fixed, paraffin-embedded spleen and lymph node sections using immunohistochemistry and immunofluorescence. Results: The absolute numbers of Th17 cells in peripheral blood mononuclear cells and the percentages of Th17 cells in spleen cell suspensions were higher in patients with chronic lymphocytic leukemia than in healthy subjects; in six out of eight paired chronic lymphocytic leukemia blood and spleen sample comparisons, Th17 cells were enriched in spleen suspensions. Circulating Th17 levels correlated with better prognostic markers and longer overall survival of the patients. Two "non-Th17" interleukin-17-expressing cells were identified in chronic lymphocytic leukemia spleens: proliferating cells of the granulocytic lineage and mature mast cells. Granulocytes and mast cells in normal spleens did not express interleukin-17. Conversely, both chronic lymphocytic leukemia and healthy lymph nodes contained similar numbers of interleukin-17+ mast cells as well as Th17 cells. Conclusions: Th17 cells are elevated in chronic lymphocytic leukemia patients with better prognostic markers and correlate with longer survival. Furthermore, non-Th17 interleukin-17A-expressing cells exist in chronic lymphocytic leukemia spleens as maturing granulocytes and mature mast cells, suggesting that the microenvironmental milieu in leukemic spleens promotes the recruitment and/or expansion of Th17 and other IL-17-expressing cells. The pathophysiology of Th17 and non-Th17-interleukin-producing cells in chronic lymphocytic leukemia and their distributions and roles in this disease merit further study.}, language = {en} } @article{BoehlerCreignouGalotaetal.2012, author = {B{\"o}hler, Elmar and Creignou, Nadia and Galota, Matthias and Reith, Steffen and Schnoor, Henning and Vollmer, Heribert}, title = {Complexity Classifications for Different Equivalence and Audit Problems for Boolean Circuits}, series = {Logical Methods in Computer Science}, volume = {8}, journal = {Logical Methods in Computer Science}, number = {3:27}, doi = {10.2168/LMCS-8(3:27)2012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131121}, pages = {1 -- 25}, year = {2012}, abstract = {We study Boolean circuits as a representation of Boolean functions and conskier different equivalence, audit, and enumeration problems. For a number of restricted sets of gate types (bases) we obtain efficient algorithms, while for all other gate types we show these problems are at least NP-hard.}, language = {en} } @article{HofgaardJodalBommertetal.2012, author = {Hofgaard, Peter O. and Jodal, Henriette C. and Bommert, Kurt and Huard, Bertrand and Caers, Jo and Carlsen, Harald and Schwarzer, Rolf and Sch{\"u}nemann, Nicole and Jundt, Franziska and Lindeberg, Mona M. and Bogen, Bjarne}, title = {A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0051892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131117}, pages = {e51892}, year = {2012}, abstract = {Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10\(^4\) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM.}, language = {en} } @article{MessiNdjokoIosetHertleinAmslingeretal.2012, author = {Messi, Bernadette Biloa and Ndjoko-Ioset, Karine and Hertlein-Amslinger, Barbara and Lannang, Alain Meli and Nkengfack, Augustin E. and Wolfender, Jean-Luc and Hostettmann, Kurt and Bringmann, Gerhard}, title = {Preussianone, a New Flavanone-Chromone Biflavonoid from Garcinia preussii Engl.}, series = {Molecules}, volume = {17}, journal = {Molecules}, number = {5}, doi = {10.3390/molecules17056114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130881}, pages = {6114 - 6125}, year = {2012}, abstract = {A new flavanone-chromone biflavonoid, preussianone (1), has been isolated from the leaves of Garcinia preussii, along with four known biflavonoids. The absolute stereostructures were elucidated by chemical, spectroscopic, and chiroptical methods. The biological properties of the new biflavonoid against several bacterial strains were evaluated.}, language = {en} } @article{BetzSchneiderKressetal.2012, author = {Betz, Boris and Schneider, Reinhard and Kress, Tobias and Schick, Martin Alexander and Wanner, Christoph and Sauvant, Christoph}, title = {Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury}, series = {PPAR Research}, volume = {2012}, journal = {PPAR Research}, number = {Article ID 219319}, doi = {10.1155/2012/219319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130872}, pages = {12}, year = {2012}, abstract = {Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin-and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury.}, language = {en} } @article{ElKeredySchleyerKoenigetal.2012, author = {El-Keredy, Amira and Schleyer, Michael and K{\"o}nig, Christian and Ekim, Aslihan and Gerber, Bertram}, title = {Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040525}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130811}, pages = {e40525}, year = {2012}, abstract = {Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant.}, language = {en} } @article{BauneKonradGrotegerdetal.2012, author = {Baune, Bernhard T. and Konrad, Carsten and Grotegerd, Dominik and Suslow, Thomas and Birosova, Eva and Ohrmann, Patricia and Bauer, Jochen and Arolt, Volker and Heindel, Walter and Domschke, Katharina and Sch{\"o}ning, Sonja and Rauch, Astrid V. and Uhlmann, Christina and Kugel, Harald and Dannlowski, Udo}, title = {Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain}, series = {Journal of Neuroinflammation}, volume = {9}, journal = {Journal of Neuroinflammation}, number = {125}, doi = {10.1186/1742-2094-9-125}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130804}, year = {2012}, abstract = {Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08\% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.}, language = {en} } @article{HerbertMuthPollatosetal.2012, author = {Herbert, Beate M. and Muth, Eric R. and Pollatos, Olga and Herbert, Cornelia}, title = {Interoception across Modalities: On the Relationship between Cardiac Awareness and the Sensitivity for Gastric Functions}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0036646}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130733}, pages = {e36646}, year = {2012}, abstract = {The individual sensitivity for ones internal bodily signals ("interoceptive awareness") has been shown to be of relevance for a broad range of cognitive and affective functions. Interoceptive awareness has been primarily assessed via measuring the sensitivity for ones cardiac signals ("cardiac awareness") which can be non-invasively measured by heartbeat perception tasks. It is an open question whether cardiac awareness is related to the sensitivity for other bodily, visceral functions. This study investigated the relationship between cardiac awareness and the sensitivity for gastric functions in healthy female persons by using non-invasive methods. Heartbeat perception as a measure for cardiac awareness was assessed by a heartbeat tracking task and gastric sensitivity was assessed by a water load test. Gastric myoelectrical activity was measured by electrogastrography (EGG) and subjective feelings of fullness, valence, arousal and nausea were assessed. The results show that cardiac awareness was inversely correlated with ingested water volume and with normogastric activity after water load. However, persons with good and poor cardiac awareness did not differ in their subjective ratings of fullness, nausea and affective feelings after drinking. This suggests that good heartbeat perceivers ingested less water because they subjectively felt more intense signals of fullness during this lower amount of water intake compared to poor heartbeat perceivers who ingested more water until feeling the same signs of fullness. These findings demonstrate that cardiac awareness is related to greater sensitivity for gastric functions, suggesting that there is a general sensitivity for interoceptive processes across the gastric and cardiac modality.}, language = {en} } @article{WillemsUrlichsSeidenspinneretal.2012, author = {Willems, Coen H. M. P. and Urlichs, Florian and Seidenspinner, Silvia and Kunzmann, Steffen and Speer, Christian P. and Kramer, Boris W.}, title = {Poractant alfa (Curosurf (R)) increases phagocytosis of apoptotic neutrophils by alveolar macrophages in vivo}, series = {Respiratory Research}, volume = {13}, journal = {Respiratory Research}, number = {17}, doi = {10.1186/1465-9921-13-17}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130721}, year = {2012}, abstract = {Background: Clearance of apoptotic neutrophils in the lung is an essential process to limit inflammation, since they could become a pro-inflammatory stimulus themselves. The clearance is partially mediated by alveolar macrophages, which phagocytose these apoptotic cells. The phagocytosis of apoptotic immune cells by monocytes in vitro has been shown to be augmented by several constituents of pulmonary surfactant, e. g. phospholipids and hydrophobic surfactant proteins. In this study, we assessed the influence of exogenous poractant alfa (Curosurf (R)) instillation on the in vivo phagocytosis of apoptotic neutrophils by alveolar macrophages. Methods: Poractant alfa (200 mg/kg) was instilled intratracheally in the lungs of three months old adult male C57/Black 6 mice, followed by apoptotic neutrophil instillation. Bronchoalveloar lavage was performed and alveolar macrophages and neutrophils were counted. Phagocytosis of apoptotic neutrophils was quantified by determining the number of apoptotic neutrophils per alveolar macrophages. Results: Exogenous surfactant increased the number of alveolar macrophages engulfing apoptotic neutrophils 2.6 fold. The phagocytosis of apoptotic neutrophils was increased in the presence of exogenous surfactant by a 4.7 fold increase in phagocytosed apoptotic neutrophils per alveolar macrophage. Conclusions: We conclude that the anti-inflammatory properties of surfactant therapy may be mediated in part by increased numbers of alveolar macrophages and increased phagocytosis of apoptotic neutrophils by alveolar macrophages.}, language = {en} } @article{WeisseHeddergottHeydtetal.2012, author = {Weiße, Sebastian and Heddergott, Niko and Heydt, Matthias and Pfl{\"a}sterer, Daniel and Maier, Timo and Haraszti, Tamas and Grunze, Michael and Engstler, Markus and Rosenhahn, Axel}, title = {A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0037296}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130666}, pages = {e37296}, year = {2012}, abstract = {We present a quantitative 3D analysis of the motility of the blood parasite Trypanosoma brucei. Digital in-line holographic microscopy has been used to track single cells with high temporal and spatial accuracy to obtain quantitative data on their behavior. Comparing bloodstream form and insect form trypanosomes as well as mutant and wildtype cells under varying external conditions we were able to derive a general two-state-run-and-tumble-model for trypanosome motility. Differences in the motility of distinct strains indicate that adaption of the trypanosomes to their natural environments involves a change in their mode of swimming.}, language = {en} } @article{BugaScholzKumaretal.2012, author = {Buga, Ana-Maria and Scholz, Claus J{\"u}rgen and Kumar, Senthil and Herndon, James G. and Alexandru, Dragos and Cojocaru, Gabriel Radu and Dandekar, Thomas and Popa-Wagner, Aurel}, title = {Identification of New Therapeutic Targets by Genome-Wide Analysis of Gene Expression in the Ipsilateral Cortex of Aged Rats after Stroke}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0050985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130657}, pages = {e50985}, year = {2012}, abstract = {Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions. Methodology/Principal Findings: We employed the Affymetrix platform to analyze the whole-gene transcriptome following temporary ligation of the middle cerebral artery in aged and young rats. The correspondence, heat map, and dendrogram analyses independently suggest a differential, age-group-specific behaviour of major gene clusters after stroke. Overall, the pattern of gene expression strongly suggests that the response of the aged rat brain is qualitatively rather than quantitatively different from the young, i.e. the total number of regulated genes is comparable in the two age groups, but the aged rats had great difficulty in mounting a timely response to stroke. Our study indicates that four genes related to neuropathic syndrome, stress, anxiety disorders and depression (Acvr1c, Cort, Htr2b and Pnoc) may have impaired response to stroke in aged rats. New therapeutic options in aged rats may also include Calcrl, Cyp11b1, Prcp, Cebpa, Cfd, Gpnmb, Fcgr2b, Fcgr3a, Tnfrsf26, Adam 17 and Mmp14. An unexpected target is the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 in aged rats, a key enzyme in the cholesterol synthesis pathway. Post-stroke axonal growth was compromised in both age groups. Conclusion/Significance: We suggest that a multi-stage, multimodal treatment in aged animals may be more likely to produce positive results. Such a therapeutic approach should be focused on tissue restoration but should also address other aspects of patient post-stroke therapy such as neuropathic syndrome, stress, anxiety disorders, depression, neurotransmission and blood pressure.}, language = {en} } @article{KrehanHeubeckMenzeletal.2012, author = {Krehan, Mario and Heubeck, Christian and Menzel, Nicolas and Seibel, Peter and Sch{\"o}n, Astrid}, title = {RNase MRP RNA and RNase P activity in plants are associated with a Pop1p containing complex}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {16}, doi = {10.1093/nar/gks476}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130648}, pages = {7956- 7966}, year = {2012}, abstract = {RNase P processes the 5'-end of tRNAs. An essential catalytic RNA has been demonstrated in Bacteria, Archaea and the nuclei of most eukaryotes; an organism-specific number of proteins complement the holoenzyme. Nuclear RNase P from yeast and humans is well understood and contains an RNA, similar to the sister enzyme RNase MRP. In contrast, no protein subunits have yet been identified in the plant enzymes, and the presence of a nucleic acid in RNase P is still enigmatic. We have thus set out to identify and characterize the subunits of these enzymes in two plant model systems. Expression of the two known Arabidopsis MRP RNA genes in vivo was verified. The first wheat MRP RNA sequences are presented, leading to improved structure models for plant MRP RNAs. A novel mRNA encoding the central RNase P/MRP protein Pop1p was identified in Arabidopsis, suggesting the expression of distinct protein variants from this gene in vivo. Pop1p-specific antibodies precipitate RNase P activity and MRP RNAs from wheat extracts. Our results provide evidence that in plants, Pop1p is associated with MRP RNAs and with the catalytic subunit of RNase P, either separately or in a single large complex.