TY - JOUR A1 - Haeusler, Karl Georg A1 - Herm, Juliane A1 - Kunze, Claudia A1 - Krüll, Matthias A1 - Brechtel, Lars A1 - Lock, Jürgen A1 - Hohenhaus, Marc A1 - Heuschmann, Peter U. A1 - Fiebach, Jochen B. A1 - Haverkamp, Wilhelm A1 - Endres, Matthias A1 - Jungehulsing, Gerhard Jan T1 - Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study JF - BMC Cardiovascular Disorders N2 - Background: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. Methods/Design: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38\(^{th}\) BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. Results: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 \(\pm\) 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 \(\pm\) 6.6 marathon races within the last 5 years and a mean of 16 \(\pm\) 36 marathon races in total. Their weekly running distance prior to the 38\(^{th}\) BMW BERLIN-MARATHON was 65 \(\pm\) 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38\(^{th}\) BMW BERLIN-MARATHON 2011. Discussion: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage. KW - marathon running KW - cardiac arrhythmia KW - atrial fibrillation KW - physical activity KW - cardiovascular events KW - carotid artery KW - risk factor KW - stroke KW - exercise KW - death KW - metaanalysis KW - mechanisms KW - ECG-recording KW - magnetic resonance imaging KW - blood sampling Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133677 VL - 12 IS - 69 ER - TY - JOUR A1 - Wiessner, M. A1 - Rodriguez Lastra, N. S. A1 - Ziroff, J. A1 - Forster, F. A1 - Puschnig, P. A1 - Dössel, L. A1 - Müllen, K. A1 - Schöll, A. A1 - Reinert, F. T1 - Different views on the electronic structure of nanoscale graphene: aromatic molecule versus quantum dot JF - New Journal of Physics N2 - 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. KW - well KW - confinement KW - states KW - Ag(111) KW - photoemission KW - vicinal surfaces KW - coronene KW - energy KW - films KW - nanographenes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130184 VL - 14 IS - 113008 ER - TY - JOUR A1 - Kiryluk, Krzysztof A1 - Yifu, Li A1 - Sanna-Cherchi, Simone A1 - Rohanizadegan, Mersedeh A1 - Suzuki, Hitoshi A1 - Eitner, Frank A1 - Snyder, Holly J. A1 - Choi, Murim A1 - Hou, Ping A1 - Scolari, Francesco A1 - Izzi, Claudia A1 - Gigante, Maddalena A1 - Gesualdo, Loreto A1 - Savoldi, Silvana A1 - Amoroso, Antonio A1 - Cusi, Daniele A1 - Zamboli, Pasquale A1 - Julian, Bruce A. A1 - Novak, Jan A1 - Wyatt, Robert J. A1 - Mucha, Krzysztof A1 - Perola, Markus A1 - Kristiansson, Kati A1 - Viktorin, Alexander A1 - Magnusson, Patrik K. A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - Boland, Anne A1 - Metzger, Marie A1 - Thibaudin, Lise A1 - Wanner, Christoph A1 - Jager, Kitty J. A1 - Goto, Shin A1 - Maixnerova, Dita A1 - Karnib, Hussein H. A1 - Nagy, Judit A1 - Panzer, Ulf A1 - Xie, Jingyuan A1 - Chen, Nan A1 - Tesar, Vladimir A1 - Narita, Ichiei A1 - Berthoux, Francois A1 - Floege, Jürgen A1 - Stengel, Benedicte A1 - Zhang, Hong A1 - Lifton, Richard P. A1 - Gharavi, Ali G. T1 - Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis JF - PLoS Genetics N2 - 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. KW - linkage KW - genome-wide association KW - multiple sclerosis KW - renal disease KW - New mexico KW - recombination hotspot KW - italian population KW - natural history KW - HLA KW - glomerulonephritis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130195 VL - 8 IS - 6 ER - TY - JOUR A1 - Gassen, Alwine A1 - Brechtefeld, Doris A1 - Schandry, Niklas A1 - Arteaga-Salas, J. Manuel A1 - Israel, Lars A1 - Imhof, Axel A1 - Janzen, Christian J. T1 - DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei JF - Nucleic Acids Research N2 - 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. KW - variants KW - cell-cycle regulation KW - blood-stream forms KW - african trypanosomes KW - mammalian cells KW - DNA replication KW - DOT1 KW - protein KW - transcription KW - cultivation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131449 VL - 40 IS - 20 ER - TY - JOUR A1 - Schwerk, Christian A1 - Papandreou, Thalia A1 - Schuhmann, Daniel A1 - Nickol, Laura A1 - Borkowski, Julia A1 - Steinmann, Ulrike A1 - Quednau, Natascha A1 - Stump, Carolin A1 - Weiss, Christel A1 - Berger, Jürgen A1 - Wolburg, Hartwig A1 - Claus, Heike A1 - Vogel, Ulrich A1 - Ishikawa, Hiroshi A1 - Tenenbaum, Tobias A1 - Schroten, Horst T1 - Polar Invasion and Translocation of Neisseria meningitidis and Streptococcus suis in a Novel Human Model of the Blood-Cerebrospinal Fluid Barrier JF - PLoS One N2 - 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. KW - gene expression KW - plexus epithelial-cells KW - central-nervous-system KW - microvascular endothelial-cells KW - choroid-plexus KW - in vitro KW - brain barrier KW - tight junctions KW - meningococcal disease KW - bacterial meningitis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131459 VL - 7 IS - 1 ER - TY - JOUR A1 - Herbert, Beate M. A1 - Muth, Eric R. A1 - Pollatos, Olga A1 - Herbert, Cornelia T1 - Interoception across Modalities: On the Relationship between Cardiac Awareness and the Sensitivity for Gastric Functions JF - PLoS One N2 - 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. KW - anterior insula KW - water load test KW - cephalic-vagal influences KW - emotional experience KW - heartbeat perception KW - myoelectric activity KW - cardiovascular arousal KW - dyspeptic symptoms KW - balloon distension KW - eating disorders Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130733 VL - 7 IS - 5 ER - TY - JOUR A1 - Baune, Bernhard T. A1 - Konrad, Carsten A1 - Grotegerd, Dominik A1 - Suslow, Thomas A1 - Birosova, Eva A1 - Ohrmann, Patricia A1 - Bauer, Jochen A1 - Arolt, Volker A1 - Heindel, Walter A1 - Domschke, Katharina A1 - Schöning, Sonja A1 - Rauch, Astrid V. A1 - Uhlmann, Christina A1 - Kugel, Harald A1 - Dannlowski, Udo T1 - Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain JF - Journal of Neuroinflammation N2 - 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. KW - aging brain KW - hippocampal neurogenesis KW - cholinergic neurons KW - neurothrophic factor KW - Alzheimers disease KW - neurite outgrowth KW - inflammatory cytokines KW - major depression KW - nervour system KW - dentate gyrus KW - genetics KW - inflammation KW - interleukin 6 KW - neuroprotection KW - voxel-based morphometry Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130804 VL - 9 IS - 125 ER - TY - JOUR A1 - El-Keredy, Amira A1 - Schleyer, Michael A1 - König, Christian A1 - Ekim, Aslihan A1 - Gerber, Bertram T1 - Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila JF - PLoS One N2 - 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. KW - honeybees KW - chemosensory system KW - bitter taste KW - melanogaster KW - receptor KW - reward KW - brain KW - organization KW - architecture KW - perception Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130811 VL - 7 IS - 7 ER - TY - JOUR A1 - Betz, Boris A1 - Schneider, Reinhard A1 - Kress, Tobias A1 - Schick, Martin Alexander A1 - Wanner, Christoph A1 - Sauvant, Christoph T1 - Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury JF - PPAR Research N2 - 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. KW - dysfunction KW - activated-receptor gamma KW - ischemia-reperfusion injury KW - failure KW - kidney KW - agnoists KW - mices KW - inos KW - pathophysiology KW - pioglitazone Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130872 VL - 2012 IS - Article ID 219319 ER - TY - JOUR T1 - Search for doubly charged Higgs bosons in like-sign dilepton final states at √s=7 TeV with the ATLAS detector JF - The European Physical Journal C N2 - 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. KW - background expectation KW - cross section time KW - acceptance time efficiency KW - partial decay width KW - WZ production KW - extrapolation factor KW - dilepton mass KW - charge misidentification KW - systematic uncertainty KW - non-prompt lepton KW - neutral Higgs boson KW - producation cross section KW - invariant mass distribution KW - MC simulation KW - leptonic final state Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129540 VL - 72 IS - 2244 ER - TY - JOUR T1 - 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 JF - Journal of High Energy Physics N2 - 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. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129555 VL - 09 IS - 41 ER - TY - JOUR T1 - 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 JF - The European Physical Journal C N2 - 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. KW - signal cross section KW - jet energy scale KW - jet energy scale uncertainty KW - dead region KW - jet energy resolution KW - top quark pair KW - charingo mass KW - top quark decay KW - SM background KW - simulaed event sample KW - MC simulation KW - visible cross section KW - anti-k jet KW - top event dilepton invariant mass Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129561 VL - 72 IS - 2237 ER - TY - JOUR A1 - Bechtle, Philip A1 - Bringmann, Torsten A1 - Desch, Klaus A1 - Dreiner, Herbi A1 - Hamer, Matthias A1 - Hensel, Carsten A1 - Krämer, Michael A1 - Nguyen, Nelly A1 - Porod, Werner A1 - Prudent, Xavier A1 - Sarrazin, Björn A1 - Uhlenbrock, Mathias A1 - Wienemann, Peter T1 - Constrained supersymmetry after two years of LHC data: a global view with Fittino JF - Journal of High Energy Physics N2 - 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. KW - supersymmetry phenomenology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129573 VL - 06 IS - 098 ER - TY - JOUR A1 - Zoephel, Judith A1 - Reiher, Wencke A1 - Rexer, Karl-Heinz A1 - Kahnt, Jörg A1 - Wegener, Christian T1 - Peptidomics of the Agriculturally Damaging Larval Stage of the Cabbage Root Fly Delia radicum (Diptera: Anthomyiidae) JF - PLoS One N2 - 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. KW - adult drosophila KW - central-nervous-system KW - blowfly calliphora-vomitoria KW - drosophila melanogaster KW - mass spectometry KW - feeding behavior KW - fruit fly KW - functional characterization KW - immunoreactive neurons KW - neobellieria bullata Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131727 VL - 7 IS - 7 ER - TY - JOUR A1 - Pils, Stefan A1 - Kopp, Kathrin A1 - Peterson, Lisa A1 - Tascon, Julia Delgado A1 - Nyffenegger-Jann, Naja J. A1 - Hauck, Christof R. T1 - The Adaptor Molecule Nck Localizes the WAVE Complex to Promote Actin Polymerization during CEACAM3-Mediated Phagocytosis of Bacteria JF - PLoS One N2 - 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. KW - activation KW - neisseria gonorrhoeae KW - human pathogens KW - T cell KW - signal transduction KW - escherichia coli KW - epithelial cells KW - tyrosine kinase KW - receptor KW - adhesion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131747 VL - 7 IS - 3 ER - TY - JOUR A1 - Schneider, Christof W. A1 - Tautz, Jürgen A1 - Grünewald, Bernd A1 - Fuchs, Stefan T1 - RFID Tracking of Sublethal Effects of Two Neonicotinoid Insecticides on the Foraging Behavior of Apis mellifera JF - PLoS One N2 - 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. KW - memory KW - nicotinic acetylcholine-receptors KW - unpaired median neurons KW - honey bees KW - learning performances KW - toxicity KW - hymenoptera KW - pesticides KW - relevance KW - agonist Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131753 VL - 7 IS - 1 ER - TY - JOUR A1 - Fernández-Rodríguez, Juana A1 - Quiles, Francisco A1 - Blanco, Ignacio A1 - Teulé, Alex A1 - Feliubadaló, Lídia A1 - del Valle, Jesús A1 - Salinas, Mónica A1 - Izquierdo, Ángel A1 - Darder, Esther A1 - Schindler, Detlev A1 - Capellá, Gabriel A1 - Brunet, Joan A1 - Lázaro, Conxi A1 - Angel Pujana, Miguel T1 - Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families JF - BMC Cancer N2 - 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. KW - SLX4 KW - Holliday junction reolvass KW - Fanconi-anemia subtype KW - susceptibility gene KW - helicase BRIP1 KW - ovarian cancer KW - DNA repair KW - mutations KW - protein KW - RAD51C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131772 VL - 12 IS - 84 ER - TY - JOUR A1 - Samimi, C. A1 - Fink, A. H. A1 - Paeth, H. T1 - The 2007 flood in the Sahel: causes, characteristics and its presentation in the media and FEWS NET JF - Natural Hazards and Earth System Sciences N2 - 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. KW - prediction KW - satellite rainfall products KW - tropical North-Africa KW - West-Africa KW - climate change KW - summer rainfall KW - variability KW - SST KW - teleconnection KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131790 VL - 12 IS - 2 SP - 313 EP - 325 ER - TY - JOUR A1 - Naseem, Muhammad A1 - Dandekar, Thomas T1 - The Role of Auxin-Cytokinin Antagonism in Plant-Pathogen Interactions JF - PLOS Pathogens N2 - No abstract available. KW - disease KW - pseudomas-syringae KW - arabidpsis thaliana KW - immunity KW - organogenesis KW - transcription KW - resistance KW - crosstalk Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131901 VL - 8 IS - 11 ER - TY - JOUR A1 - Galimberti, Daniela A1 - Dell'Osso, Bernardo A1 - Fenoglio, Chiara A1 - Villa, Chiara A1 - Cortini, Francesca A1 - Serpente, Maria A1 - Kittel-Schneider, Sarah A1 - Weigl, Johannes A1 - Neuner, Maria A1 - Volkert, Juliane A1 - Leonhard, C. A1 - Olmes, David G. A1 - Kopf, Juliane A1 - Cantoni, Claudia A1 - Ridolfi, Elisa A1 - Palazzo, Carlotta A1 - Ghezzi, Laura A1 - Bresolin, Nereo A1 - Altamura, A.C. A1 - Scarpini, Elio A1 - Reif, Andreas T1 - Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia JF - PLoS One N2 - 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. KW - people KW - frontotemporal lobar degeneration KW - genome-wide association KW - Alzheimers disease KW - risk genes KW - dementia KW - GRN KW - mutation KW - families KW - linkage Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131910 VL - 7 IS - 4 ER - TY - JOUR A1 - Spivey, Tara L. A1 - De Giorgi, Valeria A1 - Zhao, Yingdong A1 - Bedognetti, Davide A1 - Pos, Zoltan A1 - Liu, Qiuzhen A1 - Tomei, Sara A1 - Ascierto, Maria Libera A1 - Uccellini, Lorenzo A1 - Reinboth, Jennifer A1 - Chouchane, Lotfi A1 - Stroncek, David F. A1 - Wang, Ena A1 - Marincola, Francesco M. T1 - The stable traits of melanoma genetics: an alternate approach to target discovery JF - BMC Genomics N2 - Background: The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number. Results: Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis. Conclusions: This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy. KW - tumors KW - comparative genomic hybridization KW - coloteral cancer KW - prognostic relevance KW - aquired resistance KW - malignant melanoma KW - antigen expression KW - tissue microarray KW - cell carcinoma KW - T cells Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131992 VL - 13 IS - 156 ER - TY - JOUR A1 - Kessler, Michael A1 - Hertel, Dietrich A1 - Jungkunst, Hermann F. A1 - Kluge, Jürgen A1 - Abrahamczyk, Stefan A1 - Bos, Merijn A1 - Buchori, Damayanti A1 - Gerold, Gerhard A1 - Gradstein, S. Robbert A1 - Köhler, Stefan A1 - Leuschner, Christoph A1 - Moser, Gerald A1 - Pitopang, Ramadhanil A1 - Saleh, Shahabuddin A1 - Schulze, Christian H. A1 - Sporn, Simone G. A1 - Steffan-Dewenter, Ingolf A1 - Tjitrosoedirdjo, Sri S. A1 - Tscharntke, Teja T1 - Can Joint Carbon and Biodiversity Management in Tropical Agroforestry Landscapes Be Optimized? JF - PLoS One N2 - Managing ecosystems for carbon storage may also benefit biodiversity conservation, but such a potential 'win-win' scenario has not yet been assessed for tropical agroforestry landscapes. We measured above-and below-ground carbon stocks as well as the species richness of four groups of plants and eight of animals on 14 representative plots in Sulawesi, Indonesia, ranging from natural rainforest to cacao agroforests that have replaced former natural forest. The conversion of natural forests with carbon stocks of 227-362 Mg C ha\(^{-1}\) to agroforests with 82-211 Mg C ha\(^{-1}\) showed no relationships to overall biodiversity but led to a significant loss of forest-related species richness. We conclude that the conservation of the forest-related biodiversity, and to a lesser degree of carbon stocks, mainly depends on the preservation of natural forest habitats. In the three most carbon-rich agroforestry systems, carbon stocks were about 60% of those of natural forest, suggesting that 1.6 ha of optimally managed agroforest can contribute to the conservation of carbon stocks as much as 1 ha of natural forest. However, agroforestry systems had comparatively low biodiversity, and we found no evidence for a tight link between carbon storage and biodiversity. Yet, potential win-win agroforestry management solutions include combining high shade-tree quality which favours biodiversity with cacao-yield adapted shade levels. KW - forest soils KW - stocks KW - diversity KW - sequestration KW - conversion KW - balance KW - root Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132016 VL - 7 IS - 10 ER - TY - JOUR A1 - Klauke, Benedikt A1 - Winter, Bernward A1 - Gajewska, Agnes A1 - Zwanzger, Peter A1 - Reif, Andreas A1 - Herrmann, Martin J. A1 - Dlugos, Andrea A1 - Warrings, Bodo A1 - Jacob, Christian A1 - Mühlberger, Andreas A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Domschke, Katharina T1 - Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma JF - PLoS One N2 - The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. KW - COMT VAL(158)MET polymorphism KW - serotonin transporter gene KW - life events KW - community sample KW - acoustic startle KW - prepulse inhibition KW - panic disorder KW - caffeine-induced anxiety KW - fear-potentiated startle KW - posttraumatic-stress-disorder Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132184 VL - 7 IS - 6 ER - TY - JOUR A1 - Ponnuswamy, Padmapriya A1 - Schröttle, Angelika A1 - Ostermeier, Eva A1 - Grüner, Sabine A1 - Huang, Paul L. A1 - Ertl, Georg A1 - Hoffmann, Ulrich A1 - Nieswandt, Bernhard A1 - Kuhlencordt, Peter J. T1 - eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice JF - PLoS One N2 - Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels. Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects. KW - platelet adhesion KW - lesion formation KW - nitric oxide synthase KW - endothelial cell interactions KW - double knockout mice KW - apolipoprotein E KW - deficient mice KW - in vivo KW - accelerated atherosclerosis KW - leukocyte adhesion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134866 VL - 7 IS - 1 ER - TY - JOUR A1 - Biermann, Daniel A1 - Heilmann, Andreas A1 - Didié, Michael A1 - Schlossarek, Saskia A1 - Wahab, Azadeh A1 - Grimm, Michael A1 - Römer, Maria A1 - Reichenspurner, Hermann A1 - Sultan, Karim R. A1 - Steenpass, Anna A1 - Ergün, Süleyman A1 - Donzelli, Sonia A1 - Carrier, Lucie A1 - Ehmke, Heimo A1 - Zimmermann, Wolfram H. A1 - Hein, Lutz A1 - Böger, Rainer H. A1 - Benndorf, Ralf A. T1 - Impact of AT2 Receptor Deficiency on Postnatal Cardiovascular Development JF - PLoS One N2 - Background: The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. Methodology/Principal Findings: Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of \(\alpha\)-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca\(^{2+}\) transient in response to isoprenaline when stimulated concomitantly with angiotensin II. Conclusion: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart. KW - mice KW - II type-2 receptor KW - human endothelial cells KW - chronic kidney disease KW - angiotensin II KW - blood pressure KW - in vitro KW - cardiac hyperthrophy KW - tube formation KW - rat heart Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134902 VL - 7 IS - 10 ER - TY - JOUR A1 - Reiter, Theresa A1 - Gensler, Daniel A1 - Ritter, Oliver A1 - Weiss, Ingo A1 - Geistert, Wolfgang A1 - Kaufmann, Ralf A1 - Hoffmeister, Sabine A1 - Friedrich, Michael T. A1 - Wintzheimer, Stefan A1 - Düring, Markus A1 - Nordbeck, Peter A1 - Jakob, Peter M. A1 - Ladd, Mark E. A1 - Quick, Harald H. A1 - Bauer, Wolfgang R. T1 - Direct cooling of the catheter tip increases safety for CMR-guided electrophysiological procedures JF - Journal of Cardiovascular Magnetic Resonance N2 - Background: One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating. Methods: A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. Results: A maximum temperature rise of 22.4 degrees C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2 degrees C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8 degrees C. Conclusion: Up to a maximum of 22.4 degrees C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner. KW - EP Procedures KW - radiofrequency ablation KW - contact force KW - lesion size KW - MRI KW - temperature KW - tissue KW - wires KW - model KW - ablation KW - safety KW - catheter tip KW - MR guidance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134927 VL - 14 IS - 12 ER - TY - JOUR A1 - Naidoo, Robin A1 - Du Preez, Pierre A1 - Stuart-Hill, Greg A1 - Jago, Mark A1 - Wegmann, Martin T1 - Home on the Range: Factors Explaining Partial Migration of African Buffalo in a Tropical Environment JF - PLoS One N2 - Partial migration (when only some individuals in a population undertake seasonal migrations) is common in many species and geographical contexts. Despite the development of modern statistical methods for analyzing partial migration, there have been no studies on what influences partial migration in tropical environments. We present research on factors affecting partial migration in African buffalo (Syncerus caffer) in northeastern Namibia. Our dataset is derived from 32 satellite tracking collars, spans 4 years and contains over 35,000 locations. We used remotely sensed data to quantify various factors that buffalo experience in the dry season when making decisions on whether and how far to migrate, including potential man-made and natural barriers, as well as spatial and temporal heterogeneity in environmental conditions. Using an information-theoretic, non-linear regression approach, our analyses showed that buffalo in this area can be divided into 4 migratory classes: migrants, non-migrants, dispersers, and a new class that we call "expanders". Multimodel inference from least-squares regressions of wet season movements showed that environmental conditions (rainfall, fires, woodland cover, vegetation biomass), distance to the nearest barrier (river, fence, cultivated area) and social factors (age, size of herd at capture) were all important in explaining variation in migratory behaviour. The relative contributions of these variables to partial migration have not previously been assessed for ungulates in the tropics. Understanding the factors driving migratory decisions of wildlife will lead to better-informed conservation and land-use decisions in this area. KW - Savannas KW - utilization distributions KW - movement ecology KW - predation risk KW - animal ecology KW - South Africa KW - size KW - conservation KW - Serengeti KW - ecosystem Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134935 VL - 7 IS - 5 ER - TY - JOUR A1 - Roesler, Joachim A1 - Segerer, Florian A1 - Morbach, Henner A1 - Kleinert, Stefan A1 - Thieme, Sebastian A1 - Rösen-Wolff, Angela A1 - Liese, Johannes G. T1 - P67-phox (NCF2) Lacking Exons 11 and 12 Is Functionally Active and Leads to an Extremely Late Diagnosis of Chronic Granulomatous Disease (CGD) JF - PLoS One N2 - Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000+2T -> G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage. KW - P67(PHOX) KW - NADPH oxidase KW - European experience KW - interferon gamma KW - gene KW - region KW - prophylaxis KW - infection KW - mutation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134948 VL - 7 IS - 4 ER - TY - JOUR A1 - Ronchi, Cristina L. A1 - Leich, Ellen A1 - Sbiera, Silviu A1 - Weismann, Dirk A1 - Rosenwald, Andreas A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways JF - Neoplasia N2 - The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors. KW - kinase KW - comparative genomic hybridization KW - high-resolution analysis KW - Cushings syndrome KW - neutral loss KW - tumors KW - serum KW - expression KW - carcinoma KW - catenin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134953 VL - 14 IS - 3 ER - TY - JOUR A1 - Moremi, Nyambura A1 - Mshana, Stephen E. A1 - Kamugisha, Erasmus A1 - Kataraihya, Johannes B. A1 - Tappe, Dennis A1 - Vogel, Ulrich A1 - Lyamuya, Eligius F. A1 - Claus, Heike T1 - Predominance of methicillin resistant Staphylococcus aureus-ST88 and new ST1797 causing wound infection and abscesses JF - Journal of Infection in Developing Countries N2 - Introduction: Although there has been a worldwide emergence and spread of methicillin-resistant Staphylococcus aureus (MRSA), little is known about the molecular epidemiology of MRSA in Tanzania. Methodology: In this study, we characterized MRSA strains isolated from clinical specimens at the Bugando Medical Centre, Tanzania, between January and December 2008. Of 160 S. aureus isolates from 600 clinical specimens, 24 (15%) were found to be MRSA. Besides molecular screening for the Panton Valentine leukocidin (PVL) genes by PCR, MRSA strains were further characterized by Multi-Locus Sequence Typing (MLST) and spa typing. Results: Despite considerable genetic diversity, the spa types t690 (29.1%) and t7231 (41.6%), as well as the sequence types (ST) 88 (54.2%) and 1797 (29.1%), were dominant among clinical isolates. The PVL genes were detected in 4 isolates; of these, 3 were found in ST 88 and one in ST1820. Resistance to erythromycin, clindamicin, gentamicin, tetracycline and co-trimoxazole was found in 45.8%, 62.5%, 41.6%, 45.8% and 50% of the strains, respectively. Conclusion: We present the first thorough typing of MRSA at a Tanzanian hospital. Despite considerable genetic diversity, ST88 was dominant among clinical isolates at the Bugando Medical Centre. Active and standardized surveillance of nosocomial MRSA infection should be conducted in the future to analyse the infection and transmission rates and implement effective control measures. KW - Tanzania KW - panton-valentine leukocidin KW - field gel-electrophoreresis KW - molecular epidemiology KW - aureus infections KW - MRSA KW - ST88 KW - ST1797 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134746 VL - 6 IS - 8 ER - TY - JOUR A1 - Hardcastle, Nicholas A1 - Tomé, Wolfgang A. A1 - Cannon, Donald M. A1 - Brouwer, Charlotte L. A1 - Wittendorp, Paul W. H. A1 - Dogan, Nesrin A1 - Guckenberger, Matthias A1 - Allaire, Stéphane A1 - Mallya, Yogish A1 - Kumar, Prashant A1 - Oechsner, Markus A1 - Richter, Anne A1 - Song, Shiyu A1 - Myers, Michael A1 - Polat, Bülent A1 - Bzdusek, Karl T1 - A multi-institution evaluation of deformable image registration algorithms for automatic organ delineation in adaptive head and neck radiotherapy JF - Radiation Oncology N2 - Background: Adaptive Radiotherapy aims to identify anatomical deviations during a radiotherapy course and modify the treatment plan to maintain treatment objectives. This requires regions of interest (ROIs) to be defined using the most recent imaging data. This study investigates the clinical utility of using deformable image registration (DIR) to automatically propagate ROIs. Methods: Target (GTV) and organ-at-risk (OAR) ROIs were non-rigidly propagated from a planning CT scan to a per-treatment CT scan for 22 patients. Propagated ROIs were quantitatively compared with expert physician-drawn ROIs on the per-treatment scan using Dice scores and mean slicewise Hausdorff distances, and center of mass distances for GTVs. The propagated ROIs were qualitatively examined by experts and scored based on their clinical utility. Results: Good agreement between the DIR-propagated ROIs and expert-drawn ROIs was observed based on the metrics used. 94% of all ROIs generated using DIR were scored as being clinically useful, requiring minimal or no edits. However, 27% (12/44) of the GTVs required major edits. Conclusion: DIR was successfully