}, language = {en} } @article{AsoHerbOguetaetal.2012, author = {Aso, Yoshinori and Herb, Andrea and Ogueta, Maite and Siwanowicz, Igor and Templier, Thomas and Friedrich, Anja B. and Ito, Kei and Scholz, Henrike and Tanimoto, Hiromu}, title = {Three Dopamine Pathways Induce Aversive Odor Memories with Different Stability}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {7}, doi = {10.1371/journal.pgen.1002768}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130631}, pages = {e1002768}, year = {2012}, abstract = {Animals acquire predictive values of sensory stimuli through reinforcement. In the brain of Drosophila melanogaster, activation of two types of dopamine neurons in the PAM and PPL1 clusters has been shown to induce aversive odor memory. Here, we identified the third cell type and characterized aversive memories induced by these dopamine neurons. These three dopamine pathways all project to the mushroom body but terminate in the spatially segregated subdomains. To understand the functional difference of these dopamine pathways in electric shock reinforcement, we blocked each one of them during memory acquisition. We found that all three pathways partially contribute to electric shock memory. Notably, the memories mediated by these neurons differed in temporal stability. Furthermore, combinatorial activation of two of these pathways revealed significant interaction of individual memory components rather than their simple summation. These results cast light on a cellular mechanism by which a noxious event induces different dopamine signals to a single brain structure to synthesize an aversive memory.}, language = {en} } @article{RamachandranShearerJacobetal.2012, author = {Ramachandran, Vinoy K. and Shearer, Neil and Jacob, Jobin J. and Sharma, Cynthia M. and Thompson, Arthur}, title = {The architecture and ppGpp-dependent expression of the primary transcriptome of Salmonella Typhimurium during invasion gene expression}, series = {BMC Genomics}, volume = {13}, journal = {BMC Genomics}, number = {25}, doi = {10.1186/1471-2164-13-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130625}, year = {2012}, abstract = {Background: Invasion of intestinal epithelial cells by Salmonella enterica serovar Typhimurium (S. Typhimurium) requires expression of the extracellular virulence gene expression programme (STEX), activation of which is dependent on the signalling molecule guanosine tetraphosphate (ppGpp). Recently, next-generation transcriptomics (RNA-seq) has revealed the unexpected complexity of bacterial transcriptomes and in this report we use differential RNA sequencing (dRNA-seq) to define the high-resolution transcriptomic architecture of wildtype S. Typhimurium and a ppGpp null strain under growth conditions which model STEX. In doing so we show that ppGpp plays a much wider role in regulating the S. Typhimurium STEX primary transcriptome than previously recognised. Results: Here we report the precise mapping of transcriptional start sites (TSSs) for 78\% of the S. Typhimurium open reading frames (ORFs). The TSS mapping enabled a genome-wide promoter analysis resulting in the prediction of 169 alternative sigma factor binding sites, and the prediction of the structure of 625 operons. We also report the discovery of 55 new candidate small RNAs (sRNAs) and 302 candidate antisense RNAs (asRNAs). We discovered 32 ppGpp-dependent alternative TSSs and determined the extent and level of ppGpp-dependent coding and non-coding transcription. We found that 34\% and 20\% of coding and non-coding RNA transcription respectively was ppGpp-dependent under these growth conditions, adding a further dimension to the role of this remarkable small regulatory molecule in enabling rapid adaptation to the infective environment. Conclusions: The transcriptional architecture of S. Typhimurium and finer definition of the key role ppGpp plays in regulating Salmonella coding and non-coding transcription should promote the understanding of gene regulation in this important food borne pathogen and act as a resource for future research.}, language = {en} } @article{AntoniouKuchenbaeckerSoucyetal.2012, author = {Antoniou, Antonis C. and Kuchenbaecker, Karoline B. and Soucy, Penny and Beesley, Jonathan and Chen, Xiaoqing and McGuffog, Lesley and Lee, Andrew and Barrowdale, Daniel and Healey, Sue and Sinilnikova, Olga M. and Caligo, Maria A. and Loman, Niklas and Harbst, Katja and Lindblom, Annika and Arver, Brita and Rosenquist, Richard and Karlsson, Per and Nathanson, Kate and Domchek, Susan and Rebbeck, Tim and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Zlowowcka-Perłowska, Elżbieta and Osorio, Ana and Dur{\´a}n, Mercedes and Andr{\´e}s, Raquel and Ben{\´i}tez, Javier and Hamann, Ute and Hogervorst, Frans B. and van Os, Theo A. and Verhoef, Senno and Meijers-Heijboer, Hanne E. J. and Wijnen, Juul and Garcia, Encarna B. G{\´o}mez and Ligtenberg, Marjolijn J. and Kriege, Mieke and Coll{\´e}e, Margriet and Ausems, Margreet G. E. M. and Oosterwijk, Jan C. and Peock, Susan and Frost, Debra and Ellis, Steve D. and Platte, Radka and Fineberg, Elena and Evans, D. Gareth and Lalloo, Fiona and Jacobs, Chris and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Cook, Jackie and Paterson, Joan and Douglas, Fiona and Brewer, Carole and Hodgson, Shirley and Morrison, Patrick J. and Walker, Lisa and Rogers, Mark T. and Donaldson, Alan and Dorkins, Huw and Godwin, Andrew K. and Bove, Betsy and Stoppa-Lyonnet, Dominique and Houdayer, Claude and Buecher, Bruno and de Pauw, Antoine and Mazoyer, Sylvie and Calender, Alain and L{\´e}on{\´e}, M{\´e}lanie and Bressac-de Paillerets, Brigitte and Caron, Olivier and Sobol, Hagay and Frenay, Marc and Prieur, Fabienne and Ferrer, Sandra Fert and Mortemousque, Isabelle and Buys, Saundra and Daly, Mary and Miron, Alexander and Terry, Mary Beth and Hopper, John L. and John, Esther M. and Southey, Melissa and Goldgar, David and Singer, Christian F. and Fink-Retter, Anneliese and Muy-Kheng, Tea and Geschwantler Kaulich, Daphne and Hansen, Thomas V. O. and Nielsen, Finn C. and Barkardottir, Rosa B. and Gaudet, Mia and Kirchhoff, Tomas and Joseph, Vijai and Dutra-Clarke, Ana and Offit, Kenneth and Piedmonte, Marion and Kirk, Judy and Cohn, David and Hurteau, Jean and Byron, John and Fiorica, James and Toland, Amanda E. and Montagna, Marco and Oliani, Cristina and Imyanitov, Evgeny and Isaacs, Claudine and Tihomirova, Laima and Blanco, Ignacio and Lazaro, Conxi and Teul{\´e}, Alex and Del Valle, J. and Gayther, Simon A. and Odunsi, Kunle and Gross, Jenny and Karlan, Beth Y. and Olah, Edith and Teo, Soo-Hwang and Ganz, Patricia A. and Beattie, Mary S. and Dorfling, Cecelia M. and Jansen van Rensburg, Elizabeth and Diez, Orland and Kwong, Ava and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Heidemann, Simone and Niederacher, Dieter and Preisler-Adams, Sabine and Gadzicki, Dorothea and Varon-Mateeva, Raymonda and Deissler, Helmut and Gehrig, Andrea and Sutter, Christian and Kast, Karin and Fiebig, Britta and Sch{\"a}fer, Dieter and Caldes, Trinidad and de la Hoya, Miguel and Nevanlinna, Heli and Muranen, Taru A. and Lesp{\´e}rance, Bernard and Spurdle, Amanda B. and Neuhausen, Susan L. and Ding, Yuan C. and Wang, Xianshu and Fredericksen, Zachary and Pankratz, Vernon S. and Lindor, Noralane M. and Peterlongo, Paulo and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Bonanni, Bernardo and Bernard, Loris and Dolcetti, Riccardo and Papi, Laura and Ottini, Laura and Radice, Paolo and Greene, Mark H. and Loud, Jennifer T. and Andrulis, Irene L. and Ozcelik, Hilmi and Mulligan, Anna Marie and Glendon, Gord and Thomassen, Mads and Gerdes, Anne-Marie and Jensen, Uffe B. and Skytte, Anne-Bine and Kruse, Torben A. and Chenevix-Trench, Georgia and Couch, Fergus J. and Simard, Jacques and Easton, Douglas F.}, title = {Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers}, series = {Breast Cancer Research}, volume = {14}, journal = {Breast Cancer Research}, number = {R33}, organization = {CIMBA; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators}, doi = {10.1186/bcr3121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130449}, year = {2012}, abstract = {Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95\% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95\% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95\% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95\% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.}, language = {en} } @article{HuserRohwedderApostolopoulouetal.2012, author = {Huser, Annina and Rohwedder, Astrid and Apostolopoulou, Anthi A. and Widmann, Annekathrin and Pfitzenmaier, Johanna E. and Maiolo, Elena M. and Selcho, Mareike and Pauls, Dennis and von Essen, Alina and Gupta, Tript and Sprecher, Simon G. and Birman, Serge and Riemensperger, Thomas and Stocker, Reinhard F. and Thum, Andreas S.}, title = {The Serotonergic Central Nervous System of the Drosophila Larva: Anatomy and Behavioral Function}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {10}, doi = {10.1371/journal.pone.0047518}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130437}, pages = {e47518}, year = {2012}, abstract = {The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naive odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.}, language = {en} } @article{HartungSeufertBergesetal.2012, author = {Hartung, Andreas and Seufert, Florian and Berges, Carsten and Gessner, Viktoria H. and Holzgrabe, Ulrike}, title = {One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties}, series = {Molecules}, volume = {17}, journal = {Molecules}, number = {12}, doi = {10.3390/molecules171214685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130423}, pages = {14685-14699}, year = {2012}, abstract = {The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic alpha-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with beta-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses.}, language = {en} } @article{HolstHolstHirschfelderetal.2012, author = {Holst, Alexandra Ioana and Holst, Stefan and Hirschfelder, Ursula and von Seckendorff, Volker}, title = {Retrieval analysis of different orthodontic brackets: the applicability of electron microprobe techniques for determining material heterogeneities and corrosive potential}, series = {Journal of applied oral science}, volume = {20}, journal = {Journal of applied oral science}, number = {4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130415}, pages = {478- 485}, year = {2012}, abstract = {Objective: The objective of this study was to investigate the applicability of microanalytical methods with high spatial resolution to the characterization of the composition and corrosion behavior of two bracket systems. Material and methods: The surfaces of six nickel-free brackets and six nickel-containing brackets were examined for signs of corrosion and qualitative surface analysis using an electron probe microanalyzer (EPMA), prior to bonding to patient's tooth surfaces and four months after clinical use. The surfaces were characterized qualitatively by secondary electron (SE) images and back scattered electron (BSE) images in both compositional and topographical mode. Qualitative and quantitative wavelength-dispersive analyses were performed for different elements, and by utilizing qualitative analysis the relative concentration of selected elements was mapped two-dimensionally. The absolute concentration of the elements was determined in specially prepared brackets by quantitative analysis using pure element standards for calibration and calculating correction-factors (ZAF). Results: Clear differences were observed between the different bracket types. The nickel-containing stainless steel brackets consist of two separate pieces joined by a brazing alloy. Compositional analysis revealed two different alloy compositions, and reaction zones on both sides of the brazing alloy. The nickel-free bracket was a single piece with only slight variation in element concentration, but had a significantly rougher surface. After clinical use, no corrosive phenomena were detectable with the methods applied. Traces of intraoral wear at the contact areas between the bracket slot and the arch wire were verified. Conclusion: Electron probe microanalysis is a valuable tool for the characterization of element distribution and quantitative analysis for corrosion studies.}, language = {en} } @article{AhmadWolberEckardtetal.2012, author = {Ahmad, Ruhel and Wolber, Wanja and Eckardt, Sigrid and Koch, Philipp and Schmitt, Jessica and Semechkin, Ruslan and Geis, Christian and Heckmann, Manfred and Br{\"u}stle, Oliver and McLaughlin, John K. and Sir{\´e}n, Anna-Leena and M{\"u}ller, Albrecht M.}, title = {Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0042800}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130268}, pages = {e42800}, year = {2012}, abstract = {Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases.}, language = {en} } @article{DupuisDenglerHenekaetal.2012, author = {Dupuis, Luc and Dengler, Reinhard and Heneka, Michael T. and Meyer, Thomas and Zierz, Stephan and Kassubek, Jan and Fischer, Wilhelm and Steiner, Franziska and Lindauer, Eva and Otto, Markus and Dreyhaupt, Jens and Grehl, Torsten and Hermann, Andreas and Winkler, Andrea S. and Bogdahn, Ulrich and Benecke, Reiner and Schrank, Bertold and Wessig, Carsten and Grosskreutz, Julian and Ludolph, Albert C.}, title = {A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0037885}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130255}, pages = {e37885}, year = {2012}, abstract = {Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95\% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.