used on 22 patients to propagate target and OAR structures for ART with good anatomical agreement for OARs. It is recommended that propagated target structures be thoroughly reviewed by the treating physician. KW - intensity-modulated radiotherapy KW - megavoltage computed-tomography KW - cancer KW - variability KW - strategies KW - risk Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134756 VL - 7 IS - 90 ER - TY - JOUR A1 - Van de Kerkhof, Noortje W. A. A1 - Feenstra, Ilse A1 - van der Heijden, Frank M. M. A. A1 - de Leeuw, Nicole A1 - Pfundt, Rolph A1 - Stöber, Gerald A1 - Egger, Jos I. M. A1 - Verhoeven, Willem M. A. T1 - Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice? JF - Neuropsychiatric Disease and Treatment N2 - With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment. KW - microarrays KW - spectrum disorders KW - schizophrenia KW - gene KW - psychopathology KW - polymorphisms KW - microdeletion KW - perspectives KW - association KW - environment KW - copy number variants KW - 1q21 KW - 7q11.2 KW - 1p13.3 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134769 VL - 8 ER - TY - JOUR A1 - van de Kerkhof, Noortje W. A. A1 - van der Heijden, Frank M. M. A. A1 - Schneider, Marc K. F. A1 - Pfuhlmann, Bruno A1 - Stöber, Gerald A1 - Egger, Jos I. M. A1 - Verhoeven, Willem M. A. T1 - Cycloid psychoses: Leonhard's descriptions revisited JF - European Journal of Psychiatry N2 - Background and Objectives: Cycloid psychoses are characterized by polymorphic symptomatology with intraphasic bipolarity, a remitting and recurrent course and favourable prognosis. Perris and Brocicington (P&B) described the first set of operational criteria that were partly incorporated in ICD-10. The present study investigates psychopathological profiles according to the P&B criteria and the original descriptions by Leonhard, both against the background of the criteria from the prevailing international classification systems. Methods: Eighty patients with psychotic disorders were recruited and assessed with various psychometric instruments at baseline and after six weeks of antipsychotic treatment in order to investigate the presence of cycloid psychoses according to Leonhard (LCP) and the effect of treatment with antipsychotics. The overlap between LCP and DSM-IV Brief Psychotic Disorder (BPD), ICD Acute Polymorphic Psychotic Disorder (APP) and P&B criteria was calculated. Results: Using P&B criteria and a symptom checklist adapted from the original descriptions by Leonhard, 14 and 12 cases of cycloid psychosis were identified respectively reflecting a prevalence of 15-18%. Small though significant concordance rates were found between LCP and both DSM-BPD and ICD-APP. Concordance between LCP and P&B criteria was also significant, but modest. Conclusions: This study demonstrates that LCP can be identified in a substantial number of patients with psychotic disorders. Cycloid psychoses are not adequately covered in current classification systems and criteria. Since they are demonstrated to have a specific psychopathological profile, relapsing course and favourable prognosis, it is advocated to include these psychoses in daily differential diagnostic procedures. KW - P300 KW - endogenous psychoses KW - follow-up KW - schizophrenia KW - disorder KW - classification KW - validity KW - family Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134779 VL - 26 IS - 4 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study JF - BMC Nephrology N2 - Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23-6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8.15.7 +/- 14.3% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - XA KW - low molecular weight KW - severe renal insufficiency KW - unfractionated heparin KW - standard heparin KW - enoxaparin KW - metaanalysis KW - coagulation KW - fragmin KW - sodium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134845 VL - 13 IS - 50 ER - TY - JOUR A1 - Brevoord, Daniel A1 - Kranke, Peter A1 - Kuijpers, Marijn A1 - Weber, Nina A1 - Hollmann, Markus A1 - Preckel, Benedikt T1 - Remote Ischemic Conditioning to Protect against Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis JF - PLoS One N2 - Background: Remote ischemic conditioning is gaining interest as potential method to induce resistance against ischemia reperfusion injury in a variety of clinical settings. We performed a systematic review and meta-analysis to investigate whether remote ischemic conditioning reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia reperfusion injury. Methods and Results: Medline, EMBASE and Cochrane databases were searched for randomized clinical trials comparing remote ischemic conditioning, regardless of timing, with no conditioning. Two investigators independently selected suitable trials, assessed trial quality and extracted data. 23 studies in patients undergoing cardiac surgery (15 studies), percutaneous coronary intervention (four studies) and vascular surgery (four studies), comprising in total 1878 patients, were included in this review. Compared to no conditioning, remote ischemic conditioning did not reduce mortality (odds ratio 1.22 [95% confidence interval 0.48, 3.07]) or major adverse cardiovascular events (0.65 [0.38, 1.14]). However, the incidence of myocardial infarction was reduced with remote ischemic conditioning (0.50 [0.31, 0.82]), as was peak troponin release (standardized mean difference -0.28 [-0.47, -0.09]). Conclusion: There is no evidence that remote ischemic conditioning reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events. However, remote ischemic conditioning did reduce the incidence of peri-procedural myocardial infarctions, as well as the release of troponin. KW - cardiac protection KW - stent KW - acute kidney injury KW - coronary artery bypass KW - randomized controlled trial KW - myocardial-infarction KW - aneurysm repair KW - graft surgery KW - humans KW - angioplasty Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134471 VL - 7 IS - 7 ER - TY - JOUR A1 - Molochnikov, Leonid A1 - Rabey, Jose M. A1 - Dobronevsky, Evgenya A1 - Bonuccelli, Ubaldo A1 - Ceravolo, Roberto A1 - Frosini, Daniela A1 - Grünblatt, Edna A1 - Riederer, Peter A1 - Jacob, Christian A1 - Aharon-Peretz, Judith A1 - Bashenko, Yulia A1 - Youdim, Moussa B. H. A1 - Mandel, Silvia A. T1 - A molecular signature in blood identifies early Parkinson's disease JF - Molecular Neurodegeneration N2 - Background: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. Results: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). Conclusions: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder. KW - cerebrospina KW - magnetic-resonance-spectroscopy KW - protein KW - biomarkers KW - E3 ubiquitin ligase KW - SCF KW - SKP1 KW - heat shock protein Hsc-70 KW - early diagnosis KW - fluid KW - alpha-synuclein KW - dehydrogenases KW - Alzheimer's disease KW - sporadic Parkinson's disease KW - blood biomarker KW - CSF KW - multiple system atrophy KW - clinical diagnosis KW - substantia nigra KW - gene expression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134508 VL - 7 IS - 26 ER - TY - JOUR A1 - Vieira, Jacqueline A1 - Jones, Alex R. A1 - Danon, Antoine A1 - Sakuma, Michiyo A1 - Hoang, Nathalie A1 - Robles, David A1 - Tait, Shirley A1 - Heyes, Derren J. A1 - Picot, Marie A1 - Yoshii, Taishi A1 - Helfrich-Förster, Charlotte A1 - Soubigou, Guillaume A1 - Coppee, Jean-Yves A1 - Klarsfeld, André A1 - Rouyer, Francois A1 - Scrutton, Nigel S. A1 - Ahmad, Margaret T1 - Human Cryptochrome-1 Confers Light Independent Biological Activity in Transgenic Drosophila Correlated with Flavin Radical Stability JF - PLoS One N2 - Cryptochromes are conserved flavoprotein receptors found throughout the biological kingdom with diversified roles in plant development and entrainment of the circadian clock in animals. Light perception is proposed to occur through flavin radical formation that correlates with biological activity in vivo in both plants and Drosophila. By contrast, mammalian (Type II) cryptochromes regulate the circadian clock independently of light, raising the fundamental question of whether mammalian cryptochromes have evolved entirely distinct signaling mechanisms. Here we show by developmental and transcriptome analysis that Homo sapiens cryptochrome - 1 (HsCRY1) confers biological activity in transgenic expressing Drosophila in darkness, that can in some cases be further stimulated by light. In contrast to all other cryptochromes, purified recombinant HsCRY1 protein was stably isolated in the anionic radical flavin state, containing only a small proportion of oxidized flavin which could be reduced by illumination. We conclude that animal Type I and Type II cryptochromes may both have signaling mechanisms involving formation of a flavin radical signaling state, and that light independent activity of Type II cryptochromes is a consequence of dark accumulation of this redox form in vivo rather than of a fundamental difference in signaling mechanism. KW - arabidopsi KW - dependent magnetosensitvity KW - protein KW - clock KW - gene KW - mechanism KW - rhythm KW - oscillator KW - circadian photoreception KW - mammalian CRY1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134513 VL - 7 IS - 3 ER - TY - JOUR A1 - Heddergott, Niko A1 - Krüger, Timothy A1 - Babu, Sujin B. A1 - Wei, Ai A1 - Stellamanns, Erik A1 - Uppaluri, Sravanti A1 - Pfohl, Thomas A1 - Stark, Holger A1 - Engstler, Markus T1 - Trypanosome Motion Represents an Adaptation to the Crowded Environment of the Vertebrate Bloodstream JF - PLoS Pathogens N2 - Blood is a remarkable habitat: it is highly viscous, contains a dense packaging of cells and perpetually flows at velocities varying over three orders of magnitude. Only few pathogens endure the harsh physical conditions within the vertebrate bloodstream and prosper despite being constantly attacked by host antibodies. African trypanosomes are strictly extracellular blood parasites, which evade the immune response through a system of antigenic variation and incessant motility. How the flagellates actually swim in blood remains to be elucidated. Here, we show that the mode and dynamics of trypanosome locomotion are a trait of life within a crowded environment. Using high-speed fluorescence microscopy and ordered micro-pillar arrays we show that the parasites mode of motility is adapted to the density of cells in blood. Trypanosomes are pulled forward by the planar beat of the single flagellum. Hydrodynamic flow across the asymmetrically shaped cell body translates into its rotational movement. Importantly, the presence of particles with the shape, size and spacing of blood cells is required and sufficient for trypanosomes to reach maximum forward velocity. If the density of obstacles, however, is further increased to resemble collagen networks or tissue spaces, the parasites reverse their flagellar beat and consequently swim backwards, in this way avoiding getting trapped. In the absence of obstacles, this flagellar beat reversal occurs randomly resulting in irregular waveforms and apparent cell tumbling. Thus, the swimming behavior of trypanosomes is a surprising example of micro-adaptation to life at low Reynolds numbers. For a precise physical interpretation, we compare our high-resolution microscopic data to results from a simulation technique that combines the method of multi-particle collision dynamics with a triangulated surface model. The simulation produces a rotating cell body and a helical swimming path, providing a functioning simulation method for a microorganism with a complex swimming strategy. KW - simulation KW - multiparticle collision dynamics KW - propulsion KW - viscosity KW - flagellar KW - motility KW - solvent KW - model KW - hydrodynamics KW - spiroplasma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134595 VL - 8 IS - 11 ER - TY - JOUR A1 - Darwish, Hany W. A1 - Attia, Mohamed I. T1 - New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl} acetamide: a contaminant in commercial melatonin preparations JF - Chemistry Central Journal N2 - Background: Melatonin (MLT) has many health implications, therefore it is of valuable importance to develop specific analytical methods for determination of MLT in the presence of its main contaminant, N-{2-[1-({3-[2(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (10). For development of these analytical methods, compound 10 had to be prepared in an adequate amount. Results: Compound 10 was synthesized in six steps starting from 5-methoxyindole-2-carboxylic acid (1). Analytical performance of the proposed spectrofluorimetric methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 60 % of compound 10 and in commercial MLT tablets with recoveries not less than 99.00 %. No interference was observed from common pharmaceutical additives and the results were favorably compared with those obtained by a reference method. Conclusions: This work describes simple, sensitive, and reliable second derivative spectrofluorimetric method in addition to two multivariate calibration methods, principal component regression (PCR) and partial least square (PLS), for the determination of MLT in the presence of compound 10. KW - melatonin KW - commercial preparations KW - spectrofluorimetry KW - synthesis KW - contaminants Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134606 VL - 6 IS - 36 ER - TY - JOUR A1 - Gresle, Melissa M. A1 - Alexandrou, Estella A1 - Wu, Qizhu A1 - Egan, Gary A1 - Jokubaitis, Vilija A1 - Ayers, Margaret A1 - Jonas, Anna A1 - Doherty, William A1 - Friedhuber, Anna A1 - Shaw, Gerry A1 - Sendtner, Michael A1 - Emery, Ben A1 - Kilpatrick, Trevor A1 - Butzkueven, Helmut T1 - Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism JF - PLoS One N2 - Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG\(_{35-55}\) EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1\(\pm\)0.14 vs 2.6\(\pm\)0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540\(\pm\)207 \(\mu\)m\(^2\)-/s vs 1310\(\pm\)175 \(\mu\)m\(^2\)-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism. KW - receptor KW - ciliary neurotrophic factor KW - mulitple-sclerosis patients KW - factor prevents KW - demyelination KW - survival KW - neurons KW - injury KW - degeneration KW - motoneurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134617 VL - 7 IS - 10 ER - TY - JOUR A1 - Poppe, Lidia Marilia A1 - Anders, Diana A1 - Kneitz, Hermann A1 - Bröcker, Eva-Bettina A1 - Benoit, Sandrine T1 - Flagellate dermatitis caused by shiitake mushrooms T1 - Dermatite flagelada após a ingestão de fungos shiitake JF - Anais Brasileiros de Dermatologia N2 - Shiitake (Lentinus edodes) is the second most consumed mushroom in the world. It has long been known in Asian medicine for its anticarcinogenic, antihypertensive and serum cholesterol level reduction properties. Nevertheless, the consumption of raw or not well-cooked mushrooms may cause skin eruptions which usually occur 24 to 48 hours after ingestion and are characterized by linearly arranged pruritic erythematous papules and plaques. We present a 36-year-old patient that developed typical symptoms 24 hours after consumption of shiitake mushrooms and summarize therapeutic options and particularities of this disease. N2 - Shiitake (Lentinus edodes) é o segundo tipo de cogumelo mais consumido no mundo. Suas propriedades terapêuticas antitumorais, anti-hipertensivas e redutoras dos níveis elevados de colesterol são há muito conhecidas pela população asiática. Após ingestão desse cogumelo, cru ou malcozido, podem desenvolver-se lesões eritematosas lineares, pruriginosas, que surgem após 24 ou 48 horas em todo o corpo. Apresentamos um paciente de 36 anos com anamnese e clínica típicos, e comentamos as alternativas terapêuticas e nuances dessa dermatose. KW - bleomicina KW - shiitake-dermatite KW - bleomycin KW - flagellate dermatitis KW - shiitake dermatitis KW - shiitake mushrooms KW - dermatite flagelada KW - fungos shiitake Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134362 VL - 87 IS - 3 ER - TY - JOUR A1 - Gruss, L. Forest A1 - Wieser, Matthias J. A1 - Schweinberger, Stefan R. A1 - Keil, Andreas T1 - Face-evoked steady-state visual potentials: effects of presentation rate and face inversion JF - Frontiers in Human Neuroscience N2 - Face processing can be explored using electrophysiological methods. Research with event-related potentials has demonstrated the so-called face inversion effect, in which the N170 component is enhanced in amplitude and latency to inverted, compared to upright, faces. The present study explored the extent to which repetitive lower-level visual cortical engagement, reflected in flicker steady-state visual evoked potentials (ssVEPs), shows similar amplitude enhancement to face inversion. We also asked if inversion-related ssVEP modulation would be dependent on the stimulation rate at which upright and inverted faces were flickered. To this end, multiple tagging frequencies were used (5, 10, 15, and 20 Hz) across two studies (n=21, n=18). Results showed that amplitude enhancement of the ssVEP for inverted faces was found solely at higher stimulation frequencies (15 and 20 Hz). By contrast, lower frequency ssVEPs did not show this inversion effect. These findings suggest that stimulation frequency affects the sensitivity of ssVEPs to face inversion. KW - N170 KW - upside-down faces KW - selective attention KW - spatial attention KW - cortex KW - perception KW - recognition KW - brain KW - FMRI KW - area Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134399 VL - 6 IS - 316 ER - TY - JOUR A1 - Brecht, Isabel A1 - Weissbrich, Benedikt A1 - Braun, Julia A1 - Toyka, Klaus Viktor A1 - Weishaupt, Andreas A1 - Buttmann, Mathias T1 - Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis JF - PLoS One N2 - Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated. KW - MS KW - cerebrospinal fluid KW - differential diagnosis KW - nervous-system KW - criteria KW - serum Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134426 VL - 7 IS - 7 ER - TY - JOUR A1 - Nanguneri, Siddharth A1 - Flottmann, Benjamin A1 - Horstmann, Heinz A1 - Heilemann, Mike A1 - Kuner, Thomas T1 - Three-Dimensional, Tomographic Super-Resolution Fluorescence Imaging of Serially Sectioned Thick Samples JF - PLoS One N2 - Three-dimensional fluorescence imaging of thick tissue samples with near-molecular resolution remains a fundamental challenge in the life sciences. To tackle this, we developed tomoSTORM, an approach combining single-molecule localization-based super-resolution microscopy with array tomography of structurally intact brain tissue. Consecutive sections organized in a ribbon were serially imaged with a lateral resolution of 28 nm and an axial resolution of 40 nm in tissue volumes of up to 50 \(\mu\)mx50\(\mu\)mx2.5\(\mu\)m. Using targeted expression of membrane bound (m)GFP and immunohistochemistry at the calyx of Held, a model synapse for central glutamatergic neurotransmission, we delineated the course of the membrane and fine-structure of mitochondria. This method allows multiplexed super-resolution imaging in large tissue volumes with a resolution three orders of magnitude better than confocal microscopy. KW - architecture KW - rat calyx KW - in-vivo KW - microscopy KW - resolution KW - proteins KW - transmission KW - ultrastructure KW - reconstruction KW - localization Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134434 VL - 7 IS - 5 ER - TY - JOUR A1 - Schokraie, Elham A1 - Warnken, Uwe A1 - Hotz-Wagenblatt, Agnes A1 - Grohme, Markus A. A1 - Hengherr, Steffen A1 - Förster, Frank A1 - Schill, Ralph O. A1 - Frohme, Marcus A1 - Dandekar, Thomas A1 - Schnölzer, Martina T1 - Comparative proteome analysis of Milnesium tardigradum in early embryonic state versus adults in active and anhydrobiotic state JF - PLoS One N2 - Tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. However, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. Our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. High-throughput, high-accuracy proteomics in combination with a newly developed tardigrade specific protein database resulted in the identification of more than 3000 proteins in three different states: early embryonic state and adult animals in active and anhydrobiotic state. This comprehensive proteome resource includes protein families such as chaperones, antioxidants, ribosomal proteins, cytoskeletal proteins, transporters, protein channels, nutrient reservoirs, and developmental proteins. A comparative analysis of protein families in the different states was performed by calculating the exponentially modified protein abundance index which classifies proteins in major and minor components. This is the first step to analyzing the proteins involved in early embryonic development, and furthermore proteins which might play an important role in the transition into the anhydrobiotic state. KW - life-span regulation KW - genes KW - Yolk protein KW - water stress KW - expression KW - tolerance KW - richtersius coronifer KW - superoxide-dismutase KW - caenorhabditis elegans KW - arabidopsis thaliana KW - vitellogenin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134447 VL - 7 IS - 9 ER - TY - JOUR A1 - Jäger, Dominik A1 - Pernitzsch, Sandy R. A1 - Richter, Andreas S. A1 - Backofen, Rolf A1 - Sharma, Cynthia M. A1 - Schmitz, Ruth A. T1 - An archaeal sRNA targeting cis- and trans-encoded mRNAs via two distinct domains JF - Nucleic Acids Research N2 - We report on the characterization and target analysis of the small (s) RNA\(_{162}\) in the methanoarchaeon Methanosarcina mazei. Using a combination of genetic approaches, transcriptome analysis and computational predictions, the bicistronic MM2441-MM2440 mRNA encoding the transcription factor MM2441 and a protein of unknown function was identified as a potential target of this sRNA, which due to processing accumulates as three stabile 5' fragments in late exponential growth. Mobility shift assays using various mutants verified that the non-structured single-stranded linker region of sRNA\(_{162}\) (SLR) base-pairs with the MM2440-MM2441 mRNA internally, thereby masking the predicted ribosome binding site of MM2441. This most likely leads to translational repression of the second cistron resulting in dis-coordinated operon expression. Analysis of mutant RNAs in vivo confirmed that the SLR of sRNA\(_{162}\) is crucial for target interactions. Furthermore, our results indicate that sRNA\(_{162}\)-controlled MM2441 is involved in regulating the metabolic switch between the carbon sources methanol and methylamine. Moreover, biochemical studies demonstrated that the 50 end of sRNA\(_{162}\) targets the 5'-untranslated region of the cis-encoded MM2442 mRNA. Overall, this first study of archaeal sRNA/mRNA-target interactions unraveled that sRNA\(_{162}\) acts as an antisense (as) RNA on cis- and trans-encoded mRNAs via two distinct domains, indicating that cis-encoded asRNAs can have larger target regulons than previously anticipated. KW - strain KW - escherichia coli KW - methanosarcina mazei GO1 KW - methanol methyltransferase isozymes KW - small nucleolar RNAs KW - acetivorans C2A KW - antisense RNAs KW - GO1 KW - transcriptional regulator KW - translational initiation KW - pyrococcus furiosus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134972 VL - 40 IS - 21 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Kroner, Antje A1 - Groh, Janos A1 - Huber, Marianne A1 - Klein, Dennis A1 - Spahn, Irene A1 - Diem, Ricarda A1 - Williams, Sarah K. A1 - Nave, Klaus-Armin A1 - Edgar, Julia M. A1 - Martini, Rudolf T1 - Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse JF - PLoS One N2 - Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. KW - myelin KW - experimental autoimmune encephalomyelitis KW - degeneration KW - axonopathic changes KW - neural apoptosis KW - nervous system KW - motor function KW - proteolipid protein gene KW - retinal ganglion cells KW - granzyme B KW - multiple sclerosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134982 VL - 7 IS - 8 ER - TY - JOUR A1 - Kneissl, Sabrina A1 - Abel, Tobias A1 - Rasbach, Anke A1 - Brynza, Julia A1 - Schneider-Schaulies, Jürgen A1 - Buchholz, Christian J. T1 - Measles Virus Glycoprotein-Based Lentiviral Targeting Vectors That Avoid Neutralizing Antibodies JF - PLoS One N2 - Lentiviral vectors (LVs) are potent gene transfer vehicles frequently applied in research and recently also in clinical trials. Retargeting LV entry to cell types of interest is a key issue to improve gene transfer safety and efficacy. Recently, we have developed a targeting method for LVs by incorporating engineered measles virus (MV) glycoproteins, the hemagglutinin (H), responsible for receptor recognition, and the fusion protein into their envelope. The H protein displays a single-chain antibody (scFv) specific for the target receptor and is ablated for recognition of the MV receptors CD46 and SLAM by point mutations in its ectodomain. A potential hindrance to systemic administration in humans is pre-existing MV-specific immunity due to vaccination or natural infection. We compared transduction of targeting vectors and non-targeting vectors pseudotyped with MV glycoproteins unmodified in their ectodomains (MV-LV) in presence of \(\alpha\)-MV antibody-positive human plasma. At plasma dilution 1: 160 MV-LV was almost completely neutralized, whereas targeting vectors showed relative transduction efficiencies from 60% to 90%. Furthermore, at plasma dilution 1: 80 an at least 4-times higher multiplicity of infection (MOI) of MV-LV had to be applied to obtain similar transduction efficiencies as with targeting vectors. Also when the vectors were normalized to their p24 values, targeting vectors showed partial protection against \(\alpha\)-MV antibodies in human plasma. Furthermore, the monoclonal neutralizing antibody K71 with a putative epitope close to the receptor binding sites of H, did not neutralize the targeting vectors, but did neutralize MV-LV. The observed escape from neutralization may be due to the point mutations in the H ectodomain that might have destroyed antibody binding sites. Furthermore, scFv mediated cell entry via the target receptor may proceed in presence of a-MV antibodies interfering with entry via the natural MV receptors. These results are promising for in vivo applications of targeting vectors in humans. KW - vivo KW - gene delivery KW - hemagglutinin KW - cells KW - neurovirulence KW - encephalitis KW - transduction KW - domain Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134993 VL - 7 IS - 10 ER - TY - JOUR A1 - Masic, Anita A1 - Hurdayal, Ramona A1 - Nieuwenhuizen, Natalie E. A1 - Brombacher, Frank A1 - Moll, Heidrun T1 - Dendritic Cell-Mediated Vaccination Relies on Interleukin-4 Receptor Signaling to Avoid Tissue Damage after Leishmania major Infection of BALB/c Mice JF - PLoS Neglected Tropical Diseases N2 - Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is involved in the redirection of the immune response towards a type 1 profile, we were interested in further exploring the role of IL-4. Thus, wild-type (wt) BALB/c mice or DC-specific IL-4 receptor \(\alpha\) (IL-4R \(\alpha\))-deficient (CD11c\(^{cre}\)IL-4R \(\alpha^{-/lox}\) BALB/c mice were given either wt or IL-4R \(\alpha\)-deficient LmAg-loaded bone marrow-derived DC exposed or not to CpG ODN prior to inoculation of 2x10\(^5\) stationary-phase L. major promastigotes into the BALB/c footpad. The results provide evidence that IL4/IL-4R alpha-mediated signaling in the vaccinating DC is required to prevent tissue damage at the site of L. major inoculation, as properly conditioned wt DC but not IL-4R alpha-deficient DC were able to confer resistance. Furthermore, uncontrolled L. major population size expansion was observed in the footpad and the footpad draining lymph nodes of CD11c\(^{cre}\)IL-4R \(\alpha^{-/lox}\) mice immunized with CpG ODN-exposed LmAg-loaded IL-4R \(\alpha\)-deficient DC, indicating the influence of IL-4R \(\alpha\)-mediated signaling in host DC to control parasite