}, language = {en} } @article{KirylukYifuSannaCherchietal.2012, author = {Kiryluk, Krzysztof and Yifu, Li and Sanna-Cherchi, Simone and Rohanizadegan, Mersedeh and Suzuki, Hitoshi and Eitner, Frank and Snyder, Holly J. and Choi, Murim and Hou, Ping and Scolari, Francesco and Izzi, Claudia and Gigante, Maddalena and Gesualdo, Loreto and Savoldi, Silvana and Amoroso, Antonio and Cusi, Daniele and Zamboli, Pasquale and Julian, Bruce A. and Novak, Jan and Wyatt, Robert J. and Mucha, Krzysztof and Perola, Markus and Kristiansson, Kati and Viktorin, Alexander and Magnusson, Patrik K. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Stefansson, Kari and Boland, Anne and Metzger, Marie and Thibaudin, Lise and Wanner, Christoph and Jager, Kitty J. and Goto, Shin and Maixnerova, Dita and Karnib, Hussein H. and Nagy, Judit and Panzer, Ulf and Xie, Jingyuan and Chen, Nan and Tesar, Vladimir and Narita, Ichiei and Berthoux, Francois and Floege, J{\"u}rgen and Stengel, Benedicte and Zhang, Hong and Lifton, Richard P. and Gharavi, Ali G.}, title = {Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {6}, doi = {10.1371/journal.pgen.1002765}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130195}, pages = {e1002765}, year = {2012}, abstract = {IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5x10\(^{-32}\) 3x10\(^{-10}\), with heterogeneity detected only at the PSMB9/TAP1 locus (I\(^{-2}\) = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5x10\(^{-4}\)). A seven-SNP genetic risk score, which explained 4.7\% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3x10\(^{-128}\)). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.}, language = {en} } @article{WiessnerRodriguezLastraZiroffetal.2012, author = {Wiessner, M. and Rodriguez Lastra, N. S. and Ziroff, J. and Forster, F. and Puschnig, P. and D{\"o}ssel, L. and M{\"u}llen, K. and Sch{\"o}ll, A. and Reinert, F.}, title = {Different views on the electronic structure of nanoscale graphene: aromatic molecule versus quantum dot}, series = {New Journal of Physics}, volume = {14}, journal = {New Journal of Physics}, number = {113008}, doi = {10.1088/1367-2630/14/11/113008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130184}, pages = {12}, year = {2012}, abstract = {Graphene's peculiar electronic band structure makes it of interest for new electronic and spintronic approaches. However, potential applications suffer from quantization effects when the spatial extension reaches the nanoscale. We show by photoelectron spectroscopy on nanoscaled model systems (disc-shaped, planar polyacenes) that the two-dimensional band structure is transformed into discrete states which follow the momentum dependence of the graphene Bloch states. Based on a simple model of quantum wells, we show how the band structure of graphene emerges from localized states, and we compare this result with ab initio calculations which describe the orbital structure.}, language = {en} } @article{HaddadChenCarlinetal.2012, author = {Haddad, Dana and Chen, Chun-Hao and Carlin, Sean and Silberhumer, Gerd and Chen, Nanhai G. and Zhang, Qian and Longo, Valerie and Carpenter, Susanne G. and Mittra, Arjun and Carson, Joshua and Au, Joyce and Gonen, Mithat and Zanzonico, Pat B. and Szalay, Aladar A. and Fong, Yuman}, title = {Imaging Characteristics, Tissue Distribution, and Spread of a Novel Oncolytic Vaccinia Virus Carrying the Human Sodium Iodide Symporter}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0041647}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130041}, pages = {e41647}, year = {2012}, abstract = {Introduction: Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS. Methods: GLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide \(^{131}\)I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP) and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via \(^{124}\)I-positron emission tomography (PET). Detection of systemic administration of virus was investigated with both \(^{124}\)I-PET and 99m-technecium gamma-scintigraphy. Results: GLV-1h153 successfully facilitated time-dependent intracellular uptake of \(^{131}\)I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P < 0.05). In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 10\(^9\) plaque-forming unit (PFU)/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean \% ID/gm of 3.82 \(\pm\) 60.46 (P < 0.05) 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV1h153-infected tumors were detected via \(^{124}\)I-PET and 99m-technecium-scintigraphy. Conclusion: GLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic cancer cells, facilitating detection by PET with both intratumoral and systemic administration. Therefore, GLV-1h153 is a promising candidate for the noninvasive imaging of virotherapy and warrants further study into longterm monitoring of virotherapy and potential radiocombination therapies with this treatment and imaging modality.}, language = {en} } @article{WangChenMinevetal.2012, author = {Wang, Huiqiang and Chen, Nanhai G. and Minev, Boris R. and Szalay, Aladar A.}, title = {Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells}, series = {Journal of Translational Medicine}, volume = {10}, journal = {Journal of Translational Medicine}, number = {167}, doi = {10.1186/1479-5876-10-167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130019}, year = {2012}, abstract = {Background: Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy. Methods: Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44\(^+\)CD24\(^+\)ESA\(^+\) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models. Results: We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44\(^+\)CD24\(^+\)ESA\(^+\) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44\(^+\)CD24\(^-\)ESA\(^+\) cells. Conclusions: Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.}, language = {en} } @article{SchaeferWeibelDonatetal.2012, author = {Sch{\"a}fer, Simon and Weibel, Stephanie and Donat, Ulrike and Zhang, Quian and Aguilar, Richard J. and Chen, Nanhai G. and Szalay, Aladar A.}, title = {Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {366}, doi = {10.1186/1471-2407-12-366}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140800}, year = {2012}, abstract = {Background Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors. Methods For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation. Results GLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV. Conclusions Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.}, language = {en} } @article{PatilGentschevAdelfingeretal.2012, author = {Patil, Sandeep S. and Gentschev, Ivaylo and Adelfinger, Marion and Donat, Ulrike and Hess, Michael and Weibel, Stephanie and Nolte, Ingo and Frentzen, Alexa and Szalay, Aladar A.}, title = {Virotherapy of Canine Tumors with Oncolytic Vaccinia Virus GLV-1h109 Expressing an Anti-VEGF Single-Chain Antibody}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {10}, doi = {10.1371/journal.pone.0047472}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130039}, pages = {e47472}, year = {2012}, abstract = {Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients.}, language = {en} } @article{GentschevAdelfingerJosupeitetal.2012, author = {Gentschev, Ivaylo and Adelfinger, Marion and Josupeit, Rafael and Rudolph, Stephan and Ehrig, Klaas and Donat, Ulrike and Weibel, Stephanie and Chen, Nanhai G. and Yu, Yong A. and Zhang, Qian and Heisig, Martin and Thamm, Douglas and Stritzker, Jochen and MacNeill, Amy and Szalay, Aladar A.}, title = {Preclinical Evaluation of Oncolytic Vaccinia Virus for Therapy of Canine Soft Tissue Sarcoma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0037239}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129998}, year = {2012}, abstract = {Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129936}, pages = {573-579}, year = {2012}, abstract = {Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{DubovykMenzConradetal.2012, author = {Dubovyk, Olena and Menz, Gunter and Conrad, Christopher and Kann, Elena and Machwitz, Miriam and Khamzina, Asia}, title = {Spatio-temporal analyses of cropland degradation in the irrigated lowlands of Uzbekistan using remote-sensing and logistic regression modeling}, series = {Environmental Monitoring and Assessment}, volume = {185}, journal = {Environmental Monitoring and Assessment}, number = {6}, doi = {10.1007/s10661-012-2904-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129912}, pages = {4775-4790}, year = {2012}, abstract = {Advancing land degradation in the irrigated areas of Central Asia hinders sustainable development of this predominantly agricultural region. To support decisions on mitigating cropland degradation, this study combines linear trend analysis and spatial logistic regression modeling to expose a land degradation trend in the Khorezm region, Uzbekistan, and to analyze the causes. Time series of the 250-m MODIS NDVI, summed over the growing seasons of 2000-2010, were used to derive areas with an apparent negative vegetation trend; this was interpreted as an indicator of land degradation. About one third (161,000 ha) of the region's area experienced negative trends of different magnitude. The vegetation decline was particularly evident on the low-fertility lands bordering on the natural sandy desert, suggesting that these areas should be prioritized in mitigation planning. The results of logistic modeling indicate that the spatial pattern of the observed trend is mainly associated with the level of the groundwater table (odds = 330 \%), land-use intensity (odds = 103 \%), low soil quality (odds = 49 \%), slope (odds = 29 \%), and salinity of the groundwater (odds = 26 \%). Areas, threatened by land degradation, were mapped by fitting the estimated model parameters to available data. The elaborated approach, combining remote-sensing and GIS, can form the basis for developing a common tool for monitoring land degradation trends in irrigated croplands of Central Asia.}, language = {en} } @article{LangenfeldMochPfoh2012, author = {Langenfeld, Ulrich and Moch, Sven-Olaf and Pfoh, Torsten}, title = {QCD threshold corrections for gluino pair production at hadron colliders}, series = {Journal of High Energy Physics}, volume = {11}, journal = {Journal of High Energy Physics}, number = {070}, doi = {10.1007/JHEP11(2012)070}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129609}, year = {2012}, abstract = {We present the complete threshold enhanced predictions in QCD for the total cross section of gluino pair production at hadron colliders at next-to-next-to-leading order. Thanks to the computation of the required one-loop hard matching coefficients our results are accurate to the next-to-next-to-leading logarithm. In a brief phenomenological study we provide predictions for the total hadronic cross sections at the LHC and we discuss the uncertainties arising from scale variations and the parton distribution functions.}, language = {en} } @article{OPUS4-12959, title = {Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb\(^{-1}\) of √s=7TeV proton-proton collisions}, series = {The Journal of High Energy Physics}, volume = {07}, journal = {The Journal of High Energy Physics}, number = {167}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP07(2012)167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129591}, year = {2012}, abstract = {Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb\(^{-1}\) of pp collision data at √s=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95\% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV.}, language = {en} } @article{KilianOhlReuteretal.2012, author = {Kilian, W. and Ohl, T. and Reuter, J. and Speckner, C.}, title = {QCD in the color-flow representation}, series = {Journal of High Energy Physics}, volume = {10}, journal = {Journal of High Energy Physics}, number = {022}, doi = {10.1007/JHEP10(2012)022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129583}, year = {2012}, abstract = {For many practical purposes, it is convenient to formulate unbroken non-abelian gauge theories like QCD in a color-flow basis. We present a new derivation of SU(N) interactions in the color-flow basis by extending the gauge group to U(N) × U(1)′ in such a way that the two U(1) factors cancel each other. We use the quantum action principles to show the equivalence to the usual basis to all orders in perturbation theory. We extend the known Feynman rules to exotic color representations (e.g. sextets) and discuss practical applications as they occur in automatic computation programs.}, language = {en} } @article{BechtleBringmannDeschetal.2012, author = {Bechtle, Philip and Bringmann, Torsten and Desch, Klaus and Dreiner, Herbi and Hamer, Matthias and Hensel, Carsten and Kr{\"a}mer, Michael and Nguyen, Nelly and Porod, Werner and Prudent, Xavier and Sarrazin, Bj{\"o}rn and Uhlenbrock, Mathias and Wienemann, Peter}, title = {Constrained supersymmetry after two years of LHC data: a global view with Fittino}, series = {Journal of High Energy Physics}, volume = {06}, journal = {Journal of High Energy Physics}, number = {098}, doi = {10.1007/JHEP06(2012)098}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129573}, year = {2012}, abstract = {We perform global fits to the parameters of the Constrained Minimal Super-symmetric Standard Model (CMSSM) and to a variant with non-universal Higgs masses (NUHM1). In addition to constraints from low-energy precision observables and the cosmological dark matter density, we take into account the LHC exclusions from searches in jets plus missing transverse energy signatures with about 5 fb\(^{-1}\) of integrated luminosity. We also include the most recent upper bound on the branching ratio B\(_s\)  → μμ from LHCb. Furthermore, constraints from and implications for direct and indirect dark matter searches are discussed. The best fit of the CMSSM prefers a light Higgs boson just above the experimentally excluded mass. We find that the description of the low-energy observables, (g - 2)\(_μ\) in particular, and the non-observation of SUSY at the LHC become more and more incompatible within the CMSSM. A potential SM-like Higgs boson with mass around 126 GeV can barely be accommodated. Values for B(B\(_s\)→μμ) just around the Standard Model prediction are naturally expected in the best fit region. The most-preferred region is not yet affected by limits on direct WIMP searches, but the next generation of experiments will probe this region. Finally, we discuss implications from fine-tuning for the best fit regions.}, language = {en} } @article{OPUS4-12956, title = {Search for light scalar top-quark pair production in final states with two leptons with the ATLAS detector in √s=7 TeV proton-proton collisions}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2237}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2237-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129561}, year = {2012}, abstract = {A search is presented for the pair production of light scalar top quarks in √s=7 TeV proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider. This analysis uses the full data sample collected during 2011 running that corresponds to a total integrated luminosity of 4.7 fb\(^{-1}\). Light scalar top quarks are searched for in events with two opposite-sign leptons (e, μ), large missing transverse momentum and at least one jet in the final state. No excess over Standard Model expectations is found, and the results are interpreted under the assumption that the light scalar top decays to a b-quark in addition to an on-shell chargino whose decay occurs through a virtual W boson. If the chargino mass is 106 GeV, light scalar top-quark masses up to 130 GeV are excluded for neutralino masses below 70 GeV.}, language = {en} } @article{OPUS4-12955, title = {A search for \(t\overline t\) resonances in lepton+jets events with highly boosted top quarks collected in pp collisions at √s=7 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {09}, journal = {Journal of High Energy Physics}, number = {41}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP09(2012)041}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129555}, year = {2012}, abstract = {A search for resonant production of high-mass top-quark pairs is performed on 2.05 fb\(^{-1}\) of proton-proton collisions at √s=7 TeV collected in 2011 with the ATLAS experiment at the Large Hadron Collider. This analysis of the lepton+jets final state is specifically designed for the particular topology that arises from the decay of highly boosted top quarks. The observed \(t\overline t\) invariant mass spectrum is found to be compatible with the Standard Model prediction and 95\% credibility level upper limits are derived on the \(t\overline t\) production rate through new massive states. An upper limit of 0.7 pb is set on the production cross section times branching fraction of a narrow 1 TeV resonance. A Kaluza-Klein gluon with a mass smaller than 1.5 TeV is excluded.}, language = {en} } @article{OPUS4-12954, title = {Search for doubly charged Higgs bosons in like-sign dilepton final states at √s=7 TeV with the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2244}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2244-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129540}, year = {2012}, abstract = {A search for doubly charged Higgs bosons decaying to pairs of electrons and/or muons is presented. The search is performed using a data sample corresponding to an integrated luminosity of 4.7 fb\(^{-1}\) of pp collisions at √s = 7 TeV collected by the ATLAS detector at the LHC. Pairs of prompt, isolated, high-p\(_T\) leptons with the same electric charge (\(e^±e^±, e^±μ^±, μ^±μ^±\)) are selected, and their invariant mass distribution is searched for a narrow resonance. No significant excess over Standard Model background expectations is observed, and limits are placed on the cross section times branching ratio for pair production of doubly charged Higgs bosons. The masses of doubly charged Higgs bosons are constrained depending on the branching ratio into these leptonic final states. Assuming pair production, coupling to left-handed fermions, and a branching ratio of 100 \% for each final state, masses below 409 GeV, 375 GeV, and 398 GeV are excluded for \(e^±e^±, e^±μ^±\), and \(μ^±μ^±\), respectively.}, language = {en} } @article{OPUS4-12917, title = {Search for R-parity-violating supersymmetry in events with four or more leptons in √s=7 TeV pp collisions with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {12}, journal = {Journal of High Energy Physics}, number = {124}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP12(2012)124}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129179}, year = {2012}, abstract = {A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb\(^{-1}\) of √s=7 TeV proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95\% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40.}, language = {en} } @article{OPUS4-12916, title = {Search for charged Higgs bosons decaying via H\(^±\) → τν in \(t\overline t\) events using pp collision data at √s=7 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {06}, journal = {Journal of High Energy Physics}, number = {39}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP06(2012)039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129163}, year = {2012}, abstract = {The results of a search for charged Higgs bosons are presented. The analysis is based on 4.6fb\(^{-1}\) of proton-proton collision data at √s=7TeV collected by the ATLAS experiment at the Large Hadron Collider, using top quark pair events with a τ lepton in the final state. The data are consistent with the expected background from Standard Model processes. Assuming that the branching ratio of the charged Higgs boson to a τ lepton and a neutrino is 100 \%, this leads to upper limits on the branching ratio of top quark decays to a b quark and a charged Higgs boson between 5\% and 1\% for charged Higgs boson masses ranging from 90 GeV to 160 GeV, respectively. In the context of the m\(^{max}_h\) scenario of the MSSM, tan β above 12-26, as well as between 1 and 2-6, can be excluded for charged Higgs boson masses between 90 GeV and 150 GeV.}, language = {en} } @article{OPUS4-12897, title = {Jet mass and substructure of inclusive jets in √s=7 TeV pp collisions with the ATLAS experiment}, series = {Journal of High Energy Physics}, volume = {05}, journal = {Journal of High Energy Physics}, number = {128}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP05(2012)128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128970}, year = {2012}, abstract = {Recent studies have highlighted the potential of jet substructure techniques to identify the hadronic decays of boosted heavy particles. These studies all rely upon the assumption that the internal substructure of jets generated by QCD radiation is well understood. In this article, this assumption is tested on an inclusive sample of jets recorded with the ATLAS detector in 2010, which corresponds to 35 pb\(^{-1}\) of pp collisions delivered by the LHC at √s=7TeV. In a subsample of events with single pp collisions, measurements corrected for detector efficiency and resolution are presented with full systematic uncertainties. Jet invariant mass, k\(_t\) splitting scales and N-subjettiness variables are presented for anti-k\(_t\) R = 1.0 jets and Cambridge-Aachen R = 1.2 jets. Jet invariant-mass spectra for Cambridge-Aachen R = 1.2 jets after a splitting and filtering procedure are also presented. Leading-order parton-shower Monte Carlo predictions for these variables are found to be broadly in agreement with data. The dependence of mean jet mass on additional pp interactions is also explored.}, language = {en} } @article{OPUS4-12896, title = {Search for same-sign top-quark production and fourth-generation down-type quarks in pp collisions at √s=7 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {04}, journal = {Journal of High Energy Physics}, number = {69}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP04(2012)069}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128960}, year = {2012}, abstract = {A search is presented for same-sign top-quark production and down-type heavy quarks of charge -1/3 in events with two isolated leptons (e or μ) that have the same electric charge, at least two jets and large missing transverse momentum. The data are selected from pp collisions at √s=7TeV recorded by the ATLAS detector and correspond to an integrated luminosity of 1.04 fb\(^{-1}\). The observed data are consistent with expectations from Standard Model processes. Upper limits are set at 95 \% confidence level on the cross section of new sources of same-sign top-quark pair production of 1.4-2.0 pb depending on the assumed mediator mass. Upper limits are also set on the pair-production cross-section for new heavy down-type quarks; a lower limit of 450 GeV is set at 95 \% confidence level on the mass of heavy down-type quarks under the assumption that they decay 100 \% of the time to W t.}, language = {en} } @article{OPUS4-12895, title = {Search for second generation scalar leptoquarks in pp collisions at √s=7 TeV with the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2151}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2151-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128957}, year = {2012}, abstract = {The results of a search for the production of second generation scalar leptoquarks are presented for final states consisting of either two muons and at least two jets or a muon plus missing transverse momentum and at least two jets. A total of 1.03 fb\(^{-1}\) integrated luminosity of proton-proton collision data produced by the Large Hadron Collider at s√=7 TeV and recorded by the ATLAS detector is used for the search. The event yields in the signal regions are found to be consistent with the Standard Model background expectations. The production of second generation leptoquarks is excluded for a leptoquark mass m\(_{LQ}\)<594 (685) GeV at 95 \% confidence level, for a branching ratio of 0.5 (1.0) for leptoquark decay to a muon and a quark.}, language = {en} } @article{OPUS4-12893, title = {Measurement of \(t\overline t\) production with a veto on additional central jet activity in pp collisions at √s=7 TeV using the ATLAS detector}, series = {European Physical Journal C}, volume = {72}, journal = {European Physical Journal C}, number = {2043}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2043-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128931}, year = {2012}, abstract = {A measurement of the jet activity in \(t\overline t\) events produced in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented, using 2.05 fb\(^{-1}\) of integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. The \(t\overline t\) events are selected in the dilepton decay channel with two identified b-jets from the top quark decays. Events are vetoed if they contain an additional jet with transverse momentum above a threshold in a central rapidity interval. The fraction of events surviving the jet veto is presented as a function of this threshold for four different central rapidity interval definitions. An alternate measurement is also performed, in which events are vetoed if the scalar transverse momentum sum of the additional jets in each rapidity interval is above a threshold. In both measurements, the data are corrected for detector effects and compared to the theoretical models implemented in MC@NLO, Powheg, Alpgen and Sherpa. The experimental uncertainties are often smaller than the spread of theoretical predictions, allowing deviations between data and theory to be observed in some regions of phase space.}, language = {en} } @article{OPUS4-12892, title = {Measurement of the cross section for top-quark pair production in pp collisions at √s=7TeV with the ATLAS detector using final states with two high-p\(_T\) leptons}, series = {Journal of High Energy Physics}, volume = {5}, journal = {Journal of High Energy Physics}, number = {59}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP05(2012)059}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128924}, year = {2012}, abstract = {A measurement is reported of the production cross section of top-quark pairs (\(t\overline t\)) in proton-proton collisions at a center-of-mass energy of 7 TeV recorded with the ATLAS detector at the LHC. Candidate events have a signature consistent with containing two isolated leptons, large missing transverse momentum, and at least two jets. Using a data sample corresponding to an integrated luminosity of 0.70 fb\(^{-1}\), a \(t\overline t\) production cross section σ\(_{t\overline t}\)=176±5(stat.)\(^{+14}_{-11}\)(syst.)±8(lum.) pb is measured for an assumed top-quark mass of m\(_t\)  = 172.5 GeV. This measurement is in good agreement with Standard Model predictions.}, language = {en} } @article{OPUS4-12891, title = {Measurement of the top quark mass with the template method in the \(t\overline t\)→lepton+jets channel using ATLAS data}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2046}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2046-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128912}, year = {2012}, abstract = {The top quark mass has been measured using the template method in the \(t\overline t\)→lepton+jets channel based on data recorded in 2011 with the ATLAS detector at the LHC. The data were taken at a proton-proton centre-of-mass energy of √s=7 TeV and correspond to an integrated luminosity of 1.04 fb\(^{-1}\). The analyses in the e+jets and μ+jets decay channels yield consistent results. The top quark mass is measured to be m\(_{top}\)=174.5±0.6\(_{stat}\)±2.3\(_{syst}\) GeV.}, language = {en} } @article{OPUS4-12890, title = {Measurement of the charge asymmetry in top quark pair production in pp collisions at √s=7 TeV using the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2039}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2039-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128904}, year = {2012}, abstract = {A measurement of the top-antitop production charge asymmetry A C is presented using data corresponding to an integrated luminosity of 1.04 fb\(^{-1}\) of pp collisions at √s=7 TeV collected by the ATLAS detector at the LHC. Events are selected with a single lepton (electron or muon), missing transverse momentum and at least four jets of which at least one jet is identified as coming from a b-quark. A kinematic fit is used to reconstruct the t\(\overline t\) event topology. After background subtraction, a Bayesian unfolding procedure is performed to correct for acceptance and detector effects. The measured value of A\(_C\) is AC=-0.019±0.028 (stat.)