replication. In addition, no footpad damage occurred in BALB/c mice that were systemically immunized with LmAg-loaded wt DC doubly exposed to CpG ODN and recombinant IL-4. We discuss these findings and suggest that the IL4/IL4R \(\alpha\) signaling pathway could be a key pathway to trigger when designing vaccines aimed to prevent damaging processes in tissues hosting intracellular microorganisms. KW - cytokines KW - necrosis-factor-alpha KW - T helper cell KW - visceral leishmaniasis KW - intracellular pathogen KW - interferon-gamma KW - IL-12 production KW - deficient mice KW - resistance KW - responses Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133869 VL - 6 IS - 7 ER - TY - JOUR A1 - Drechsler, Johannes A1 - Groetzinger, Joachim A1 - Hermanns, Heike M. T1 - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor JF - PLoS One N2 - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology. KW - in vitro KW - leukemia-inhibitory factor KW - ciliary neurotrophic factor KW - T cell development KW - swiss model KW - fetal liver KW - interleukin-6-type cytokines KW - rheumatoid arthritis KW - signal transduction KW - growth regulator Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133879 VL - 7 IS - 8 ER - TY - JOUR A1 - Neugebauer, Hermann A1 - Heuschmann, Peter U. A1 - Jüttler, Eric T1 - DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY - Registry (DESTINY-R): design and protocols JF - BMC Neurology N2 - Background: Randomized controlled trials (RCT) on the treatment of severe space-occupying infarction of the middle cerebral artery (malignant MCA infarction) showed that early decompressive hemicraniectomy (DHC) is life saving and improves outcome without promoting most severe disablity in patients aged 18-60 years. It is, however, unknown whether the results obtained in the randomized trials are reproducible in a broader population in and apart from an academical setting and whether hemicraniectomy has been implemented in clinical practice as recommended by national and international guidelines. In addition, they were not powered to answer further relevant questions, e. g. concerning the selection of patients eligible for and the timing of hemicraniectomy. Other important issues such as the acceptance of disability following hemicraniectomy, the existence of specific prognostic factors, the value of conservative therapeutic measures, and the overall complication rate related to hemicraniectomy have not been sufficiently studied yet. Methods/Design: DESTINY-R is a prospective, multicenter, open, controlled registry including a 12 months follow-up. The only inclusion criteria is unilateral ischemic MCA stroke affecting more than 50% of the MCA-territory. The primary study hypothesis is to confirm the results of the RCT (76% mRS <= 4 after 12 months) in the subgroup of patients additionally fulfilling the inclusion cirteria of the RCT in daily routine. Assuming a calculated proportion of 0.76 for successes and a sample size of 300 for this subgroup, the width of the 95% CI, calculated using Wilson's method, will be 0.096 with the lower bound 0.709 and the upper bound 0.805. Discussion: The results of this study will provide information about the effectiveness of DHC in malignant MCA infarction in a broad population and a real-life situation in addition to and beyond RCT. Further prospectively obtained data will give crucial information on open questions and will be helpful in the plannig of upcomming treatment studies. KW - registry KW - quality of life KW - territory infaction KW - brain edema KW - hemicraniectomy KW - multicenter KW - crantiectomy KW - predictors KW - stroke KW - trial KW - decompressive surgery KW - ischaemic stroke KW - malignant MCA infarct Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133892 VL - 12 IS - 115 ER - TY - JOUR A1 - Hommers, Wilfried A1 - Lewand, Martin A1 - Ehrmann, Dominic T1 - Testing the moral algebra of two Kohlbergian informers JF - Psícologica N2 - This paper seeks to unify two major theories of moral judgment: Kohlberg's stage theory and Anderson's moral information integration theory. Subjects were told about thoughts of actors in Kohlberg's classic altruistic Heinz dilemma and in a new egoistical dilemma. These actors's thoughts represented Kohlberg's stages I (Personal Risk) and IV (Societal Risk) and had three levels, High, Medium, and Low. They were presented singly and in a 3 x 3 integration design. Subjects judged how many months of prison the actor deserved. The data supported the averaging model of moral integration theory, whereas Kohlberg's theory has no way to handle the integration problem. Following this, subjects ranked statements related to Kohlberg's first four stages in a procedure similar to that of Rest (1975). Higher score went with larger effect of Societal Risk as predicted by Kohlberg's theory. But contrary to Kohlberg's theory, no age trends were found. Also strongly contrary to Kohlberg's theory, effects of Personal Risk (Stage I) and Societal Risk (Stage IV) correlated positively. KW - integration KW - information KW - judgements KW - intent KW - damage KW - rules Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133917 VL - 33 IS - 3 ER - TY - JOUR A1 - Schwitter, Juerg A1 - Wacker, Christian M. A1 - Wilke, Norbert A1 - Al-Saadi, Nidal A1 - Sauer, Ekkehart A1 - Huettle, Kalman A1 - Schönberg, Stefan O. A1 - Debl, Kurt A1 - Strohm, Oliver A1 - Ahlstrom, Hakan A1 - Dill, Thorsten A1 - Hoebel, Nadja A1 - Simor, Tamas T1 - Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial) JF - Journal of Cardiovascular Magnetic Resonance N2 - Background: Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. Methods: In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. Results: The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated-SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1-3 vessel disease and p = 0.015, n = 140 in MVD). Conclusion: In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. KW - coronary disease KW - perfusion KW - contrast KW - ischemia KW - women KW - emission-computed-tomography KW - noninvasive detection KW - intervention KW - randomized-trial KW - cardiovascular magnetic resonance KW - stress perfusion KW - prognostic value KW - angiography KW - scintigraphy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134256 VL - 14 IS - 61 ER - TY - JOUR A1 - Kotte, K. A1 - Löw, F. A1 - Huber, S. G. A1 - Krause, T. A1 - Mulder, I. A1 - Schöler, H. F. T1 - Organohalogen emissions from saline environments - spatial extrapolation using remote sensing as most promising tool JF - Biogeosciences N2 - Due to their negative water budget most recent semi-/arid regions are characterized by vast evaporates (salt lakes and salty soils). We recently identified those hyper-saline environments as additional sources for a multitude of volatile halogenated organohalogens (VOX). These compounds can affect the ozone layer of the stratosphere and play a key role in the production of aerosols. A remote sensing based analysis was performed in the Southern Aral Sea basin, providing information of major soil types as well as their extent and spatial and temporal evolution. VOX production has been determined in dry and moist soil samples after 24 h. Several C1- and C2 organohalogens have been found in hyper-saline topsoil profiles, including CH3Cl, CH3Br, CHBr3 and CHCl3. The range of organohalogens also includes trans-1,2-dichloroethene (DCE), which is reported here to be produced naturally for the first time. Using MODIS time series and supervised image classification a daily production rate for DCE has been calculated for the 15 000 km\(^2\) ranging research area in the southern Aralkum. The applied laboratory setup simulates a short-term change in climatic conditions, starting from dried-out saline soil that is instantly humidified during rain events or flooding. It describes the general VOX production potential, but allows only for a rough estimation of resulting emission loads. VOX emissions are expected to increase in the future since the area of salt affected soils is expanding due to the regressing Aral Sea. Opportunities, limits and requirements of satellite based rapid change detection and salt classification are discussed. KW - aral sea basin KW - methyl-bromide KW - methane emissions KW - abiotic formation KW - time series KW - salt lakes KW - land KW - Uzbekistan KW - soils/sediments KW - classifiaction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134265 VL - 9 IS - 3 ER - TY - JOUR A1 - Rahimi, Kazem A1 - Bhala, Neeraj A1 - Kamphuisen, Pieter A1 - Emberson, Jonathan A1 - Biere-Rafi, Sara A1 - Krane, Vera A1 - Robertson, Michele A1 - Wikstrand, John A1 - McMurray, John T1 - Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials JF - PLoS Medicine N2 - Background: It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. Methods and Findings: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78-1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72-1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76-1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82-1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80-1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Conclusions: The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out. Please see later in the article for the Editors' Summary. KW - deep-vein thrombosis KW - cardiovascular disease KW - placebo-controlled trial KW - coronary-heart-disease KW - coa reductase inhibitors KW - lipid-lowering therapy KW - high-dose atorvastatin KW - myocardial-infarction KW - primary prevention KW - double-blind Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134279 VL - 9 IS - 9 ER - TY - JOUR A1 - Nono, Justin Komguep A1 - Pletinckx, Katrien A1 - Lutz, Manfred B. A1 - Brehm, Klaus T1 - Excretory/Secretory-Products of Echinococcus multilocularis Larvae Induce Apoptosis and Tolerogenic Properties in Dendritic Cells In Vitro JF - PLoS Neglected Tropical Diseases N2 - 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. KW - granulosus KW - hydatid disease KW - metacestode vesicles KW - antigen-B KW - alveoar echinococcosis KW - TGF-BETA KW - regulatory T cells KW - gene expression KW - Brugia Malayi KW - TNF-alpha Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134280 VL - 6 IS - 2 ER - TY - JOUR A1 - Prugger, Christof A1 - Heidrich, Jan A1 - Wellmann, Jürgen A1 - Dittrich, Ralf A1 - Brand, Stefan-Martin A1 - Telgmann, Ralph A1 - Breithardt, Günter A1 - Reinecke, Holger A1 - Scheld, Hans A1 - Kleine-Katthöfer, Peter A1 - Heuschmann, Peter U. A1 - Keil, Ulrich T1 - Trends in Cardiovascular Risk Factors Among Patients With Coronary Heart Disease : Results From the EUROASPIRE I, II, and III Surveys in the Münster Region JF - Deutsches Ärzteblatt International N2 - Background: Target values for cardiovascular risk factors in patients with coronary heart disease (CHD) are stated in guidelines for the prevention of cardiovascular disease. We studied secular trends in risk factors over a 12-year period among CHD patients in the region of Munster, Germany. Methods: The cross-sectional EUROASPIRE I, II and III surveys were performed in multiple centers across Europe. For all three, the Munster region was the participating German region. In the three periods 1995/96, 1999/2000, and 2006/07, the surveys included (respectively) 392, 402 and 457 <= 70-year-old patients with CHD in Munster who had sustained a coronary event at least 6 months earlier. Results: The prevalence of smoking remained unchanged, with 16.8% in EUROASPIRE I and II and 18.4% in EUROASPIRE III (p=0.898). On the other hand, high blood pressure and high cholesterol both became less common across the three EUROASPIRE studies (60.7% to 69.4% to 55.3%, and 94.3% to 83.4% to 48.1%, respectively; p<0.001 for both). Obesity became more common (23.0% to 30.6% to 43.1%, p<0.001), as did treatment with antihypertensive and lipid-lowering drugs (80.4% to 88.6% to 94.3%, and 35.0% to 67.4% to 87.0%, respectively; p<0.001 for both). Conclusion: The observed trends in cardiovascular risk factors under-score the vital need for better preventive strategies in patients with CHD. KW - smoking-cessation KW - follow up KW - primary-care physicians KW - myocardial infarction KW - secondary prevention KW - clinical practice KW - European countries KW - drug therapies KW - life style KW - task force Y1 - 2012 U6 - https://doi.org/10.3238/arztebl.2012.0303 VL - 109 IS - 17 ER - TY - JOUR A1 - Stölting, Miriam A1 - Wiesner, Christiane A1 - van Vliet, Vanessa A1 - Butt, Elke A1 - Pavenstädt, Hermann A1 - Linder, Stefan A1 - Kremerskothen, Joachim T1 - Lasp-1 Regulates Podosome Function JF - PLoS One N2 - Eukaryotic cells form a variety of adhesive structures to connect with their environment and to regulate cell motility. In contrast to classical focal adhesions, podosomes, highly dynamic structures of different cell types, are actively engaged in matrix remodelling and degradation. Podosomes are composed of an actin-rich core region surrounded by a ring-like structure containing signalling molecules, motor proteins as well as cytoskeleton-associated proteins. Lasp-1 is a ubiquitously expressed, actin-binding protein that is known to regulate cytoskeleton architecture and cell migration. This multidomain protein is predominantely present at focal adhesions, however, a second pool of Lasp-1 molecules is also found at lamellipodia and vesicle-like microdomains in the cytosol. In this report, we show that Lasp-1 is a novel component and regulator of podosomes. Immunofluorescence studies reveal a localization of Lasp-1 in the podosome ring structure, where it colocalizes with zyxin and vinculin. Life cell imaging experiments demonstrate that Lasp-1 is recruited in early steps of podosome assembly. A siRNA-mediated Lasp-1 knockdown in human macrophages affects podosome dynamics as well as their matrix degradation capacity. In summary, our data indicate that Lasp-1 is a novel component of podosomes and is involved in the regulation of podosomal function. KW - discrete KW - smooth muscle cells KW - microdomains KW - actin cytoskeleton KW - endothelial cells KW - epithelial cells KW - cancer cells KW - phosphorylation KW - invadopodia KW - dependent protein-kinase KW - camp signaling pathway Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134315 VL - 7 IS - 4 ER - TY - JOUR A1 - Vandenberg, Laura N. A1 - Chahoud, Ibrahim A1 - Heindel, Jerrold J. A1 - Padmanabhan, Vasantha A1 - Paumgartten, Francisco J. R. A1 - Schönfelder, Gilbert T1 - Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A T1 - Estudos de biomonitoração do sistema urinário, circulatório e tecidos indicam grande exposição ao Bisfenol A JF - Ciência & Saúde Coletiva N2 - Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. We examined many possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions. More than 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism were examined. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes. N2 - Bisfenol A (BPA) é um dos produtos químicos mais produzido em todo o mundo, e a exposição humana a ele é considerada onipresente. Assim, há preocupações de que a quantidade de BPA para o qual os seres humanos estão expostos podem causar efeitos adversos à saúde. Nós examinamos muitas possibilidades sobre o porquê estudos de biomonitorização e toxicocinética podem chegar a conclusões aparentemente conflitantes. Mais de 80 estudos publicados de biomonitorização humana que mediram a concentração de BPA em tecidos humanos, urina, sangue e outros fluidos, juntamente com dois estudos de toxicocinética do metabolismo humano BPA foram examinados. BPA não conjugado foi detectado no sangue (nonanogramas por mililitro gama), e BPA conjugado foi detectado na grande maioria das amostras de urina. Em contraste, estudos de toxico-cinética propuseram que os seres humanos não são internamente expostos ao BPA. Dados disponíveis de estudos de biomonitorização indicam que a população em geral está exposta ao BPA e em risco de exposição interna ao BPA não conjugado. Os dois estudos de toxicocinética, que sugeriram a exposição humana ao BPA é insignificante, têm deficiências significativas e estão diretamente refutados por outros estudos e, portanto não são confiáveis para fins de avaliação de risco. KW - human KW - performance liquid-chromatography KW - toxicocinética KW - serum KW - fluorescence detection KW - disrupting chemicals KW - endocrine disruptor KW - human exposure KW - PBPK/PBTK model KW - pregnancy KW - risk assessment KW - toxicokinetics KW - solid-phase extraction KW - tandem mass-spectrometry KW - HPLC-MS/MS method KW - environmental phenols KW - estrogen receptor KW - adipose tissue KW - disruptor endócrino KW - exposição humana KW - modelo PBPK/PBTK KW - gravidez KW - avaliação de risco Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134332 VL - 17 IS - 2 ER - TY - JOUR A1 - Steinmann, Diana A1 - Paelecke-Habermann, Yvonne A1 - Geinitz, Hans A1 - Aschoff, Raimund A1 - Bayerl, Anja A1 - Bölling, Tobias A1 - Bosch, Elisabeth A1 - Bruns, Frank A1 - Eichenseder-Seiss, Ute A1 - Gerstein, Johanna A1 - Gharbi, Nadine A1 - Hagg, Juliane A1 - Hipp, Matthias A1 - Kleff, Irmgard A1 - Müller, Axel A1 - Schäfer, Christof A1 - Schleicher, Ursula A1 - Sehlen, Susanne A1 - Theodorou, Marilena A1 - Wypior, Hans-Joachim A1 - Zehentmayr, Franz A1 - van Oorschot, Birgitt A1 - Vordermark, Dirk T1 - Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases JF - BMC Cancer N2 - Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information. KW - breast cancer KW - brain tumours KW - survival KW - validation KW - symptoms KW - EORTC-QLQ-C15-PAL KW - EORTC-BN20 KW - whole-brain radiotherapy KW - partitioning analysis RPA KW - cancer patients KW - lung cancer KW - prognostic index KW - radiation oncology KW - clinical trials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135254 VL - 12 IS - 283 ER - TY - JOUR A1 - Bender, Stephan A1 - Resch, Franz A1 - Klein, Christoph A1 - Renner, Tobias A1 - Fallgatter, Andreas J. A1 - Weisbrod, Matthias A1 - Romanos, Marcel T1 - Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder JF - PLoS One N2 - Background: Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. Methods: We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. Results: We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes. Conclusions: A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. KW - deficit-hyperactivity disorder KW - anticipatory mechanisms KW - motor preparation KW - TIC disorder KW - children KW - ADHD KW - methylphenidate KW - contingent negative-variation KW - continuous performance-test KW - slow cortical potentials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135262 VL - 7 IS - 6 ER - TY - JOUR A1 - Havik, Bjarte A1 - Degenhardt, Franziska A. A1 - Johansson, Stefan A1 - Fernandes, Carla P. D. A1 - Hinney, Anke A1 - Scherag, André A1 - Lybaek, Helle A1 - Djurovic, Srdjan A1 - Christoforou, Andrea A1 - Ersland, Kari M. A1 - Giddaluru, Sudheer A1 - O'Donovan, Michael C. A1 - Owen, Michael J. A1 - Craddock, Nick A1 - Mühleisen, Thomas W. A1 - Mattheisen, Manuel A1 - Schimmelmann, Benno G. A1 - Renner, Tobias A1 - Warnke, Andreas A1 - Herpertz-Dahlmann, Beate A1 - Sinzig, Judith A1 - Albayrak, Özgür A1 - Rietschel, Marcella A1 - Nöthen, Markus M. A1 - Bramham, Clive R. A1 - Werge, Thomas A1 - Hebebrand, Johannes A1 - Haavik, Jan A1 - Andreassen, Ole A. A1 - Cichon, Sven A1 - Steen, Vidar M. A1 - Le Hellard, Stephanie T1 - DCLK1 Variants Are Associated across Schizophrenia and Attention Deficit/Hyperactivity Disorder JF - PLoS One N2 - Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4x10\(^{-5}\) and 4x10\(^{-6}\), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity. KW - psychosis KW - deficit hyperactivity disorder KW - genome-wide association KW - bipolar disorder KW - VAL66MET polymorphism KW - doublecortine-like KW - genes KW - kinase KW - BDNF KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135285 VL - 7 IS - 4 ER - TY - JOUR A1 - Neuhoff, Nina A1 - Bruder, Jennifer A1 - Bartling, Jürgen A1 - Warnke, Andreas A1 - Remschmidt, Helmut A1 - Müller-Myhsok, Bertram A1 - Schulte-Körne, Gerd T1 - Evidence for the Late MMN as a Neurophysiological Endophenotype for Dyslexia JF - PLoS One N2 - Dyslexia affects 5-10% of school-aged children and is therefore one of the most common learning disorders. Research on auditory event related potentials (AERP), particularly the mismatch negativity (MMN) component, has revealed anomalies in individuals with dyslexia to speech stimuli. Furthermore, candidate genes for this disorder were found through molecular genetic studies. A current challenge for dyslexia research is to understand the interaction between molecular genetics and brain function, and to promote the identification of relevant endophenotypes for dyslexia. The present study examines MMN, a neurophysiological correlate of speech perception, and its potential as an endophenotype for dyslexia in three groups of children. The first group of children was clinically diagnosed with dyslexia, whereas the second group of children was comprised of their siblings who had average reading and spelling skills and were therefore "unaffected'' despite having a genetic risk for dyslexia. The third group consisted of control children who were not related to the other groups and were also unaffected. In total, 225 children were included in the study. All children showed clear MMN activity to/da/-/ba/ contrasts that could be separated into three distinct MMN components. Whilst the first two MMN components did not differentiate the groups, the late MMN component (300-700 ms) revealed significant group differences. The mean area of the late MMN was attenuated in both the dyslexic children and their unaffected siblings in comparison to the control children. This finding is indicative of analogous alterations of neurophysiological processes in children with dyslexia and those with a genetic risk for dyslexia, without a manifestation of the disorder. The present results therefore further suggest that the late MMN might be a potential endophenotype for dyslexia. KW - processing deficits KW - children KW - event-related potentials KW - mismatch negativity mmn KW - developmental dyslexia KW - reading disability KW - auditory discrimination KW - susceptibility gene KW - speech perception KW - novelty detection Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133686 VL - 7 IS - 5 ER - TY - JOUR A1 - Gross, Henrik A1 - Hennard, Christine A1 - Masouris, Ilias A1 - Cassel, Christian A1 - Barth, Stephanie A1 - Stober-Grässer, Ute A1 - Mamiani, Alfredo A1 - Moritz, Bodo A1 - Ostareck, Dirk A1 - Ostareck-Lederer, Antje A1 - Neuenkirchen, Nils A1 - Fischer, Utz A1 - Deng, Wen A1 - Leonhardt, Heinrich A1 - Noessner, Elfriede A1 - Kremmer, Elisabeth A1 - Grässer, Friedrich A. T1 - Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression JF - PLoS One N2 - The Epstein-Barr Virus (EBV) -encoded EBNA2 protein, which is essential for the in vitro transformation of B-lymphocytes, interferes with cellular processes by binding to proteins via conserved sequence motifs. Its Arginine-Glycine (RG) repeat element contains either symmetrically or asymmetrically di-methylated arginine residues (SDMA and ADMA, respectively). EBNA2 binds via its SDMA-modified RG-repeat to the survival motor neurons protein (SMN) and via the ADMA-RG-repeat to the NP9 protein of the human endogenous retrovirus K (HERV-K (HML-2) Type 1). The hypothesis of this work was that the methylated RG-repeat mimics an epitope shared with cellular proteins that is used for interaction with target structures. With monoclonal antibodies against the modified RG-repeat, we indeed identified cellular homologues that apparently have the same surface structure as methylated EBNA2. With the SDMA-specific antibodies, we precipitated the Sm protein D3 (SmD3) which, like EBNA2, binds via its SDMA-modified RG-repeat to SMN. With the ADMA-specific antibodies, we precipitated the heterogeneous ribonucleoprotein K (hnRNP K). Specific binding of the ADMA-antibody to hnRNP K was demonstrated using E. coli expressed/ADMA-methylated hnRNP K. In addition, we show that EBNA2 and hnRNP K form a complex in EBV-infected B-cells. Finally, hnRNP K, when co-expressed with EBNA2, strongly enhances viral latent membrane protein 2A (LMP2A) expression by an unknown mechanism as we did not detect a direct association of hnRNP K with DNA-bound EBNA2 in gel shift experiments. Our data support the notion that the methylated surface of EBNA2 mimics the surface structure of cellular proteins to interfere with or co-opt their functional properties. KW - SM proteins KW - protein argentine methyltranserase KW - motor-neuron protein KW - RNA-polymerase-II KW - messenger RNA KW - C-MYC KW - gene expression KW - splicing factor KW - down regulation KW - living cells Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133707 VL - 7 IS - 8 ER - TY - JOUR A1 - Grafe, T. Ulmar A1 - Preininger, Doris A1 - Sztatecsny, Marc A1 - Kasah, Rosli A1 - Dehling, J. Maximilian A1 - Proksch, Sebastian A1 - Hödl, Walter T1 - Multimodal Communication in a Noisy Environment: A Case Study of the Bornean Rock Frog Staurois parvus JF - PLoS One N2 - High background noise is an impediment to signal detection and perception. We report the use of multiple solutions to improve signal perception in the acoustic and visual modality by the Bornean rock frog, Staurois parvus. We discovered that vocal communication was not impaired by continuous abiotic background noise characterised by fast-flowing water. Males modified amplitude, pitch, repetition rate and duration of notes within their advertisement call. The difference in sound pressure between advertisement calls and background noise at the call dominant frequency of 5578 Hz was 8 dB, a difference sufficient for receiver detection. In addition, males used several visual signals to communicate with conspecifics with foot flagging and foot flashing being the most common and conspicuous visual displays, followed by arm waving, upright posture, crouching, and an open-mouth display. We used acoustic playback experiments to test the efficacy-based alerting signal hypothesis of multimodal communication. In support of the alerting hypothesis, we found that acoustic signals and foot flagging are functionally linked with advertisement calling preceding foot flagging. We conclude that S. parvus has solved the problem of continuous broadband low-frequency noise by both modifying its advertisement call in multiple ways and by using numerous visual signals. This is the first example of a frog using multiple acoustic and visual solutions to communicate in an environment characterised by continuous noise. KW - call KW - dart-poison frog KW - animal communication KW - auditory masking KW - acoustic communication KW - anthropogenic noise KW - courtship displays KW - traffic noise KW - higher pitch KW - signals Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133718 VL - 7 IS - 5 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Araragi, Naozumi A1 - Merker, Sören A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Mlinar, Boris A1 - Baccini, Gilda A1 - Mayer, Ute A1 - Proft, Florian A1 - Hamon, Michel A1 - Schmitt, Angelika G. A1 - Corradetti, Renato A1 - Lanfumey, Laurence A1 - Lesch, Klaus-Peter T1 - Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification JF - PLoS One N2 - Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2-/-) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT\(_{1A}\) and 5-HT\(_{1B}\) receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis. KW - lacking KW - knock-out mice KW - energy expenditure KW - locomotor activity KW - 5-HT transporter KW - anxiety like KW - receptors KW - behavior KW - tryptophan KW - nucleus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133728 VL - 7 IS - 8 ER - TY - JOUR A1 - Harrington, John M. A1 - Scelsi, Chris A1 - Hartel, Andreas A1 - Jones, Nicola G. A1 - Engstler, Markus A1 - Capewell, Paul