±0.024 (syst.), consistent with the prediction from the MC@NLO Monte Carlo generator of A\(_C\) =0.006±0.002. Measurements of A\(_C\) in two ranges of invariant mass of the top-antitop pair are also shown.}, language = {en} } @article{OPUS4-12915, title = {A search for flavour changing neutral currents in top-quark decays in pp collision data collected with the ATLAS detector at √s=7 TeV}, series = {Journal of High Energy Physics}, volume = {9}, journal = {Journal of High Energy Physics}, number = {139}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP09(2012)139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129152}, year = {2012}, abstract = {A search for flavour changing neutral current (FCNC) processes in top-quark decays by the ATLAS Collaboration is presented. Data collected from pp collisions at the LHC at a centre-of-mass energy of √s=7TeV during 2011, corresponding to an integrated luminosity of 2.1 fb\(^{-1}\), were used. A search was performed for top-quark pair-production events, with one top quark decaying through the t → Zq FCNC (q = u, c) channel, and the other through the Standard Model dominant mode t → W b. Only the decays of the Z boson to charged leptons and leptonic W -boson decays were considered as signal. Consequently, the final-state topology is characterised by the presence of three isolated charged leptons, at least two jets and missing transverse momentum from the undetected neutrino. No evidence for an FCNC signal was found. An upper limit on the t → Zq branching ratio of BR(t → Zq) < 0.73\% is set at the 95\% confidence level.}, language = {en} } @article{OPUS4-12889, title = {Search for supersymmetry in events with large missing transverse momentum, jets, and at least one tau lepton in 7 TeV proton-proton collision data with the}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2215}, organization = {ATLAS Collaboration}, doi = {dx.doi.org/10.1140/epjc/s10052-012-2215-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128891}, year = {2012}, abstract = {A search for supersymmetry (SUSY) in events with large missing transverse momentum, jets, and at least one hadronically decaying τ lepton, with zero or one additional light lepton (e/μ), has been performed using 4.7 fb\(^{-1}\) of proton-proton collision data at \(\sqrt s\)=7TeV recorded with the ATLAS detector at the Large Hadron Collider. No excess above the Standard Model background expectation is observed and a 95 \% confidence level visible cross-section upper limit for new phenomena is set. In the framework of gauge-mediated SUSY-breaking models, lower limits on the mass scale Λ are set at 54 TeV in the regions where the \(\tilde τ_1\) is the next-to-lightest SUSY particle (tanβ>20). These limits provide the most stringent tests to date of GMSB models in a large part of the parameter space considered.}, language = {en} } @article{OPUS4-12888, title = {ATLAS search for a heavy gauge boson decaying to a charged lepton and a neutrino in pp collisions at √s=7 TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2241}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2241-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128888}, year = {2012}, abstract = {The ATLAS detector at the LHC is used to search for high-mass states, such as heavy charged gauge bosons (W′), decaying to a charged lepton (electron or muon) and a neutrino. Results are presented based on the analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.7 fb\(^{-1}\). No excess beyond Standard Model expectations is observed. A W′ with Sequential Standard Model couplings is excluded at the 95 \% credibility level for masses up to 2.55 TeV. Excited chiral bosons (W∗) with equivalent coupling strength are excluded for masses up to 2.42 TeV.}, language = {en} } @article{OPUS4-12813, title = {Search for pair production of massive particles decaying into three quarks with the ATLAS detector in √s=7TeV pp collisions at the LHC}, series = {Journal of High Energy Physics}, volume = {12}, journal = {Journal of High Energy Physics}, number = {86}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP12(2012)086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128133}, year = {2012}, abstract = {A search is conducted for hadronic three-body decays of a new massive coloured particle in √s=7TeV pp collisions at the LHC using an integrated luminosity of 4.6 fb\(^{-1}\) collected by the ATLAS detector. Supersymmetric gluino pair production in the context of a model with R-parity violation is used as a benchmark scenario. The analysis is divided into two search channels, each optimised separately for their sensitivity to high-mass and low-mass gluino production. The first search channel uses a stringent selection on the transverse momentum of the six leading jets and is performed as a counting experiment. The second search channel focuses on low-mass gluinos produced with a large boost. Large-radius jets are selected and the invariant mass of each of the two leading jets is used as a discriminant between the signal and the background. The results are found to be consistent with Standard Model expectations and limits are set on the allowed gluino mass.}, language = {en} } @article{OPUS4-12812, title = {Time-dependent angular analysis of the decay B\(^0_s\)→J/ψϕ and extraction of ΔΓ\(_s\) and the CP-violating weak phase ϕ\(_s\) by ATLAS}, series = {Journal of High Energy Physics}, volume = {12}, journal = {Journal of High Energy Physics}, number = {072}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP12(2012)072}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128125}, year = {2012}, abstract = {A measurement of B\(^0_s\)→J/ψϕ decay parameters, including the CP -violating weak phase ϕ\(_s\) and the decay width difference ΔΓ\(_s\) is reported, using 4.9 fb\(^{-1}\) of integrated luminosity collected in 2011 by the ATLAS detector from LHC pp collisions at a centre-of-mass energy √s=7 TeV. The mean decay width Γ\(_s\) and the transversity amplitudes |A\(_0\)(0)|\(^2\) and |A\(_∥\)(0)|\(^2\) are also measured. The values reported for these parameters are: ϕ\(_s\)=0.22±0.41 (stat.)±0.10 (syst.) rad ΔΓ\(_s\)=0.053±0.021 (stat.)±0.010 (syst.)ps\(^{-1}\) Γ\(_s\)=0.677±0.007 (stat.)±0.004 (syst.) ps\(^{-1}\) |A\(_0\)(0)|\(^2\)=0.528±0.006 (stat.)±0.009 (syst.) |A\(_∥\)(0)|\(^2\)=0.220±0.008 (stat.)±0.007 (syst.) where the values quoted for ϕ\(_s\) and ΔΓ\(_s\) correspond to the solution compatible with the external measurements to which the strong phase δ\(_⊥\) is constrained and where ΔΓ\(_s\) is constrained to be positive. The fraction of S-wave KK or f\(_0\) contamination through the decays B\(^0_s\)→J/ψK\(^+\)K\(^-\)(f\(_0\)) is measured as well and is found to be consistent with zero. Results for ϕ\(_s\) and ΔΓ\(_s\) are also presented as 68\%, 90\% and 95\% likelihood contours, which show agreement with Standard Model expectations.}, language = {en} } @article{OPUS4-12799, title = {Measurements of the pseudorapidity dependence of the total transverse energy in proton-proton collisions at √s=7 TeV with ATLAS}, series = {Journal of High Energy Physics}, volume = {11}, journal = {Journal of High Energy Physics}, number = {033}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP11(2012)033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127998}, year = {2012}, abstract = {This paper describes measurements of the sum of the transverse energy of particles as a function of particle pseudorapidity, η, in proton-proton collisions at a centre-of-mass energy, √s=7 TeV using the ATLAS detector at the Large Hadron Collider. The measurements are performed in the region |η| < 4.8 for two event classes: those requiring the presence of particles with a low transverse momentum and those requiring particles with a significant transverse momentum. In the second dataset measurements are made in the region transverse to the hard scatter. The distributions are compared to the predictions of various Monte Carlo event generators, which generally tend to underestimate the amount of transverse energy at high |η|.}, language = {en} } @article{OPUS4-12798, title = {Search for anomalous production of prompt like-sign lepton pairs at √s=7TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {12}, journal = {Journal of High Energy Physics}, number = {7}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP12(2012)007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127983}, year = {2012}, abstract = {An inclusive search for anomalous production of two prompt, isolated leptons with the same electric charge is presented. The search is performed in a data sample corresponding to 4.7 fb\(^{-1}\) of integrated luminosity collected in 2011 at √s=7TeV with the ATLAS detector at the LHC. Pairs of leptons (e\(^{±}\)e\(^{±}\), e\(^{±}\)μ\(^{±}\), and μ\(^{±}\)μ\(^{±}\)) with large transverse momentum are selected, and the dilepton invariant mass distribution is examined for any deviation from the Standard Model expectation. No excess is found, and upper limits on the production cross section of like-sign lepton pairs from physics processes beyond the Standard Model are placed as a function of the dilepton invariant mass within a fiducial region close to the experimental selection criteria. The 95\% confidence level upper limits on the cross section of anomalous e\(^{±}\)e\(^{±}\), e\(^{±}\)μ\(^{±}\), or μ\(^{±}\)μ\(^{±}\) production range between 1.7 fb and 64 fb depending on the dilepton mass and flavour combination.}, language = {en} } @article{OPUS4-12797, title = {Search for high-mass resonances decaying to dilepton final states in pp collisions at √s=7 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {11}, journal = {Journal of High Energy Physics}, number = {138}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP11(2012)138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127974}, year = {2012}, abstract = {The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z* bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb\(^{-1}\) in the e\(^+\)e\(^-\) channel and 5.0 fb\(^{-1}\) in the μ\(^+\)μ\(^-\)channel. A Z′ boson with Standard Model-like couplings is excluded at 95 \% confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/\(\overline M_{Pl}\)=0.1 is excluded at 95 \% confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models.}, language = {en} } @article{OPUS4-12796, title = {Measurement of W\(^{±}\)Z production in proton-proton collisions at √s=7 TeV with the ATLAS detector}, series = {European Physical Journal C}, volume = {72}, journal = {European Physical Journal C}, number = {2173}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2173-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127963}, year = {2012}, abstract = {A study of W\(^{±}\)Z production in proton-proton collisions at √s=7 TeV is presented using data corresponding to an integrated luminosity of 4.6 fb\(^{-1}\) collected with the ATLAS detector at the Large Hadron Collider in 2011. In total, 317 candidates, with a background expectation of 68±10 events, are observed in double-leptonic decay final states with electrons, muons and missing transverse momentum. The total cross-section is determined to be σ\(^{tot}_{WZ}\)=19.0\(^{+1.4}_{-1.3}\)(stat.)±0.9(syst.)±0.4(lumi.) pb, consistent with the Standard Model expectation of 17.6\(^{+1.1}_{-1.0}\) pb. Limits on anomalous triple gauge boson couplings are derived using the transverse momentum spectrum of Z bosons in the selected events. The cross-section is also presented as a function of Z boson transverse momentum and diboson invariant mass.}, language = {en} } @article{OPUS4-12795, title = {A search for \(t\overline t\) resonances with the ATLAS detector in 2.05 fb\(^{-1}\) of proton-proton collisions at √s=7 TeV}, series = {European Physical Journal C}, volume = {72}, journal = {European Physical Journal C}, number = {2083}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2083-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127959}, year = {2012}, abstract = {A search for top quark pair resonances in final states containing at least one electron or muon has been performed with the ATLAS experiment at the CERN Large Hadron Collider. The search uses a data sample corresponding to an integrated luminosity of 2.05 fb\(^{-1}\), which was recorded in 2011 at a proton-proton centre-of-mass energy of 7 TeV. No evidence for a resonance is found and limits are set on the production cross-section times branching ratio to \(t\overline t\) for narrow and wide resonances. For narrow Z′ bosons, the observed 95 \% Bayesian credibility level limits range from 9.3 pb to 0.95 pb for masses in the range of m Z′=500 GeV to m\(_{Z′}\)=1300 GeV. The corresponding excluded mass region for a leptophobic topcolour Z′ boson (Kaluza-Klein gluon excitation in the Randall-Sundrum model) is m\(_{Z′}\)<880 GeV (m\(_{gKK}\)<1130 GeV).}, language = {en} } @article{OPUS4-12781, title = {Measurement of event shapes at large momentum transfer with the ATLAS detector in pp collisions at √s=7 TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2211}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2211-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127813}, year = {2012}, abstract = {A measurement of event shape variables is presented for large momentum transfer proton-proton collisions using the ATLAS detector at the Large Hadron Collider. Six event shape variables calculated using hadronic jets are studied in inclusive multi-jet events in 35 pb\(^{-1}\) of integrated luminosity at a center-of-mass energy of √s=7 TeV. These measurements are compared to predictions by three Monte Carlo event generators containing leading-logarithmic parton showers matched to leading order matrix elements for 2→2 and 2→n (n=2,…,6) scattering. Measurements of the third-jet resolution parameter, aplanarity, thrust, sphericity, and transverse sphericity are generally well described. The mean value of each event shape variable is evaluated as a function of the average momentum of the two leading jets p\(_{T,1}\) and p\(_{T,2}\), with a mean p\(_T\) approaching 1 TeV.