A1 - MacLeod, Annette A1 - Hajduk, Stephen T1 - Novel African Trypanocidal Agents: Membrane Rigidifying Peptides JF - PLoS One N2 - The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini coordinate phosphates of the polar lipid headgroups. This mechanism reveals a necessary phenotype in bloodstream form African trypanosomes, high membrane fluidity, and we suggest that targeting the plasma membrane lipid bilayer as a whole may be a novel strategy for the development of new pharmaceutical agents. Additionally, the peptides we have described may be valuable tools for probing the biosynthetic machinery responsible for the unique composition and characteristics of African trypanosome plasma membranes. KW - depth KW - trypanosome lytic factor KW - signal peptides KW - cell surface KW - protein KW - brucei KW - environment KW - bilayers KW - binding KW - probes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135179 VL - 7 IS - 9 ER - TY - JOUR A1 - Wolter, Steffen A1 - Aizezers, Janis A1 - Fennel, Franziska A1 - Seidel, Marcus A1 - Würthner, Frank A1 - Kühn, Oliver A1 - Lochbrunner, Stefan T1 - Size-dependent exciton dynamics in one-dimensional perylene bisimide aggregates JF - New Journal of Physics N2 - The size-dependent exciton dynamics of one-dimensional aggregates of substituted perylene bisimides are studied by ultrafast transient absorption spectroscopy and kinetic Monte-Carlo simulations as a function of the excitation density and the temperature in the range of 25-90 degrees C. For low temperatures, the aggregates can be treated as infinite chains and the dynamics is dominated by diffusion-driven exciton-exciton annihilation. With increasing temperature the aggregates dissociate into small fragments consisting of very few monomers. This scenario is also supported by the time-dependent anisotropy deduced from polarization-dependent experiments. KW - rotational diffusion KW - spectroscopy KW - dyes KW - annihilation KW - migration KW - films Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135190 VL - 14 IS - 105027 ER - TY - JOUR A1 - Roier, Sandro A1 - Leitner, Deborah R. A1 - Iwashkiw, Jeremy A1 - Schild-Prüfert, Kristina A1 - Feldman, Mario F. A1 - Krohne, Georg A1 - Reidl, Joachim A1 - Schild, Stefan T1 - Intranasal Immunization with Nontypeable Haemophilus influenzae Outer Membrane Vesicles Induces Cross-Protective Immunity in Mice JF - PLoS One N2 - Haemophilus influenzae is a Gram-negative human-restricted bacterium that can act as a commensal and a pathogen of the respiratory tract. Especially nontypeable H. influenzae (NTHi) is a major threat to public health and is responsible for several infectious diseases in humans, such as pneumonia, sinusitis, and otitis media. Additionally, NTHi strains are highly associated with exacerbations in patients suffering from chronic obstructive pulmonary disease. Currently, there is no licensed vaccine against NTHi commercially available. Thus, this study investigated the utilization of outer membrane vesicles (OMVs) as a potential vaccine candidate against NTHi infections. We analyzed the immunogenic and protective properties of OMVs derived from various NTHi strains by means of nasopharyngeal immunization and colonization studies with BALB/c mice. The results presented herein demonstrate that an intranasal immunization with NTHi OMVs results in a robust and complex humoral and mucosal immune response. Immunoprecipitation revealed the most important immunogenic proteins, such as the heme utilization protein, protective surface antigen D15, heme binding protein A, and the outer membrane proteins P1, P2, P5 and P6. The induced immune response conferred not only protection against colonization with a homologous NTHi strain, which served as an OMV donor for the immunization mixtures, but also against a heterologous NTHi strain, whose OMVs were not part of the immunization mixtures. These findings indicate that OMVs derived from NTHi strains have a high potential to act as a vaccine against NTHi infections. KW - conjugate KW - obstructive pulmonary disease KW - vaccine KW - vibrio cholerae KW - detoxified lipooligosaccharide KW - nasopharyngeal colonization KW - functional characterization KW - growing escherichia coli KW - DNA-binding vesicles KW - otitis media KW - hemophilus influenzae Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135201 VL - 7 IS - 8 ER - TY - JOUR A1 - Leistner, Stefanie A1 - Benik, Steffen A1 - Laumeier, Inga A1 - Ziegler, Annerose A1 - Nieweler, Gabriele A1 - Nolte, Christian H. A1 - Heuschmann, Peter U. A1 - Audebert, Heinrich J. T1 - Secondary Prevention after Minor Stroke and TIA - Usual Care and Development of a Support Program JF - PLoS One N2 - Background: Effective methods of secondary prevention after stroke or TIA are available but adherence to recommended evidence-based treatments is often poor. The study aimed to determine the quality of secondary prevention in usual care and to develop a stepwise modeled support program. Methods: Two consecutive cohorts of patients with acute minor stroke or TIA undergoing usual outpatient care versus a secondary prevention program were compared. Risk factor control and medication adherence were assessed in 6-month follow-ups (6M-FU). Usual care consisted of detailed information concerning vascular risk factor targets given at discharge and regular outpatient care by primary care physicians. The stepwise modeled support program additionally employed up to four outpatient appointments. A combination of educational and behavioral strategies was employed. Results: 168 patients in the observational cohort who stated their openness to participate in a prevention program (mean age 64.7 y, admission blood pressure (BP): 155/84 mmHg) and 173 patients participating in the support program (mean age 67.6 y, BP: 161/84 mmHg) were assessed at 6 months. Proportions of patients with BP according to guidelines were 50% in usual-care and 77% in the support program (p<0.01). LDL<100 mg/dl was measured in 62 versus 71% (p = 0.12). Proportions of patients who stopped smoking were 50 versus 79% (p<0.01). 72 versus 89% of patients with atrial fibrillation were on oral anticoagulation (p = 0.09). Conclusions: Risk factor control remains unsatisfactory in usual care. Targets of secondary prevention were met more often within the supported cohort. Effects on (cerebro-)vascular recurrence rates are going to be assessed in a multicenter randomized trial. KW - atherothrombosis KW - multifactorial KW - clinical trial KW - hypertension KW - disease KW - transient ischemic attack KW - randomized controlled trial KW - cardiovascular risk factors KW - blood pressure KW - event rates Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135247 VL - 7 IS - 12 ER - TY - JOUR T1 - ATLAS search for a heavy gauge boson decaying to a charged lepton and a neutrino in pp collisions at √s=7 TeV JF - The European Physical Journal C N2 - 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. KW - systematic uncertainty KW - muon decay channel KW - partial decay width KW - simulated signal event KW - background cross section KW - primary vertex KW - sequential standard model KW - muon spectrometer KW - Cl Lowe limit KW - QCD background KW - coupling strength KW - isolation requirement KW - chiral boson KW - experimental systematic uncertainty Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128888 VL - 72 IS - 2241 ER - TY - JOUR T1 - 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 JF - The European Physical Journal C N2 - 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. KW - multi-jet background KW - jet energy scale KW - systematic uncertainty KW - jet background KW - anti-k jet KW - jet energy resolution KW - MC expectation KW - GMSB model KW - Cl Lowe limit KW - transverse momentum KW - single top event KW - SM background KW - MC simulation KW - transverse momentum vector KW - SUSY breaking scale Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128891 VL - 72 IS - 2215 ER - TY - JOUR T1 - Measurement of the charge asymmetry in top quark pair production in pp collisions at √s=7 TeV using the ATLAS detector JF - The European Physical Journal C N2 - 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. KW - jet multiplicity KW - B-tagged jet KW - systematic uncertainty KW - jet energy resolution KW - top quark masse KW - muon channel KW - jet scale energy KW - light quark jet KW - heavy flavour KW - single top production KW - single top event KW - fake lepton KW - top quark pair KW - multijet background KW - JES Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128904 VL - 72 IS - 2039 ER - TY - JOUR T1 - Measurement of the top quark mass with the template method in the \(t\overline t\)→lepton+jets channel using ATLAS data JF - The European Physical Journal C N2 - 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. KW - JES uncertainty KW - jet energy scale KW - top quark mass KW - jet channel KW - single top quark KW - jet energy scale uncertainty KW - systematic uncertainty KW - calorimeter response KW - simulated signal event KW - top quark decay KW - jet reconstruction efficiency KW - jet energy measurement KW - light quark jet KW - single top quark production KW - inclusive jet sample Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128912 VL - 72 IS - 2046 ER - TY - JOUR T1 - 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 JF - Journal of High Energy Physics N2 - 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. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128924 VL - 5 IS - 59 ER - TY - JOUR T1 - 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 JF - European Physical Journal C N2 - 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. KW - jet reconstruction efficiency KW - jet energy scale KW - jet energy scale uncertainty KW - fiducial cross section KW - individual systematic uncertainty KW - jet energy resolution KW - systematic uncertainty KW - muon reconstruction efficiency KW - rapidity interval KW - pythia parton shower KW - jet transverse momentum KW - underlying event tune KW - particle level jet KW - additional jet KW - MC event generator Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128931 VL - 72 IS - 2043 ER - TY - JOUR A1 - Dupuis, Luc A1 - Dengler, Reinhard A1 - Heneka, Michael T. A1 - Meyer, Thomas A1 - Zierz, Stephan A1 - Kassubek, Jan A1 - Fischer, Wilhelm A1 - Steiner, Franziska A1 - Lindauer, Eva A1 - Otto, Markus A1 - Dreyhaupt, Jens A1 - Grehl, Torsten A1 - Hermann, Andreas A1 - Winkler, Andrea S. A1 - Bogdahn, Ulrich A1 - Benecke, Reiner A1 - Schrank, Bertold A1 - Wessig, Carsten A1 - Grosskreutz, Julian A1 - Ludolph, Albert C. T1 - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis JF - PLoS One N2 - 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. KW - ALS KW - transgenic mouse model KW - central nervous system KW - nonalcoholic steatohepatitis KW - PPAR-gamme KW - hexanucleotide repeat KW - disease progression KW - delays progression KW - SOD1 mutations KW - monocycline Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255 VL - 7 IS - 6 ER - TY - JOUR A1 - Ahmad, Ruhel A1 - Wolber, Wanja A1 - Eckardt, Sigrid A1 - Koch, Philipp A1 - Schmitt, Jessica A1 - Semechkin, Ruslan A1 - Geis, Christian A1 - Heckmann, Manfred A1 - Brüstle, Oliver A1 - McLaughlin, John K. A1 - Sirén, Anna-Leena A1 - Müller, Albrecht M. T1 - Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells JF - PLoS One N2 - 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. KW - methylation KW - derivation KW - blastocysts KW - pluripotent KW - differentiation KW - lines KW - brain development KW - in-vitro KW - mice KW - specification Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130268 VL - 7 IS - 8 ER - TY - JOUR A1 - Ramachandran, Vinoy K. A1 - Shearer, Neil A1 - Jacob, Jobin J. A1 - Sharma, Cynthia M. A1 - Thompson, Arthur T1 - The architecture and ppGpp-dependent expression of the primary transcriptome of Salmonella Typhimurium during invasion gene expression JF - BMC Genomics N2 - 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. KW - legionella pneumophila KW - growth rate control KW - escherichia coli K-12 KW - pathogenicity island 2 KW - bacterial signal molecule KW - enterica serovar typhimurium KW - messenger RNA KW - protein synthesis KW - sationary phase KW - environmental regulation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130625 VL - 13 IS - 25 ER - TY - JOUR A1 - Aso, Yoshinori A1 - Herb, Andrea A1 - Ogueta, Maite A1 - Siwanowicz, Igor A1 - Templier, Thomas A1 - Friedrich, Anja B. A1 - Ito, Kei A1 - Scholz, Henrike A1 - Tanimoto, Hiromu T1 - Three Dopamine Pathways Induce Aversive Odor Memories with Different Stability JF - PLoS Genetics N2 - 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. KW - dynamics KW - serotonin KW - expression KW - melanogaster KW - neurons form KW - olfactory memory KW - long-term-memory KW - drosophila mushroom body KW - sensitization KW - localization Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130631 VL - 8 IS - 7 ER - TY - JOUR A1 - Krehan, Mario A1 - Heubeck, Christian A1 - Menzel, Nicolas A1 - Seibel, Peter A1 - Schön, Astrid T1 - RNase MRP RNA and RNase P activity in plants are associated with a Pop1p containing complex JF - Nucleic Acids Research N2 - 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. KW - enzyme KW - binding KW - sequence KW - cyanelle KW - in vitro KW - partial purification KW - protein subunit KW - ribonuclease-P KW - genes KW - identification Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130648 VL - 40 IS - 16 ER - TY - JOUR A1 - Buga, Ana-Maria A1 - Scholz, Claus Jürgen A1 - Kumar, Senthil A1 - Herndon, James G. A1 - Alexandru, Dragos A1 - Cojocaru, Gabriel Radu A1 - Dandekar, Thomas A1 - Popa-Wagner, Aurel T1 - Identification of New Therapeutic Targets by Genome-Wide Analysis of Gene Expression in the Ipsilateral Cortex of Aged Rats after Stroke JF - PLoS One N2 - 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. KW - gamma KW - corticotropin-releasing hormone KW - colony-stimulating factor KW - cerebral ischemia KW - receptor KW - brain KW - protein KW - inhibitor KW - mouse KW - differentiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130657 VL - 7 IS - 12 ER - TY - JOUR A1 - Weiße, Sebastian A1 - Heddergott, Niko A1 - Heydt, Matthias A1 - Pflästerer, Daniel A1 - Maier, Timo A1 - Haraszti, Tamas A1 - Grunze, Michael A1 - Engstler, Markus A1 - Rosenhahn, Axel T1 - A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy JF - PLoS One N2 - 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. KW - african trypanosomes KW - actin cortex KW - flagellum KW - tracking KW - surface KW - models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130666 VL - 7 IS - 5 ER - TY - JOUR A1 - Willems, Coen H. M. P. A1 - Urlichs, Florian A1 - Seidenspinner, Silvia A1 - Kunzmann, Steffen A1 - Speer, Christian P. A1 - Kramer, Boris W. T1 - Poractant alfa (Curosurf (R)) increases phagocytosis of apoptotic neutrophils by alveolar macrophages in vivo JF - Respiratory Research N2 - 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. KW - preterm KW - surfactant protein-A KW - respiratory-distress-syndrome KW - synthetic surfactant KW - human monocytes KW - SIRP-alpha KW - lung KW - cells KW - inflammation KW - resolution KW - anti inflammation KW - drug therapy KW - surfactant Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130721 VL - 13 IS - 17 ER - TY - JOUR A1 - Holst, Alexandra Ioana A1 - Holst, Stefan A1 - Hirschfelder, Ursula A1 - von Seckendorff, Volker T1 - Retrieval analysis of different orthodontic brackets: the applicability of electron microprobe techniques for determining material heterogeneities and corrosive potential JF - Journal of applied oral science N2 - 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. KW - orthodontic brackets KW - dental casting alloys KW - metallurgical characterization KW - galvanic corrosion KW - surface analysis KW - nickel release KW - archwires KW - titanium KW - fluoride KW - biocompatibility KW - appliances KW - electron probe microanalysis KW - nickel Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130415 VL - 20 IS - 4 ER - TY - JOUR A1 - Hartung, Andreas A1 - Seufert, Florian A1 - Berges, Carsten A1 - Gessner, Viktoria H. A1 - Holzgrabe, Ulrike T1 - One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties JF - Molecules N2 - 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. KW - multicomponent Ugi-type reaction KW - intramolecular Michael addition KW - strategy KW - derivates KW - diketopiperazines KW - chemistry KW - T cell KW - 2,5-diketopiperazines KW - anti-proliferative effects Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130423 VL - 17 IS - 12 ER - TY - JOUR A1 - Huser, Annina A1 - Rohwedder, Astrid A1 - Apostolopoulou, Anthi A. A1 - Widmann, Annekathrin A1 - Pfitzenmaier, Johanna E. A1 - Maiolo, Elena M. A1 - Selcho, Mareike A1 - Pauls, Dennis A1 - von Essen, Alina A1 - Gupta, Tript A1 - Sprecher, Simon G. A1 - Birman, Serge A1 - Riemensperger, Thomas A1 - Stocker, Reinhard F. A1 - Thum, Andreas S. T1 - The Serotonergic Central Nervous System of the Drosophila Larva: Anatomy and Behavioral Function JF - PLoS One N2 - 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. KW - term memory KW - light avoidance KW - decision making KW - olfactory memory KW - immunoreactive neurons KW - containing neurons KW - moth manduca sexta KW - head involution KW - mushroom bodies KW - biogenic amines Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130437 VL - 7 IS - 10 ER - TY - JOUR A1 - Antoniou, Antonis C. A1 - Kuchenbaecker, Karoline B. A1 - Soucy, Penny A1 - Beesley, Jonathan A1 - Chen, Xiaoqing A1 - McGuffog, Lesley A1 - Lee, Andrew A1 - Barrowdale, Daniel A1 - Healey, Sue A1 - Sinilnikova, Olga M. A1 - Caligo, Maria A. A1 - Loman, Niklas A1 - Harbst, Katja A1 - Lindblom, Annika A1 - Arver, Brita A1 - Rosenquist, Richard A1 - Karlsson, Per A1 - Nathanson, Kate A1 - Domchek, Susan A1 - Rebbeck, Tim A1 - Jakubowska, Anna A1 - Lubinski, Jan A1 - Jaworska, Katarzyna A1 - Durda, Katarzyna A1 - Zlowowcka-Perłowska, Elżbieta A1 - Osorio, Ana A1 - Durán, Mercedes A1 - Andrés, Raquel A1 - Benítez, Javier A1 - Hamann, Ute A1 - Hogervorst, Frans B. A1 - van Os, Theo A. A1 - Verhoef, Senno A1 - Meijers-Heijboer, Hanne E. J. A1 - Wijnen, Juul A1 - Garcia, Encarna B. Gómez A1 - Ligtenberg, Marjolijn J. A1 - Kriege, Mieke A1 - Collée, Margriet A1 - Ausems, Margreet G. E. M. A1 - Oosterwijk, Jan C. A1 - Peock, Susan A1 - Frost, Debra A1 - Ellis, Steve D. A1 - Platte, Radka A1 - Fineberg, Elena A1 - Evans, D. Gareth A1 - Lalloo, Fiona A1 - Jacobs, Chris A1 - Eeles, Ros A1 - Adlard, Julian A1 - Davidson, Rosemarie A1 - Cole, Trevor A1 - Cook, Jackie A1 - Paterson, Joan A1 - Douglas, Fiona A1 - Brewer, Carole A1 - Hodgson, Shirley A1 - Morrison, Patrick J. A1 - Walker, Lisa A1 - Rogers, Mark T. A1 - Donaldson, Alan A1 - Dorkins, Huw A1 - Godwin, Andrew K. A1 - Bove, Betsy A1 - Stoppa-Lyonnet, Dominique A1 - Houdayer, Claude A1 - Buecher, Bruno A1 - de Pauw, Antoine A1 - Mazoyer, Sylvie A1 - Calender, Alain A1 - Léoné, Mélanie A1 - Bressac-de Paillerets, Brigitte A1 - Caron, Olivier A1 - Sobol, Hagay A1 - Frenay, Marc A1 - Prieur, Fabienne A1 - Ferrer, Sandra Fert A1 - Mortemousque, Isabelle A1 - Buys, Saundra A1 - Daly, Mary A1 - Miron, Alexander A1 - Terry, Mary Beth A1 - Hopper, John L. A1 - John, Esther M. A1 - Southey, Melissa A1 - Goldgar, David A1 - Singer, Christian F. A1 - Fink-Retter, Anneliese A1 - Muy-Kheng, Tea A1 - Geschwantler Kaulich, Daphne A1 - Hansen, Thomas V. O. A1 - Nielsen, Finn C. A1 - Barkardottir, Rosa B. A1 - Gaudet, Mia A1 - Kirchhoff, Tomas A1 - Joseph, Vijai A1 - Dutra-Clarke, Ana A1 - Offit, Kenneth A1 - Piedmonte, Marion A1 - Kirk, Judy A1 - Cohn, David A1 - Hurteau, Jean A1 - Byron, John A1 - Fiorica, James A1 - Toland, Amanda E. A1 - Montagna, Marco A1 - Oliani, Cristina A1 - Imyanitov, Evgeny A1 - Isaacs, Claudine A1 - Tihomirova, Laima A1 - Blanco, Ignacio A1 - Lazaro, Conxi A1 - Teulé, Alex A1 - Del Valle, J. A1 - Gayther, Simon A. A1 - Odunsi, Kunle A1 - Gross, Jenny A1 - Karlan, Beth Y. A1 - Olah, Edith A1 - Teo, Soo-Hwang A1 - Ganz, Patricia A. A1 - Beattie, Mary S. A1 - Dorfling, Cecelia M. A1 - Jansen van Rensburg, Elizabeth A1 - Diez, Orland A1 - Kwong, Ava A1 - Schmutzler, Rita K. A1 - Wappenschmidt, Barbara A1 - Engel, Christoph A1 - Meindl, Alfons A1 - Ditsch, Nina A1 - Arnold, Norbert A1 - Heidemann, Simone A1 - Niederacher, Dieter A1 - Preisler-Adams, Sabine A1 - Gadzicki, Dorothea A1 - Varon-Mateeva, Raymonda A1 - Deissler, Helmut A1 - Gehrig, Andrea A1 - Sutter, Christian A1 - Kast, Karin A1 - Fiebig, Britta A1 - Schäfer, Dieter A1 - Caldes, Trinidad A1 - de la Hoya, Miguel A1 - Nevanlinna, Heli A1 - Muranen, Taru A. A1 - Lespérance, Bernard A1 - Spurdle, Amanda B. A1 - Neuhausen, Susan L. A1 - Ding, Yuan C. A1 - Wang, Xianshu A1 - Fredericksen, Zachary A1 - Pankratz, Vernon S. A1 - Lindor, Noralane M. A1 - Peterlongo, Paulo A1 - Manoukian, Siranoush A1 - Peissel, Bernard A1 - Zaffaroni, Daniela A1 - Bonanni, Bernardo A1 - Bernard, Loris A1 - Dolcetti, Riccardo A1 - Papi, Laura A1 - Ottini, Laura A1 - Radice, Paolo A1 - Greene, Mark H. A1 - Loud, Jennifer T. A1 - Andrulis, Irene L. A1 - Ozcelik, Hilmi A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Thomassen, Mads A1 - Gerdes, Anne-Marie A1 - Jensen, Uffe B. A1 - Skytte, Anne-Bine A1 - Kruse, Torben A. A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J. A1 - Simard, Jacques A1 - Easton, Douglas F. T1 - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers JF - Breast Cancer Research N2 - 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. KW - investigators KW - genetic modifiers KW - mammographic density KW - susceptibility loci KW - ovarian cancer KW - hormone-related protein KW - genome-wide association KW - tumor subtypes KW - alleles KW - consortium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130449 VL - 14 IS - R33 ER - TY - JOUR A1 - Hofgaard, Peter O. A1 - Jodal, Henriette C. A1 - Bommert, Kurt A1 - Huard, Bertrand A1 - Caers, Jo A1 - Carlsen, Harald A1 - Schwarzer, Rolf A1 - Schünemann, Nicole A1 - Jundt, Franziska A1 - Lindeberg, Mona M. A1 - Bogen, Bjarne T1 - A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease JF - PLoS One N2 - 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. KW - resistance KW - CD4(+) T-cells KW - tumor specific antigen KW - plasma cells KW - B cell KW - C57BL/KALWRIJ mouse KW - bone disease KW - scid mice KW - idiotype KW - differentiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131117 VL - 7 IS - 12 ER - TY - JOUR A1 - Böhler, Elmar A1 - Creignou, Nadia A1 - Galota, Matthias A1 - Reith, Steffen A1 - Schnoor, Henning A1 - Vollmer, Heribert T1 - Complexity Classifications for Different Equivalence and Audit Problems for Boolean Circuits JF - Logical Methods in Computer Science N2 - 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. KW - hierarchy KW - satisfiability problems Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131121 VL - 8 IS - 3:27 SP - 1 EP - 25 ER - TY - JOUR A1 - Messi, Bernadette Biloa A1 - Ndjoko-Ioset, Karine A1 - Hertlein-Amslinger, Barbara A1 - Lannang, Alain Meli A1 - Nkengfack, Augustin E. A1 - Wolfender, Jean-Luc A1 - Hostettmann, Kurt A1 - Bringmann, Gerhard T1 - Preussianone, a New Flavanone-Chromone Biflavonoid from Garcinia preussii Engl. JF - Molecules N2 - 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. KW - multiflora KW - minimal inhibitory concentration KW - absolute configuration KW - circular dichroism KW - C-13 NMR KW - guttiferae KW - flavenoids KW - extractives KW - biflavanoids KW - livingstonei KW - high-temperature NMR KW - antibacterial activity KW - Garcinia biflavonoids Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130881 VL - 17 IS - 5 ER - TY - JOUR A1 - Kilian, W. A1 - Ohl, T. A1 - Reuter, J. A1 - Speckner, C. T1 - QCD in the color-flow representation JF - Journal of High Energy Physics N2 - 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. KW - QCD KW - scattering amplitudes KW - 1/N expansion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129583 VL - 10 IS - 022 ER - TY - JOUR T1 - 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 JF - The Journal of High Energy Physics N2 - 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. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129591 VL - 07 IS - 167 ER - TY - JOUR A1 - Langenfeld, Ulrich A1 - Moch, Sven-Olaf A1 - Pfoh, Torsten T1 - QCD threshold corrections for gluino pair production at hadron colliders JF - Journal of High Energy Physics N2 - 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. KW - resummation KW - supersymmetric standard model Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129609 VL - 11 IS - 070 ER - TY - JOUR T1 - Search for second generation scalar leptoquarks in pp collisions at √s=7 TeV with the ATLAS detector JF - The European Physical Journal C N2 - 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. KW - jet energy scale KW - top quark mass KW - multi-jet background KW - simulated event sample KW - SM background KW - acceptance time efficiency KW - top quark contribution KW - top quark pair KW - primary vertex KW - single top quark production KW - signal cross section KW - systematic uncertainty KW - single top quark Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128957 VL - 72 IS - 2151 ER - TY - JOUR T1 - Search for same-sign top-quark production and fourth-generation down-type quarks in pp collisions at √s=7 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - 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. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128960 VL - 04 IS - 69 ER - TY - JOUR T1 - Jet mass and substructure of inclusive jets in √s=7 TeV pp collisions with the ATLAS experiment JF - Journal of High Energy Physics N2 - 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. KW - hadron-hadron scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128970 VL - 05 IS - 128 ER - TY - JOUR A1 - Wang, Huiqiang A1 - Chen, Nanhai G. A1 - Minev, Boris R. A1 - Szalay, Aladar A. T1 - Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells JF - Journal of Translational Medicine N2 - 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. KW - tumors KW - therapy KW - metastasis KW - identification KW - lines KW - gene expression KW - in-vitro propagation KW - acute myeloid leukemia KW - epithelial-mesenchymal transition KW - subpopulation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130019 VL - 10 IS - 167 ER - TY - JOUR A1 - Patil, Sandeep S. A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Donat, Ulrike A1 - Hess, Michael A1 - Weibel, Stephanie A1 - Nolte, Ingo A1 - Frentzen, Alexa A1 - Szalay, Aladar A. T1 - Virotherapy of Canine Tumors with Oncolytic Vaccinia Virus GLV-1h109 Expressing an Anti-VEGF Single-Chain Antibody JF - PLoS One N2 - 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. KW - angiogenesis KW - microenvironment KW - model KW - cancer KW - therapy KW - pet dogs KW - nude-mice KW - breast-tumors KW - microvascular density KW - endothelial growth-factor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130039 VL - 7 IS - 10 ER - TY - JOUR A1 - Haddad, Dana A1 - Chen, Chun-Hao A1 - Carlin, Sean A1 - Silberhumer, Gerd A1 - Chen, Nanhai G. A1 - Zhang, Qian A1 - Longo, Valerie A1 - Carpenter, Susanne G. A1 - Mittra, Arjun A1 - Carson, Joshua A1 - Au, Joyce A1 - Gonen, Mithat A1 - Zanzonico, Pat B. A1 - Szalay, Aladar A. A1 - Fong, Yuman T1 - Imaging Characteristics, Tissue Distribution, and Spread of a Novel Oncolytic Vaccinia Virus Carrying the Human Sodium Iodide Symporter JF - PLoS One N2 - 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. KW - nude mice KW - pancreatic cancer KW - engineered measles-virus KW - positron-emission-tomography KW - malignant pleural mesothelioma KW - reporter gene KW - replicating adenovirus KW - NA/I symporter KW - breast cancer KW - viral therapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130041 VL - 7 IS - 8 ER -