}, language = {en} } @article{OPUS4-12780, title = {Measurement of τ polarization in W→τν decays with the ATLAS detector in pp collisions at s√=7 TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2062}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2062-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127807}, year = {2012}, abstract = {In this paper, a measurement of τ polarization in W→τν decays is presented. It is measured from the energies of the decay products in hadronic τ decays with a single final state charged particle. The data, corresponding to an integrated luminosity of 24 pb\(^{-1}\), were collected by the ATLAS experiment at the Large Hadron Collider in 2010. The measured value of the τ polarization is P\(_τ\)=-1.06±0.04 (stat)\(^{+0.05}_{-0.07}\) (syst), in agreement with the Standard Model prediction, and is consistent with a physically allowed 95 \% CL interval [-1,-0.91]. Measurements of τ polarization have not previously been made at hadron colliders.}, language = {en} } @article{OPUS4-12785, title = {Search for anomaly-mediated supersymmetry breaking with the ATLAS detector based on a disappearing-track signature in pp collisions at √s=7 TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {1993}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-1993-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127850}, year = {2012}, abstract = {In models of anomaly-mediated supersymmetry breaking (AMSB), the lightest chargino is predicted to have a lifetime long enough to be detected in collider experiments. This letter explores AMSB scenarios in pp collisions at √s=7 TeV by attempting to identify decaying charginos which result in tracks that appear to have few associated hits in the outer region of the tracking system. The search was based on data corresponding to an integrated luminosity of 1.02 fb\(^{-1}\) collected with the ATLAS detector in 2011. The p\(_T\) spectrum of candidate tracks is found to be consistent with the expectation from Standard Model background processes and constraints on the lifetime and the production cross section were obtained. In the minimal AMSB framework with m\(_{3/2}\)<32 TeV, m\(_0\)<1.5 TeV, tanβ=5 and μ>0, a chargino having mass below 92 GeV and a lifetime between 0.5 ns and 2 ns is excluded at 95 \% confidence level.}, language = {en} } @article{OPUS4-12779, title = {Search for heavy neutrinos and right-handed W bosons in events with two leptons and jets in pp collisions at \(\sqrt{s}\)=7TeV with the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2056}, organization = {The ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2056-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127796}, year = {2012}, abstract = {This letter reports on a search for hypothetical heavy neutrinos, N, and right-handed gauge bosons, W R, in events with high transverse momentum objects which include two reconstructed leptons and at least one hadronic jet. The results were obtained from data corresponding to an integrated luminosity of 2.1 fb\(^{-1}\) collected in proton-proton collisions at √s=7 TeV with the ATLAS detector at the CERN Large Hadron Collider. No excess above the Standard Model background expectation is observed. Excluded mass regions for Majorana and Dirac neutrinos are presented using two approaches for interactions that violate lepton and lepton-flavor numbers. One approach uses an effective operator framework, the other approach is guided by the Left-Right Symmetric Model. The results described in this letter represent the most stringent limits to date on the masses of heavy neutrinos and W\(_R\) bosons obtained in direct searches.}, language = {en} } @article{OPUS4-12763, title = {Search for lepton flavour violation in the eμ continuum with the ATLAS detector in √s=7 TeV pp collisions at the LHC}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2040}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2040-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127632}, year = {2012}, abstract = {This paper presents a search for the t-channel exchange of an R-parity violating scalar top quark ( \(\tilde{t}\) ) in the e\(^±\) μ\(^∓\) continuum using 2.1 fb\(^{-1}\) of data collected by the ATLAS detector in √s=7 TeV pp collisions at the Large Hadron Collider. Data are found to be consistent with the expectation from the Standard Model backgrounds. Limits on R-parity-violating couplings at 95 \% C.L. are calculated as a function of the scalar top mass (m\(_\tilde{t}\)). The upper limits on the production cross section for pp→eμX, through the t-channel exchange of a scalar top quark, ranges from 170 fb for m\(_\tilde{t}\)=95 GeV to 30 fb for m\(_\tilde{t}\)=1000 GeV.}, language = {en} } @article{OPUS4-12762, title = {Rapidity gap cross sections measured with the ATLAS detector in pp collisions at √s=7TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {1926}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-1926-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127629}, year = {2012}, abstract = {Pseudorapidity gap distributions in proton-proton collisions at √s=7 TeV are studied using a minimum bias data sample with an integrated luminosity of 7.1 μb\(^{-1}\). Cross sections are measured differentially in terms of Δη\(^F\), the larger of the pseudorapidity regions extending to the limits of the ATLAS sensitivity, at η=±4.9, in which no final state particles are produced above a transverse momentum threshold pcutT. The measurements span the region 0<Δη\(^F\)<8 for 200MeV50 GeV. Good agreement is found with theoretical predictions. For p\(^W_T\)>50 GeV, the values of f\(_0\) and f\(_L\)-f\(_R\), averaged over charge and lepton flavour, are measured to be: f\(_0\)=0.127±0.030±0.108 and f\(_L\)-f\(_R\)=0.252±0.017±0.030, where the first uncertainties are statistical, and the second include all systematic effects.}, language = {en} } @article{OPUS4-12753, title = {Performance of missing transverse momentum reconstruction in proton-proton collisions at √s=7 TeV with ATLAS}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {1844}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-011-1844-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127530}, year = {2012}, abstract = {The measurement of missing transverse momentum in the ATLAS detector, described in this paper, makes use of the full event reconstruction and a calibration based on reconstructed physics objects. The performance of the missing transverse momentum reconstruction is evaluated using data collected in pp collisions at a centre-of-mass energy of 7 TeV in 2010. Minimum bias events and events with jets of hadrons are used from data samples corresponding to an integrated luminosity of about 0.3 nb\(^{-1}\) and 600 nb\(^{-1}\) respectively, together with events containing a Z boson decaying to two leptons (electrons or muons) or a W boson decaying to a lepton (electron or muon) and a neutrino, from a data sample corresponding to an integrated luminosity of about 36 pb\(^{-1}\). An estimate of the systematic uncertainty on the missing transverse momentum scale is presented}, language = {en} } @article{OPUS4-12752, title = {Search for top and bottom squarks from gluino pair production in final states with missing transverse energy and at least three b-jets with the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2174}, organization = {The ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2174-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127523}, year = {2012}, abstract = {This letter reports the results of a search for top and bottom squarks from gluino pair production in 4.7 fb\(^{-1}\) of pp collisions at √s=7 TeV using the ATLAS detector at the LHC. The search is performed in events with large missing transverse momentum and at least three jets identified as originating from a b-quark. Exclusion limits are presented for a variety of gluino-mediated models with gluino masses up to 1 TeV excluded.}, language = {en} } @article{OPUS4-12751, title = {Search for a heavy top-quark partner in final states with two leptons with the ATLAS detector at the LHC}, series = {Journal of High Energy Physics}, volume = {11}, journal = {Journal of High Energy Physics}, number = {094}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP11(2012)094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127511}, year = {2012}, abstract = {The results of a search for direct pair production of heavy top-quark partners in 4.7 fb\(^{-1}\) of integrated luminosity from pp collisions at √s=7 TeV collected by the ATLAS detector at the LHC are reported. Heavy top-quark partners decaying into a top quark and a neutral non-interacting particle are searched for in events with two leptons in the final state. No excess above the Standard Model expectation is observed. Limits are placed on the mass of a supersymmetric scalar top and of a spin-1/2 top-quark partner. A spin-1/2 top-quark partner with a mass between 300 GeV and 480 GeV, decaying to a top quark and a neutral non-interacting particle lighter than 100 GeV, is excluded at 95\% confidence level.}, language = {en} } @article{OPUS4-12742, title = {Search for a fermiophobic Higgs boson in the diphoton decay channel with the ATLAS detector}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2157}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2157-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127427}, year = {2012}, abstract = {A search for a fermiophobic Higgs boson using diphoton events produced in proton-proton collisions at a centre-of-mass energy of √s=7 TeV is performed using data corresponding to an integrated luminosity of 4.9 fb\(^{-1}\) collected by the ATLAS experiment at the Large Hadron Collider. A specific benchmark model is considered where all the fermion couplings to the Higgs boson are set to zero and the bosonic couplings are kept at the Standard Model values (fermiophobic Higgs model). The largest excess with respect to the background-only hypothesis is found at 125.5 GeV, with a local significance of 2.9 standard deviations, which reduces to 1.6 standard deviations when taking into account the look-elsewhere effect. The data exclude the fermiophobic Higgs model in the ranges 110.0-118.0 GeV and 119.5-121.0 GeV at 95 \% confidence level.}, language = {en} } @article{OPUS4-12741, title = {Measurement of the W boson polarization in top quark decays with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {06}, journal = {Journal of High Energy Physics}, number = {88}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP06(2012)088}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127417}, year = {2012}, abstract = {This paper presents measurements of the polarization of W bosons in top quark decays, derived from \(t\overline{t}\) events with missing transverse momentum, one charged lepton and at least four jets, or two charged leptons and at least two jets. Data from pp collisions at a centre-of-mass energy of 7 TeV were collected with the ATLAS experiment at the LHC and correspond to an integrated luminosity of 1.04 fb\(^{-1}\). The measured fractions of longitudinally, left- and right-handed polarization are F\(_0\) = 0.67 ± 0.07, F\(_L\) = 0.32 ± 0.04 and F\(_R\) = 0.01 ± 0.05, in agreement with the Standard Model predictions. As the polarization of the W bosons in top quark decays is sensitive to the Wtb vertex Lorentz structure and couplings, the measurements were used to set limits on anomalous contributions to the Wtb couplings.}, language = {en} } @article{OPUS4-12735, title = {Measurement of inclusive two-particle angular correlations in pp collisions with the ATLAS detector at the LHC}, series = {Journal of High Energy Physics}, volume = {05}, journal = {Journal of High Energy Physics}, number = {157}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP05(2012)157}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127350}, year = {2012}, abstract = {We present a measurement of two-particle angular correlations in proton- proton collisions at √s=900 GeV and 7 TeV. The collision events were collected during 2009 and 2010 with the ATLAS detector at the Large Hadron Collider using a single-arm minimum bias trigger. Correlations are measured for charged particles produced in the kinematic range of transverse momentum p\(_T\)  > 100 MeV and pseudorapidity |η| < 2.5. A complex structure in pseudorapidity and azimuth is observed at both collision energies. Results are compared to PYTHIA 8 and HERWIG++ as well as to the AMBT2B, DW and Perugia 2011 tunes of PYTHIA 6. The data are not satisfactorily described by any of these models.}, language = {en} } @phdthesis{Mautner2012, author = {Mautner, Romana}, title = {Datenintegration f{\"u}r Bauprojekte der Gebietsk{\"o}rperschaften}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138611}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Bei der Durchf{\"u}hrung {\"o}ffentlicher Bauprojekte ist eine intensive Zusammenarbeit zwi¬schen vielen Beteiligten erforderlich: die in der Bauverwaltung des Bauherren angesiedelte Projektleitung, Bedarfstr{\"a}ger (z. B. Universit{\"a}t oder Be¬h{\"o}rde), Gre-mien des Bauherrn (Kommunal-, Kreis- oder Bundesparlament), dessen Haus-haltsabteilung, Objekt- und Fachplaner (freiberuflich oder als Mitarbeiter der Bauverwaltung), Gutachter, Bauunternehmen, Lieferanten und Dienstleister, Raumordnungs-, Planfeststellungs- und Genehmigungsbeh{\"o}rden. Der Planungs-, Genehmigungs- und Realisationsprozess erstreckt sich meist {\"u}ber mehrere Jahre. W{\"a}hrenddessen ist ein intensiver Informations- und Kommunikationsaustausch zwischen den Beteiligten erforderlich. Baupl{\"a}ne, Leistungsverzeichnisse, Ange-bote, Vertr{\"a}ge, Protokolle, Bauzeitenpl{\"a}ne und Rechnungen werden immer noch per E-Mail oder in Papierform ausgetauscht. Wegen der meist gr{\"o}ßeren Zahl zeit-gleich betreuter Bauprojekte f{\"u}hrt dies bei fast allen Beteiligten regelm{\"a}ßig zu einer herausfordernd großen Korrespondenz und einem als mangelhaft zu be-zeichnenden {\"U}berblick {\"u}ber die aktuellen Projektdaten. Wegen der hochgradigen Interdependenz der Teilprozesse {\"u}ber alle Phasen hin-weg sind aber eine m{\"o}glichst reibungslose Koordination und die st{\"a}ndige Verf{\"u}g-barkeit aktueller Daten bei allen Beteiligten unabdingbare Voraussetzungen, um eine Baumaßnahme z{\"u}gig und im vorgesehenen Kostenrahmen auszuf{\"u}hren. W{\"a}hrend Datenaustausch und Koordination bei großen gewerblichen Bauprojek-ten bereits mit Erfolg durch virtuelle Projektr{\"a}ume unterst{\"u}tzt werden, sind die {\"o}ffentlichen Bauverwaltungen hier noch z{\"o}gerlich. Die Erstellung eines einheitli-chen und prozess{\"u}bergreifenden Datenmodells speziell f{\"u}r die Abl{\"a}ufe {\"o}ffentli-cher Auftraggeber als Ziel der Arbeit k{\"o}nnte helfen, die Vorteile eines zentralen, f{\"u}r alle Beteiligten zug{\"a}nglichen Datenbestandes auch f{\"u}r die Bauverwaltungen und ihre Projekte nutzbar zu machen und vormals getrennt gehaltene Datenbe-st{\"a}nde zu einem einzigen zusammenzuf{\"u}hren (Datenintegration). Die gr{\"u}ndliche Analyse der Abl{\"a}ufe und Informationsfl{\"u}sse zwischen den Beteiligten {\"u}ber alle Phasen eines {\"o}ffentlichen Bauprojekts hinweg sowie eine Bestandsaufnahme der gegenw{\"a}rtig am Markt verf{\"u}gbaren virtuellen Projektr{\"a}ume im ersten Teil der Arbeit bilden die Grundlage f{\"u}r die Modellierung der Daten sowie ihrer Zusam-menh{\"a}nge im zweiten Teil. Mit der Gesamtdarstellung der Beteiligten, ihrer Rollen und Aufgaben, der Do-kumente und der zugeh{\"o}rigen Metadaten {\"u}ber alle Phasen und Baufachbereiche hinweg wurde ein neuer Forschungsbeitrag erarbeitet. Die unterschiedlichen Be-zeichnungen z. B. in Hoch- und Tiefbauprojekten wurden im Interesse der Ver-st{\"a}ndlichkeit erhalten, aber in einer gemeinsamen Struktur zusammengef{\"u}hrt. Diese Modellierung ist die Voraussetzung f{\"u}r eine verbesserte informationstech-nische Unterst{\"u}tzung {\"o}ffentlicher Bauprojekte und zugleich die ureigenste Aufga-be des Wirtschaftsinformatikers als Mittler zwischen Anwendern und Entwick-lern. Das in dieser Arbeit entwickelte Datenmodell erlaubt wegen seiner verwaltungs- und baufachbereichs{\"u}bergreifenden Konzeption im Sinne eines Referenzmodells den Einsatz als Basis einer Standardanwendungssoftware, die mit geringem An-passungsaufwand bei einer großen Zahl an Kunden im {\"o}ffentlichen Bereich einge-setzt werden kann. Beispiele sind Projektraumanwendungen sowie Workflow-Management-Systeme. Es ist zugleich ein Referenzvorschlag an die Entwickler bestehender Anwendungen zur Definition von Schnittstellen und schließlich zur Umsetzung applikations{\"u}bergreifender Integrationsans{\"a}tze.}, subject = {Bauvorhaben}, language = {de} } @article{AadAbbottAbdallahetal.2012, author = {Aad, G. and Abbott, B. and Abdallah, J. and Abdelalim, A. A. and Abdesselam, A.}, title = {Forward-backward correlations and charged-particle azimuthal distributions in pp interactions using the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {7}, journal = {Journal of High Energy Physics}, number = {19}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP07(2012)019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127336}, year = {2012}, abstract = {Using inelastic proton-proton interactions at s√=900 GeV and 7 TeV, recorded by the ATLAS detector at the LHC, measurements have been made of the correlations between forward and backward charged-particle multiplicities and, for the first time, between forward and backward charged-particle summed transverse momentum. In addition, jet-like structure in the events is studied by means of azimuthal distributions of charged particles relative to the charged particle with highest transverse momentum in a selected kinematic region of the event. The results are compared with predictions from tunes of the pythia and herwig++ Monte Carlo generators, which in most cases are found to provide a reasonable description of the data.}, language = {en} } @article{AadAbbottAbdallahetal.2012, author = {Aad, G. and Abbott, B. and Abdallah, J. and Abdelalim, A. A. and Abdesselam, A.}, title = {Performance of the ATLAS Trigger System in 2010}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {1849}, doi = {10.1140/epjc/s10052-011-1849-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127321}, year = {2012}, abstract = {Proton-proton collisions at √s=7 TeV and heavy ion collisions at \(\sqrt{sNN}\)=2.76 TeV were produced by the LHC and recorded using the ATLAS experiment's trigger system in 2010. The LHC is designed with a maximum bunch crossing rate of 40 MHz and the ATLAS trigger system is designed to record approximately 200 of these per second. The trigger system selects events by rapidly identifying signatures of muon, electron, photon, tau lepton, jet, and B meson candidates, as well as using global event signatures, such as missing transverse energy. An overview of the ATLAS trigger system, the evolution of the system during 2010 and the performance of the trigger system components and selections based on the 2010 collision data are shown. A brief outline of plans for the trigger system in 2011 is presented.}, language = {en} } @article{AadAbbottAbdallahetal.2012, author = {Aad, G. and Abbott, B. and Abdallah, J. and Abdelalim, A. A. and Abdesselam, A.}, title = {Electron performance measurements with the ATLAS detector using the 2010 LHC proton-proton collision data}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {1909}, doi = {10.1140/epjc/s10052-012-1909-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127313}, year = {2012}, abstract = {Detailed measurements of the electron performance of the ATLAS detector at the LHC are reported, using decays of the Z, W and J/ψ particles. Data collected in 2010 at s√=7 TeV are used, corresponding to an integrated luminosity of almost 40 pb\(^{-1}\). The inter-alignment of the inner detector and the electromagnetic calorimeter, the determination of the electron energy scale and resolution, and the performance in terms of response uniformity and linearity are discussed. The electron identification, reconstruction and trigger efficiencies, as well as the charge misidentification probability, are also presented.}, language = {en} } @article{AadAbbottAbdallahetal.2012, author = {Aad, G. and Abbott, B. and Abdallah, J. and Abdel Khalek, S. and Abdelalim, A. A.}, title = {Search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν decay mode with 4.7 fb\(^{-1}\) of ATLAS data at \(\sqrt{s}\)=7 TeV}, series = {Physics Letters B}, volume = {761}, journal = {Physics Letters B}, number = {1}, organization = {ATLAS Collaboration}, doi = {10.1016/j.physletb.2012.08.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127307}, pages = {62-81}, year = {2012}, abstract = {A search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν (ℓ=e,μℓ=e,μ) decay mode is presented. The search is performed using proton-proton collision data corresponding to an integrated luminosity of 4.7 fb\(^{-1}\) at a centre-of-mass energy of 7 TeV collected during 2011 with the ATLAS detector at the Large Hadron Collider. No significant excess of events over the expected background is observed. An upper bound is placed on the Higgs boson production cross section as a function of its mass. A Standard Model Higgs boson with mass in the range between 133 GeV and 261 GeV is excluded at 95\% confidence level, while the expected exclusion range is from 127 GeV to 233 GeV.}, language = {en} } @article{JahnSchrammSchnoelzeretal.2012, author = {Jahn, Daniel and Schramm, Sabine and Schn{\"o}lzer, Martina and Heilmann, Clemens J. and de Koster, Chris G. and Sch{\"u}tz, Wolfgang and Benavente, Ricardo and Alsheimer, Manfred}, title = {A truncated lamin A in the Lmna\(^{-/-}\) mouse line: Implications for the understanding of laminopathies}, series = {Nucleus}, volume = {3}, journal = {Nucleus}, number = {5}, doi = {10.4161/nucl.21676}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127281}, pages = {463-474}, year = {2012}, abstract = {During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna\(^{-/-}\)) by Sullivan and others,1 which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna\(^{-/-}\) mice and the concept of human laminopathies.}, language = {en} } @article{KlotzMentrupRegensburgeretal.2012, author = {Klotz, Barbara and Mentrup, Birgit and Regensburger, Martina and Zeck, Sabine and Schneidereit, Jutta and Schupp, Nicole and Linden, Christian and Merz, Cornelia and Ebert, Regina and Jakob, Franz}, title = {1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity}, series = {PLoS ONE}, volume = {7}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0029959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133392}, pages = {e29959}, year = {2012}, abstract = {1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence-and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.}, language = {en} } @article{NonoPletinckxLutzetal.2012, author = {Nono, Justin Komguep and Pletinckx, Katrien and Lutz, Manfred B. and Brehm, Klaus}, title = {Excretory/Secretory-Products of Echinococcus multilocularis Larvae Induce Apoptosis and Tolerogenic Properties in Dendritic Cells In Vitro}, series = {PLoS Neglected Tropical Diseases}, volume = {6}, journal = {PLoS Neglected Tropical Diseases}, number = {2}, doi = {10.1371/journal.pntd.0001516}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134280}, pages = {e1516}, year = {2012}, abstract = {Background: Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E. multilocularis, by excretory/secretory (E/S)-products, specifically affects DC to deviate immune responses, little information is available on the molecular nature of respective E/S-products and their mode of action. Methodology/Principal Findings: We established cultivation systems for exposing DC to live material from early (oncosphere), chronic (metacestode) and late (protoscolex) infectious stages. When co-incubated with Echinococcus primary cells, representing the invading oncosphere, or metacestode vesicles, a significant proportion of DC underwent apoptosis and the surviving DC failed to mature. In contrast, DC exposed to protoscoleces upregulated maturation markers and did not undergo apoptosis. After pre-incubation with primary cells and metacestode vesicles, DC showed a strongly impaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. While none of the larvae induced the secretion of pro-inflammatory IL-12p70, the production of immunosuppressive IL-10 was elevated in response to primary cell E/S-products. Finally, upon incubation with DC and naive T-cells, E/S-products from metacestode vesicles led to a significant expansion of Foxp3+ T cells in vitro. Conclusions: This is the first report on the induction of apoptosis in DC by cestode E/S-products. Our data indicate that the early infective stage of E. multilocularis is a strong inducer of tolerance in DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. The induction of CD4+CD25+Foxp3+ T cells through metacestode E/S-products suggests that these cells fulfill an important role for parasite persistence during chronic echinococcosis.}, language = {en} } @article{FroehlichPapenfortBergeretal.2012, author = {Fr{\"o}hlich, Kathrin S. and Papenfort, Kai and Berger, Allison A. and Vogel, J{\"o}rg}, title = {A conserved RpoS-dependent small RNA controls the synthesis of major porin OmpD}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {8}, doi = {10.1093/nar/gkr1156}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134230}, pages = {3623-3640}, year = {2012}, abstract = {A remarkable feature of many small non-coding RNAs (sRNAs) of Escherichia coli and Salmonella is their accumulation in the stationary phase of bacterial growth. Several stress response regulators and sigma factors have been reported to direct the transcription of stationary phase-specific sRNAs, but a widely conserved sRNA gene that is controlled by the major stationary phase and stress sigma factor, Sigma(S) (RpoS), has remained elusive. We have studied in Salmonella the conserved SdsR sRNA, previously known as RyeB, one of the most abundant stationary phase-specific sRNAs in E. coli. Alignments of the sdsR promoter region and genetic analysis strongly suggest that this sRNA gene is selectively transcribed by Sigma(S). We show that SdsR down-regulates the synthesis of the major Salmonella porin OmpD by Hfq-dependent base pairing; SdsR thus represents the fourth sRNA to regulate this major outer membrane porin. Similar to the InvR, MicC and RybB sRNAs, SdsR recognizes the ompD mRNA in the coding sequence, suggesting that this mRNA may be primarily targeted downstream of the start codon. The SdsR-binding site in ompD was localized by 3'-RACE, an experimental approach that promises to be of use in predicting other sRNA-target interactions in bacteria.}, language = {en} } @article{MakoahNigelArndtPradel2012, author = {Makoah Nigel, Animake and Arndt, Hans-Dieter and Pradel, Gabriele}, title = {The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention?}, series = {International Journal for Parasitology: Drugs and Drug Resistance}, volume = {2}, journal = {International Journal for Parasitology: Drugs and Drug Resistance}, doi = {10.1016/j.ijpddr.2011.12.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137777}, pages = {1-10}, year = {2012}, abstract = {The ubiquitin/proteasome system serves as a regulated protein degradation pathway in eukaryotes, and is involved in many cellular processes featuring high protein turnover rates, such as cell cycle control, stress response and signal transduction. In malaria parasites, protein quality control is potentially important because of the high replication rate and the rapid transformations of the parasite during life cycle progression. The proteasome is the core of the degradation pathway, and is a major proteolytic complex responsible for the degradation and recycling of non-functional ubiquitinated proteins. Annotation of the genome for Plasmodium falciparum, the causative agent of malaria tropica, revealed proteins with similarity to human 26S proteasome subunits. In addition, a bacterial ClpQ/hslV threonine peptidase-like protein was identified. In recent years several independent studies indicated an essential function of the parasite proteasome for the liver, blood and transmission stages. In this review, we compile evidence for protein recycling in Plasmodium parasites and discuss the role of the 26S proteasome as a prospective multi-stage target for antimalarial drug discovery programs.}, language = {en} } @article{SchubertJoniauGonteroetal.2012, author = {Schubert, Maria and Joniau, Steven and Gontero, Paolo and Kneitz, Susanne and Scholz, Claus-J{\"u}rgen and Kneitz, Burkhard and Briganti, Alberto and Karnes, R. Jeffery and Tombal, Bertrand and Walz, Jochen and Hsu, Chao-Yu and Marchioro, Giansilvio and Bader, Pia and Bangma, Chris and Frohneberg, Detlef and Graefen, Markus and Schr{\"o}der, Fritz and van Cangh, Paul and van Poppel, Hein and Spahn, Martin}, title = {The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis}, series = {Advances in Urology}, volume = {2012}, journal = {Advances in Urology}, doi = {10.1155/2012/612707}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137712}, year = {2012}, abstract = {Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n=86 ) or no adjuvant ADT (group 2, n=86). Results. Only 11.6\% of the patients died, 2.3\% PCa related. Estimated 5-10-year clinical progression-free survival was 96.9\% (94.3\%) for group 1 and 73.7\% (67.0\%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.}, language = {en} } @article{LioliouSharmaCaldelarietal.2012, author = {Lioliou, Efthimia and Sharma, Cynthia M. and Caldelari, Isabelle and Helfer, Anne-Catherine and Fechter, Pierre and Vandenesch, Fran{\c{c}}ois and Vogel, J{\"o}rg and Romby, Pascale}, title = {Global Regulatory Functions of the Staphylococcus aureus Endoribonuclease III in Gene Expression}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {6}, doi = {10.1371/journal.pgen.1002782}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127219}, pages = {e1002782}, year = {2012}, abstract = {RNA turnover plays an important role in both virulence and adaptation to stress in the Gram-positive human pathogen Staphylococcus aureus. However, the molecular players and mechanisms involved in these processes are poorly understood. Here, we explored the functions of S. aureus endoribonuclease III (RNase III), a member of the ubiquitous family of double-strand-specific endoribonucleases. To define genomic transcripts that are bound and processed by RNase III, we performed deep sequencing on cDNA libraries generated from RNAs that were co-immunoprecipitated with wild-type RNase III or two different cleavage-defective mutant variants in vivo. Several newly identified RNase III targets were validated by independent experimental methods. We identified various classes of structured RNAs as RNase III substrates and demonstrated that this enzyme is involved in the maturation of rRNAs and tRNAs, regulates the turnover of mRNAs and non-coding RNAs, and autoregulates its synthesis by cleaving within the coding region of its own mRNA. Moreover, we identified a positive effect of RNase III on protein synthesis based on novel mechanisms. RNase III-mediated cleavage in the 5′ untranslated region (5′UTR) enhanced the stability and translation of cspA mRNA, which encodes the major cold-shock protein. Furthermore, RNase III cleaved overlapping 5′UTRs of divergently transcribed genes to generate leaderless mRNAs, which constitutes a novel way to co-regulate neighboring genes. In agreement with recent findings, low abundance antisense RNAs covering 44\% of the annotated genes were captured by co-immunoprecipitation with RNase III mutant proteins. Thus, in addition to gene regulation, RNase III is associated with RNA quality control of pervasive transcription. Overall, this study illustrates the complexity of post-transcriptional regulation mediated by RNase III.}, language = {en} } @article{RakosyStreinzerPaulusetal.2012, author = {Rakosy, Demetra and Streinzer, Martin and Paulus, Hannes F. and Spaethe, Johannes}, title = {Floral visual signal increases reproductive success in a sexually deceptive orchid}, series = {Arthropod-Plant Interactions}, volume = {6}, journal = {Arthropod-Plant Interactions}, number = {4}, doi = {10.1007/s11829-012-9217-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127209}, pages = {671-681}, year = {2012}, abstract = {Sexually deceptive orchids mimic signals emitted by female insects in order to attract mate-searching males. Specific attraction of the targeted pollinator is achieved by sex pheromone mimicry, which constitutes the major attraction channel. In close vicinity of the flower, visual signals may enhance attraction, as was shown recently in the sexually deceptive orchid Ophrys heldreichii. Here, we conducted an in situ manipulation experiment in two populations of O. heldreichii on Crete to investigate whether the presence/absence of the conspicuous pink perianth affects reproductive success in two natural orchid populations. We estimated reproductive success of three treatment groups (with intact, removed and artificial perianth) throughout the flowering period as pollinaria removal (male reproductive success) and massulae deposition (female reproductive success). Reproductive success was significantly increased by the presence of a strong visual signal—the conspicuous perianth—in one study population, however, not in the second, most likely due to the low pollinator abundance in the latter population. This study provides further evidence that the coloured perianth in O. heldreichii is adaptive and thus adds to the olfactory signal to maximise pollinator attraction and reproductive success.}, language = {en} } @article{WilmsOverloeperNowrousianetal.2012, author = {Wilms, Ina and Overl{\"o}per, Aaron and Nowrousian, Minou and Sharma, Cynthia M. and Narberhaus, Franz}, title = {Deep sequencing uncovers numerous small RNAs on all four replicons of the plant pathogen Agrobacterium tumefaciens}, series = {RNA Biology}, volume = {9}, journal = {RNA Biology}, number = {446-457}, doi = {10.4161/rna.17212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127101}, pages = {4}, year = {2012}, abstract = {Agrobacterium species are capable of interkingdom gene transfer between bacteria and plants. The genome of Agrobacterium tumefaciens consists of a circular and a linear chromosome, the At-plasmid and the Ti-plasmid, which harbors bacterial virulence genes required for tumor formation in plants. Little is known about promoter sequences and the small RNA (sRNA) repertoire of this and other α-proteobacteria. We used a differential RNA sequencing (dRNA-seq) approach to map transcriptional start sites of 388 annotated genes and operons. In addition, a total number of 228 sRNAs was revealed from all four Agrobacterium replicons. Twenty-two of these were confirmed by independent RNA gel blot analysis and several sRNAs were differentially expressed in response to growth media, growth phase, temperature or pH. One sRNA from the Ti-plasmid was massively induced under virulence conditions. The presence of 76 cis-antisense sRNAs, two of them on the reverse strand of virulence genes, suggests considerable antisense transcription in Agrobacterium. The information gained from this study provides a valuable reservoir for an in-depth understanding of sRNA-mediated regulation of the complex physiology and infection process of Agrobacterium.}, language = {en} } @article{BonnSchmittAsan2012, author = {Bonn, Maria and Schmitt, Angelika and Asan, Esther}, title = {Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels}, series = {Histochemistry and Cell Biology}, volume = {137}, journal = {Histochemistry and Cell Biology}, number = {1}, doi = {10.1007/s00418-011-0882-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127080}, pages = {11-24}, year = {2012}, abstract = {Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection.}, language = {en} } @article{RoehrichNgwaWiesneretal.2012, author = {R{\"o}hrich, Christian Rene and Ngwa, Che Julius and Wiesner, Jochen and Schmidtberg, Henrike and Degenkolb, Thomas and Kollewe, Christian and Fischer, Rainer and Pradel, Gabriele and Vilcinskas, Andreas}, title = {Harmonine, a defence compound from the harlequin ladybird, inhibits mycobacterial growth and demonstrates multi-stage antimalarial activity}, series = {Biology Letters}, volume = {8}, journal = {Biology Letters}, doi = {10.1098/rsbl.2011.0760}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127079}, pages = {308-311}, year = {2012}, abstract = {The harlequin ladybird beetle Harmonia axyridis has been introduced in many countries as a biological control agent, but has become an invasive species threatening the biodiversity of native ladybirds. Its invasive success has been attributed to its vigorous resistance against diverse pathogens. This study demonstrates that harmonine ((17R,9Z)-1,17-diaminooctadec-9-ene), which is present in H. axyridis haemolymph, displays broad-spectrum antimicrobial activity that includes human pathogens. Antibacterial activity is most pronounced against fast-growing mycobacteria and Mycobacterium tuberculosis, and the growth of both chloroquine-sensitive and -resistant Plasmodium falciparum strains is inhibited. Harmonine displays gametocytocidal activity, and inhibits the exflagellation of microgametocytes and zygote formation. In an Anopheles stephensi mosquito feeding model, harmonine displays transmission-blocking activity.}, language = {en} } @article{JiangChenBelimovetal.2012, author = {Jiang, Fan and Chen, Lin and Belimov, Andrey A. and Shaposhnikov, Alexander I. and Gong, Fan and Meng, Xu and Hartung, Wolfram and Jeschke, Dieter W. and Davies, William J. and Dodd, Ian C.}, title = {Multiple impacts of the plant growth-promoting rhizobacterium Variovorax paradoxus 5C-2 on nutrient and ABA relations of Pisum sativum}, series = {Journal of Experimental Botany}, volume = {63}, journal = {Journal of Experimental Botany}, number = {18}, doi = {10.1093/jxb/ers301}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127011}, pages = {6421-6430}, year = {2012}, abstract = {Resolving the physiological mechanisms by which rhizobacteria enhance plant growth is difficult, since many such bacteria contain multiple plant growth-promoting properties. To understand further how the 1-aminocyclopropane-1-carboxylate (ACC) deaminase (ACCd)-containing rhizobacterium Variovorax paradoxus 5C-2 affects plant growth, the flows and partitioning of mineral nutrients and abscisic acid (ABA) and ABA metabolism were studied in pea (Pisum sativum) plants following rhizosphere bacterial inoculation. Although root architecture was not affected, inoculation increased root and shoot biomass, and stomatal conductance, by 20, 15, and 24\%, respectively, and increased N, P, K, Ca, and Mg uptake by 16, 81, 50, 46, and 58\%, respectively. P deposition in inoculated plant roots was 4.9 times higher than that in uninoculated controls. Rhizobacterial inoculation increased root to shoot xylem flows and shoot to root phloem flows of K by 1.8- and 2.1-fold, respectively. In control plants, major sinks for K deposition were the roots and upper shoot (43\% and 49\% of total uptake, respectively), while rhizobacterial inoculation increased K distribution to the lower shoot at the expense of other compartments (xylem, phloem, and upper shoot). Despite being unable to metabolize ABA in vitro, V. paradoxus 5C-2 decreased root ABA concentrations and accumulation by 40-60\%. Although inoculation decreased xylem ABA flows, phloem ABA flows increased. Whether bacterial ACCd attenuates root to shoot ABA signalling requires further investigation, since ABA is critical to maintain growth of droughted plants, and ACCd-containing organisms have been advocated as a means of minimizing growth inhibition of plants in drying soil.}, language = {en} } @article{SchreiberKlughammerKolbowski2012, author = {Schreiber, Ulrich and Klughammer, Christof and Kolbowski, J{\"o}rg}, title = {Assessment of wavelength-dependent parameters of photosynthetic electron transport with a new type of multi-color PAM chlorophyll fluorometer}, series = {Photosynthesis Research}, volume = {113}, journal = {Photosynthesis Research}, number = {1}, doi = {10.1007/s11120-012-9758-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127003}, pages = {127-144}, year = {2012}, abstract = {Technical features of a novel multi-color pulse amplitude modulation (PAM) chlorophyll fluorometer as well as the applied methodology and some typical examples of its practical application with suspensions of Chlorella vulgaris and Synechocystis PCC 6803 are presented. The multi-color PAM provides six colors of pulse-modulated measuring light (peak-wavelengths at 400, 440, 480, 540, 590, and 625 nm) and six colors of actinic light (AL), peaking at 440, 480, 540, 590, 625 and 420-640 nm (white). The AL can be used for continuous illumination, maximal intensity single-turnover pulses, high intensity multiple-turnover pulses, and saturation pulses. In addition, far-red light (peaking at 725 nm) is provided for preferential excitation of PS I. Analysis of the fast fluorescence rise kinetics in saturating light allows determination of the wavelength- and sample-specific functional absorption cross section of PS II, Sigma(II)λ, with which the PS II turnover rate at a given incident photosynthetically active radiation (PAR) can be calculated. Sigma(II)λ is defined for a quasi-dark reference state, thus differing from σPSII used in limnology and oceanography. Vastly different light response curves for Chlorella are obtained with light of different colors, when the usual PAR-scale is used. Based on Sigma(II)λ the PAR, in units of μmol quanta/(m2 s), can be converted into PAR(II) (in units of PS II effective quanta/s) and a fluorescence-based electron transport rate ETR(II) = PAR(II) · Y(II)/Y(II)max can be defined. ETR(II) in contrast to rel.ETR qualifies for quantifying the absolute rate of electron transport in optically thin suspensions of unicellular algae and cyanobacteria. Plots of ETR(II) versus PAR(II) for Chlorella are almost identical using either 440 or 625 nm light. Photoinhibition data are presented suggesting that a lower value of ETR(II)max with 440 nm possibly reflects photodamage via absorption by the Mn-cluster of the oxygen-evolving complex.}, language = {en} } @article{AlbertWeissenbergerStetterMeuthetal.2012, author = {Albert-Weissenberger, Christiane and Stetter, Christian and Meuth, Sven G. and G{\"o}bel, Kerstin and Bader, Michael and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph}, title = {Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {9}, doi = {10.1038/jcbfm.2012.62}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125903}, pages = {1747-1756}, year = {2012}, abstract = {The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.}, language = {en} }